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The Pdx1 bound Swi/Snf chromatin remodeling complex regulates pancreatic

progenitor cell proliferation and mature islet β cell function

Jason M. Spaeth1,2, Jin-Hua Liu1, Daniel Peters3, Min Guo1, Anna B. Osipovich1,

Fardin Mohammadi3, Nilotpal Roy4, Anil Bhushan4, Mark A. Magnuson1, Matthias Hebrok4,

Christopher V. E. Wright3, Roland Stein1,5

1 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN

2 Present address: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN

3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN

4 Diabetes Center, Department of Medicine, UCSF, San Francisco, California

5 Corresponding author: [email protected]; (615)322-7026

1

Diabetes Publish Ahead of Print, published online June 14, 2019 Diabetes Page 2 of 125

Abstract

Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes- linked transcription factor essential to pancreatic morphogenesis and adult islet-cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β cell activity, which included whole animal glucose intolerance, hyperglycemia and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β cells lost the ability to produce the mRNAs for insulin and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the insulin gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas and we discuss how disrupting their association could influence Type 1 and Type 2 diabetes susceptibility.

Keywords: Swi/Snf, pancreas hypoplasia, β cell, type 1 diabetes, type 2 diabetes, coregulator, nucleosome remodeling, transcription factor, Pdx1

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Introduction

The mammalian pancreas is comprised of two functionally distinct compartments: the

exocrine pancreas containing acinar and ductal cells essential for secreting digestive enzymes,

and the endocrine pancreas containing hormone-secreting α (glucagon), β (insulin), 

(somatostatin),  (ghrelin), and PP (pancreatic polypeptide) cells of the islets of Langerhans that

are essential for regulating glucose homeostasis. All of these pancreatic cells derive from a

common pool of progenitor cells at mouse embryonic (e) day 8.5 that express the Pancreas and

Duodenum Homeobox 1 (Pdx1) transcription factor, a critical regulator of pancreas development,

later β cell formation and adult islet β cell function. In fact, pancreas agenesis occurs in mice and

humans that lack PDX1 (1,2), while heterozygous mutations cause Type 2 diabetes (T2D)

because of islet β cell dysfunction (3).

Embryonic Pdx1+ pancreatic progenitor cells rapidly divide and acquire the expression of

other transcription factors essential to organ expansion and lineage diversification, including Ptf1a

(4) and Sox9 (5). These Pdx1+Ptf1a+Sox9+ cells form the highly proliferative multipotent

pancreatic progenitor cell (MPC) pool that differentiate into the distinct exocrine, ductal and islet

cell types (6). Notably, pancreas mass is restricted in mice by the MPC pool size (7), which is

affected by early embryonic genetic removal of Pdx1, Ptf1a or Sox9 (2,4,5). Because of

considerable variations in pancreas mass (and therefore variable β cell number) between humans

(8), understanding how the transcriptional activities of these essential MPC regulators control

growth rate and final organ size is of significant importance. It has been proposed that

dissimilarities in pancreas mass influences diabetes susceptibly, a proposal supported by the

reduced pancreas size of Type 1 diabetes (T1D) autoantibody-positive individuals (9).

In the postnatal pancreas, Pdx1 is produced at much higher levels in islet β cells than in

other pancreas cell types (10). Conditional removal of Pdx1 from these cells in mice leads to a

profound loss of β cell function and identity, as these cells rapidly transdifferentiate to glucagon+

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and insulin- α-like cells (11). This remarkable control not only derives from the positive actions of

Pdx1 on target gene transcription, but also from its repression of key α cell functional genes in β cells, such as MafB and glucagon. As a result of these novel and fundamental properties, Pdx1 is viewed as one of the most critical pancreas-enriched transcription factors (6).

Transcription factors like Pdx1 predominantly control gene expression through the recruitment of coregulators, often operating as large multiprotein complexes. These coregulators affect transcriptional activity positively and/or negatively, for example by displacing nucleosomes, epigenetically modifying histones/DNA, and affecting recruitment of the RNA polymerase II transcriptional machinery. Because of limited knowledge of the coregulators influencing Pdx1 activity, an unbiased chemical crosslinking, immunoprecipitation and mass spectrometry analysis was used to identify interacting proteins in rodent β cell lines. Numerous proteins with an array of cellular functions were found to associate with Pdx1, including the ATP-dependent Swi/Snf chromatin remodeling complex (12). Significantly, Pdx1 was the principal islet β cell-enriched transcription factor binding to Swi/Snf in mouse β cell lines (12).

The multi-subunit Swi/Snf complex utilizes the energy of ATP hydrolysis, through the actions of the two mutually exclusive Brg1 (i.e. also referred to as Smarca4) and Brm (i.e.

Smarca2) ATPase subunits (Figure 1A) (13,14), to disrupt DNA-nucleosome contacts and influence DNA accessibility. We previously discovered that in vitro knockdown of Brg1 in rodent

β cell lines negatively affected Pdx1 target gene expression (e.g. insulin, MafA and Glut2).

Moreover, Pdx1:Swi/Snf interactions were not only acutely enhanced in islet β cells by increased glucose concentrations, but were reduced in human T2D β cells (12). Here we show that the

Pdx1:Brg1/Swi/Snf complex is critical for mouse MPC proliferation, with embryonic conditional deletion of only the Brg1 gene encoded ATPase resulting in a ~50% smaller pancreas. In contrast, removing both Brg1 and Brm was necessary to impact postnatal β cells, causing severe changes in expression of insulin and other β cell regulatory genes, a hallmark feature of T2D β cells.

Collectively, our results suggest that Pdx1:Swi/Snf is required for controlling the growth rate of

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the embryonic pancreas, thus its final postnatal size, and for maintaining β cell identity in adult

islets.

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Research Design and Methods

Animals

Ptf1a-Cre (15) and MIP-CreERT (16) mice were used to remove the Loxp sites surrounding exons 17 and 18 of the Brg1 locus (Brg1f/f; (17)) and the Stop cassette in the Rosa26-Loxp-Stop-

Loxp-tdTomato lineage reporter (R26LSL-tdTomato (18)). Brm-/- mice were generated using homologous recombination to insert the Neomycin gene into Brm exon 4 (19). The following genotypes were used for the developmental studies: Control: Ptf1a-Cre;Brg1f/+ or Ptf1a-

Cre;Brg1f/+;Brm+/-; Experimental: Brg1Δpanc (Ptf1a-Cre;Brg1f/f), Brm-/- (Ptf1a-Cre;Brm-/-) and

DKOΔpanc (Ptf1a-Cre;Brg1f/f;Brm-/-). Noon of the day of the vaginal plug discovery was designated embryonic day (e) 0.5. For BrdU injections, 100 mg of 5-Bromo-2′-deoxyuridine (Sigma-B5002) per kilogram of pregnant dam body weight was injected 30 minutes prior to embryo harvest. The adult studies consisted of these genotypes: Control: MIP-CreERT;Brg1f/+;Brm+/-;R26LSL-tdTomato/+;

Experimental: Brg1Δβ;Brm+/- (MIP-CreERT;Brg1f/f;Brm+/-; R26LSLtdTomato/+), Brg1Δβ/+;Brm-/- (MIP-

CreERT; Brg1f/+; Brm-/-; R26LSLtdTomato/+), and βDKO (MIP-CreERT; Brg1f/f; Brm-/-; R26LSLtdTomato/+).

CreERT-mediated recombination of Brg1f/f and the R26LSLtdTomato was achieved by administration of

4mg of Tamoxifen (Sigma-T5648) by oral gavage 3 times over a 5-day period.

Intraperitoneal glucose tolerance test (IPGTT) and serum insulin measurements Mice (n = 5 - 12) were given intraperitoneal injection of D-glucose (2 mg/g body weight) following a 6-hour fast. Blood glucose was measured using a FreeStyle glucometer (Abbott

Diabetes Care). Serum insulin was measured by radio immunoassay at the Vanderbilt Hormone

Assay and Analytical Services Core.

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Glucose Stimulated Insulin Secretion

Secreted insulin from isolated control and βDKO mice (n = 8 - 10) islets was performed as

described previously (20). The outcome was presented as the fold change between the percent

of secreted insulin (relative to insulin content) at 16.7 mM glucose to the percent of secreted

insulin (relative to insulin content) at 2.8 mM glucose. Islet insulin content was calculated as the

concentration of insulin per islet in each reaction (nanogram/mL/islet).

Tissue Preparation and Immunostaining

Whole embryos and adult pancreas were fixed in 4% (vol./vol.) paraformaldehyde,

embedded and sectioned to 6 μm. Immunofluorescence staining was performed as described

(21) with the antibodies listed in Supplemental Table 1. Embryos were cut on the transverse

(cross-sections) plane throughout the pancreatic epithelium, and manual cell counting was

performed on antibody stained sections prepared every 60 µm (e12.5) or 90 µm (e15.5) from the

superior to inferior region.

Proximity Ligation Assay

The assay was performed on e12.5 sections following the manufacturer’s protocol (Sigma)

with goat transcription factors Pdx1 (1:20,000, Abcam, AB47383), Ptf1a (1:2,000, from C.V.E.

Wright)) or rabbit Sox9 (1:500, Millipore, AB5535) in combination with rabbit ATPase Brg1 (1:400,

Santa Cruz, sc-10768), goat Brg1 (1:500, R & D Systems, AF5738), mouse Brm (1:500, Santa

Cruz, sc-17828) or rabbit Brm (1:500, Abcam, ab1559) antibodies. Immunofluorescence Z-Stack

images were acquired on a Zeiss Axioimager M2 fluorescence scope and processed using

ImageJ software.

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Flow Cytometry, RNA Purification and Quality Control of sorted β cells

Isolated islets were dispersed into a single cell suspension (Accumax, Sigma A7089), stained with DAPI, and sorted by gating for Tomato+DAPI+ cells by fluorescence activated cell sorting at the Vanderbilt Flow Cytometry Core. RNA was isolated from FACS-purified β cells

(Control: 10215±1589 cells (n=3), βDKO:16267±3032 cells (n=3)) using the Maxwell 16 LEV simplyRNA Tissue Kit (Promega-TM351), then DNAse treated and analyzed on an Agilent 2100

Bioanalyzer. Only samples with an RNA Integrity Number above 8.0 were used for cDNA synthesis and library preparation.

RNA-Sequencing and Analysis

cDNA libraries were constructed from RNA isolated from FACS-purified control and βDKO islet β cells, and paired-end sequencing of three replicates performed on an Illumina

NovaSeq6000 (150-nucleotide reads). The generated FASTQ files were processed and interpreted using the Genialis visual informatics platform (https://www.genialis.com). Sequence quality checks were determined using raw and trimmed reads with FastQC

(http://www.bioinformatics.babraham.ac.uk/projects/fastqc), and Trimmomatic (22) was used to trim adapters and filter out poor quality reads. Trimmed reads were then mapped to the mm10 UCSC reference genome using the HISAT2 aligner (23). Gene expression levels were quantified with HTSeq-count (24), and differential gene expression analyses performed with

DESeq2 (25). Poorly expressed genes, which have expression count summed over all samples below 10, were filtered out from the differential expression analysis input matrix. RNA expression analysis of selected candidates was performed with the qPCR primers provided in Supplemental

Table 2.

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Chromatin Immunoprecipitation (ChIP) assays

Chromatin was prepared from 1000 - 1400 control or βDKO islets and ChIP was

conducted with Pdx1 (AB47383), Nkx2.2 (Sigma: HPA003468) or IgG antibodies as described

previously (21) (n=3). The chromatin was sheared to roughly 200 – 300 base pairs (bp). qPCR

was performed with immunoprecipitated DNA over Ins2 (i.e. -95/-35 bp) and Nkx6.1 (-884/-720

bp). Binding enrichment is presented as the fold enrichment of the transcription factor signal on

Ins2 or Nkx6.1 over the control β-actin signal relative to IgG. Primer sequences are available in

Supplemental Table 2.

Statistical analysis

Statistical significance was determined using the two-tailed Student t test. Data are

represented as mean ± SEM. A threshold of p < 0.05 was used to declare significance.

Study approval

All animal studies were reviewed and approved by the Institutional Animal Care and Use

Committee (IACUC) at Vanderbilt University. Mice were housed and cared for according to the

Vanderbilt Department of Animal Care and IACUC/Office of Animal Welfare Assurance standards

and guidelines.

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Results

Embryonic pancreas specific removal of the Brg1 ATPase results in pancreatic hypoplasia

To evaluate the mechanistic basis by which Swi/Snf controls pancreas mass in vivo, we crossed mice producing a Cre recombinase driven by the Ptf1a locus (Ptf1a-Cre (15)) either with mice containing Loxp sites surrounding exons 17 and 18 of the Brg1 gene (i.e. Brg1Δpanc (17)), constitutive Brm null alleles (Brm-/- (19)), or in combination to create a developmental double knockout (DKOΔpanc). Brm-/- animals are viable, fertile, and have no overt physiological or morphological phenotypes (19). Brg1 removal was observed in roughly 50% of e12.5 pancreatic epithelial cells in Brg1Δpanc and DKOΔpanc mutants. Brg1 levels did not increase in Brm-/- embryos

(Supplemental Figure 1) nor did Brm in Brg1Δpanc mutants (Supplemental Figure 2), signifying no compensatory up-regulation between these alternative ATPase Swi/Snf subunits.

At postnatal day 1 (P1), Brg1Δpanc mice showed a severe reduction in pancreas size that was not observed in Brm-/- mice or exacerbated in DKOΔpanc (Figure 1B). However, the size of the spleen, liver and kidneys were unaffected in the Swi/Snf ATPase mutants (Figure 1B, data not shown). The incomplete inactivation of Brg1 within the MPC pool (Supplemental Figure 1) led to the presence of non-recombined escaper cells, with Brg1 absent from most P1 acinar cells (in which Ptf1a expression is enriched and thereby increasing the likelihood of inactivation of Brg1f/f alleles) but present in islet hormone+ Ptf1a- cells (Supplemental Figure 3) (4). The preservation of Brg1 in DKOΔpanc islets presumably allows normal control of blood glucose levels postnatally, as β cells totally deficient in all Swi/Snf activity have a significant impairment (described below).

These observations suggest that the pancreatic hypoplasia reported in the 3-week old Brg1Δpanc mutants (26) results from a reduction in embryonic MPC numbers.

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Pdx1 binds to Brg1 and Brm1 in MPCs, and not Ptf1a or Sox9

The proximity ligation assay (PLA) was used to evaluate the ability of Pdx1, Ptf1a, and

Sox9 to interact with Brg1 and Brm in the developing pancreas, wherein a punctate fluorescent

signal is generated if the physical distance between interacting proteins is within 30-40 nm.

Pdx1:Brg1 and Pdx1:Brm signals were clearly detectable in e12.5 pancreatic epithelium, while

little binding was found between Ptf1a and Sox9 with either Swi/Snf ATPase subunits (Figure 2).

These results imply that Swi/Snf actions in MPCs are mediated principally through Pdx1.

All pancreatic cell lineages are reduced in e15.5 Brg1Δpanc mutants

To determine whether the absence of Pdx1 recruited Brg1/Swi/Snf impacted the loss of

specific pancreatic cell lineages, we immunostained and quantitated serially-cut control and

mutant e15.5 sections for cell type markers characteristic of this developmental stage. Expression

of Sox9 at e15.5 denotes a population of bipotent progenitor cells (27) and Neurogenin 3

(Neurog3) marks the subset of cells destined to become islet endocrine cells (28). We found that

the number of Sox9 and Neurog3 expressing cells were reduced by ~50% in Brg1Δpanc pancreata,

which was not decreased further in the DKOΔpanc mutant (Figures 3A, B). Moreover, the number

of insulin+, glucagon+ and somatostatin+ cells, along with carboxypeptidase 1+ (Cpa1) acinar cells

were also reduced by ~50% in the Brg1Δpanc and DKOΔpanc mutants (Figures 3C, D). In addition,

ductal branching was less expansive in Brg1Δpanc than control embryos, which was expected due

to reduced Brg1Δpanc pancreatic cell numbers (Supplemental Figure 4). Together, these results

demonstrate that all pancreatic lineages are negatively influenced by the loss of the embryonic

Pdx1:Brg1/Swi/Snf complex.

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Brg1-deficient MPCs have reduced proliferative capacity

We next investigated whether the reduction in pancreatic cell type formation directly resulted from depletion of the embryonic Brg1Δpanc MPC pool. In agreement with this prediction, the number of co-expressing Pdx1 and Sox9 cells at e12.5 was reduced by ~40% (Figure 4A).

However, there was no detectable difference in TUNEL+ cell numbers in the e12.5 control and

Brg1Δpanc E-Cadherin+ pancreatic epithelium (data not shown), suggesting that the decreased

MPC population was not due to increased cell death. Pregnant dams were then injected with BrdU to assess the proliferation of Brg1-deficient MPCs. Control, Brg1Δpanc and DKOΔpanc mutants incorporated BrdU into approximately 30% of wild type MPCs at e12.5, whereas incorporation in

Brg1-deficient MPCs was only 14.4 ± 0.7% and 14.8 ± 1.8% in the Brg1Δpanc and DKOΔpanc mutants, respectively (Figure 4B). These studies illustrate the novel function for Pdx1:Brg1/Swi/Snf in modulating MPC proliferation in the developing pancreas, which to our knowledge is the first transcriptional coregulator shown to influence MPC number and pancreas mass.

Impaired adult islet β cell function is only observed upon removal of both the Brg1 and

Brm ATPase subunits of Swi/Snf

To test if Pdx1:Swi/Snf also contributed to adult β cell function, we crossed transgenic mice containing a tamoxifen inducible, β cell-specific Cre (Mouse Insulin I Enhancer/Promoter

(MIP)-driven CreERT (16)) and the Rosa26-Loxp-Stop-Loxp-tdTomato (R26LSL-tdTomato (18)) lineage reporter with either Brg1f/f;Brm+/- (termed Brg1Δβ;Brm+/-), Brg1f/+;Brm-/- (i.e. Brg1Δβ/+;Brm-/-) or

Brg1f/f;Brm-/- (i.e. βDKO) mice. All experimental and control animals contained the MIP-CreERT transgene and received tamoxifen, since this Cre line contains the human Growth Hormone minigene sequence that has been reported to independently augment islet β cell mass, insulin content, and insulin secretion (29). Brg1 removal was induced in 4 week-old mice by three

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tamoxifen administrations every other day over a 5-day period. Two weeks following the last

tamoxifen treatment, ~70% of islet β cells expressed the fluorescent Tomato lineage reporter and

over 90% of these βDKO cells lacked Brg1 (Supplemental Figure 5).

Brg1Δβ;Brm+/- and Brg1Δβ/+;Brm-/- mice were physiologically normal two weeks after the last

tamoxifen administration, whereas βDKO animals suffered from fasting hyperglycemia, glucose

intolerance and reduced serum insulin levels (Figure 5A, B). Glucose intolerance did not worsen

in older mutant animals, and both males and females exhibited similar phenotypes (Supplemental

Figure 6). Glucose stimulated insulin secretion (GSIS) was also compromised in size-matched

islets isolated from βDKO animals, whereas Brg1Δβ;Brm+/- and Brg1Δβ/+;Brm-/- were unaffected

(Figure 5C). In addition, we observed a severe and specific reduction in βDKO islet insulin content

(Figure 5D), suggesting that their secretion deficiency results, at least in part, from limited

hormone content.

Loss of Swi/Snf activity in βDKO islet β cells severely reduces insulin production despite

retention of many important enriched transcription factors

To gain insight into the cause of the significant decrease in insulin content in βDKO islets,

we first took a candidate approach to monitor for the presence of various β cell markers in control

and βDKO pancreata. Most strikingly, nearly every Tomato-labeled cell in βDKO islets had little

to no insulin immunoreactivity (Figure 6A). There was also no overt change in islet cell mass or

apoptosis in mutant islets, contrasting from the reduced pancreas mass of Brg1Δpanc mice caused

by the developmental loss of this ATPase. As expected, Tomato-labeled Brg1Δβ;Brm+/- and

Brg1Δβ/+;Brm-/- β cells had no obvious defects in insulin production (Supplemental Figure 7).

Severe insulin deficiency is commonly observed upon β cell ablation of key lineage-

determining transcription factors like Pdx1 (11), Nkx6.1 (30), Nkx2.2 (31), Pax6 (32) and Mnx1

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(33), whereas removal of MafA impacts islet architecture and GSIS, but has little effect on insulin content (34). Interestingly, Pdx1, Nkx6.1, Nkx2.2, Pax6 and Mnx1 levels were unaffected in

Swi/Snf-deficient Tomato+ cells by immunofluorescence analysis, although MafA levels were significantly reduced (Figure 6B, Supplemental Figure 8). Moreover, βDKO Tomato+ cells did not produce the α cell-specific glucagon hormone, an effect seen upon removal of Pdx1 from adult β cells (11). In addition, somatostatin expression was not induced in this cell population

(Supplemental Figure 8), which occurs upon deletion of, for example, Mnx1 from β cells (33).

Overall, there was also no difference in the islet  and  cell mass between control and βDKO islets (Supplemental Figure 8).

Expression of Pdx1-regulated genes involved in cell maturation, insulin production and insulin secretion are affected in βDKO β cells

To more comprehensively define the molecular influence Swi/Snf has on β cells, RNA-

Sequencing was performed on fluorescence-activated cell sorted (FACS) Tomato+ cells from control and βDKO islets. Using a ± 2-fold cut-off and FDR < 0.05, there were 1789 downregulated and 1273 upregulated genes in βDKO β cells (Figure 7A). Gene ontology analysis (DAVID

(35,36)) of these differentially expressed βDKO genes led to the identification of a very diverse array of biological pathways associated with Swi/Snf control, including cell adhesion, ion transport, cell differentiation, cell migration, cell proliferation, and carbohydrate metabolism

(Supplemental Table 3). Expression of some of the most upregulated genes, including Creg1,

Scg3, Gucy1a3, and Gucy1b3 were confirmed by qPCR analysis (Figure 7B); however, the impact of these genes on β cells is unclear.

Greater insight into how Pdx1:Swi/Snf regulated gene expression was obtained upon comparing genes bound by Pdx1 in ChIP-Sequencing analysis of mouse islets (37) to those

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upregulated or downregulated in βDKO β cells. Genes upregulated and bound by Pdx1

(507/1273) resided in biological pathways linked to cell adhesion and neuromuscular functions,

whereas downregulated βDKO genes bound by Pdx1 (917/1789) defined functional networks

linked to insulin secretion and glucose homeostasis (Figure 8A, Supplemental Table 4).

Consequently, we concluded that Pdx1:Swi/Snf represents an essential positive regulator of β

cell function. Supportive evidence of these changes came from immunofluorescence and qRT-

PCR analysis of independently derived flow-sorted βDKO β cells. These genes included those

strongly linked to mature cell identity like Ins1, Ins2, Slc2a2 (Glut2), MafA, Slc30A8 and Ucn3

(Figure 8B, Supplemental Figure 9). However, their production was unaffected in Brg1Δβ;Brm+/-

and Brg1Δβ/+;Brm-/- islets (Supplemental Figures 7 and 10). Collectively, our analyses revealed

that Swi/Snf-deficient β cells have reduced expression of numerous Pdx1-regulated genes that

are essential for sustaining β cell identity.

Pdx1 binding to the Insulin enhancer is compromised in βDKO β cells

Rodent Ins1 and Ins2 gene expression is largely mediated by transcription factors that

bind within cis-acting enhancer sequences found roughly between -340 to -90 bp upstream of the

transcription start site (38), a region well-conserved in the human INSULIN gene (39). In addition

to Pdx1 binding at the A3/A4 (-201 to -195 bp in Ins2) and proximal A1 (-63 to -59 bp) elements

(40), enhancer activity is mediated by several islet-enriched transcription factors with vital roles in

developing and adult β cells, including Pax6 (-317 to -311 bp) (41), Nkx2.2 (-128 to -122 bp) (42)

and MafA (-126 to -101 bp) (43).

We compared Pdx1 binding to the Ins2 and Nkx6.1 enhancers in ChIP experiments

performed on control and βDKO islets; noting that Nkx6.1 was viewed as an internal control since

expression was unaffected in βDKO islets (Figure 8B). Nkx2.2 binding to both enhancers was

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also evaluated, with the Nkx2.2 and Pdx1 elements found roughly -807 to -796 bp upstream of the Nkx6.1 transcription start site (44)). Pdx1 binding was selectively reduced on the Ins2 gene in

βDKO islets, whereas Nkx2.2 binding was unchanged as was Pdx1 and Nkx2.2 to the Nkx6.1 enhancer (Figure 8C). These data reveal that the presence of the Brg1/Brm-associated Swi/Snf complex was necessary for Pdx1 binding to the insulin gene enhancer.

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Discussion

The binding of transcription factors to cis-acting DNA control elements is by itself not

sufficient to regulate target gene expression (45). Accordingly, their associated coregulators serve

as an essential layer of control by (for example) influencing chromatin structure, enabling

interactions amongst transcription factors and recruitment of other effectors of RNA polymerase

II. Among the hundreds of positive- and negative-acting transcriptional coregulators, very few

have been directly linked to β cell-enriched transcription factor activity, despite strong evidence

that Pdx1 (1,2,11), Nkx2.2 (31) Mnx1 (33) and Nkx6.1 (30) are essential to core programs of

pancreas formation and β cell activity. Here we evaluated the significance of Pdx1 recruitment of

the Swi/Snf chromatin remodeling complex to pancreas formation developmentally and in islet β

cells. Conditional and constitutive mutants of the core ATPase subunits in mice were used to

modulate Swi/Snf activity in vivo. Our results revealed that the Brg1 ATPase subunit regulates

pancreas size by stimulating Pdx1:Swi/Snf mediated MPC proliferation, while both Brg1 and Brm

regulate expression of Pdx1-driven genes required for islet β cell identity, including insulin.

Adult pancreas mass is limited by the size of the embryonic MPC pool (7). Here our data

demonstrated that the inability of Pdx1 to recruit Brg1/Swi/Snf in Brg1Δpanc mice reduced acinar,

ductal and islet cell numbers and pancreas mass by roughly 50%, without affecting formation of

other organs. Moreover, we showed that this resulted from reduced proliferation of the MPC pool.

Notably, only Pdx1 was found in the PLA to bind to Brg1 and Brm in MPCs, whereas no

interactions were observed with the MPC-enriched and functionally important Ptf1a (4) or Sox9

(5) transcription factors. This evidence indicated that Swi/Snf regulation of MPC expansion was

principally through Pdx1.

Interestingly, pancreas mass was only affected in Brg1Δpanc mice, and not further in the

double ATPase DKOΔpanc mutant. This may simply mean that the Brm ATPase, which has a much

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less impactful global regulatory phenotype in relation to Brg1 (19,46), has no influence on pancreatogenesis. This possibility is supported by a recent report which found BRM transcript levels increased (~17 fold) during directed differentiation of human embryonic stem cells from

Stage 5 MPC-like cells to Stage 6 β-like cells in vitro (Supplemental Table 5, data mined from reference (47)). Further, this increase in BRM provides a plausible explanation as to why eliminating both Brg1 and Brm in adult islet βDKO β cells had such a penetrant effect.

Alternatively, Pdx1 may be recruiting a distinct Swi/Snf related complex, termed PBAF

(Polybromo-associated BAF), that is only regulated by Brg1 (48). While many subunits are shared between PBAF and the Brg1 and Brm regulated BAF (Brg1-/Brm-associated factor) complex, each were shown to possess unique regulatory properties in controlling Vitamin D receptor driven anti-inflammatory and pro-survival responses in islet β cells (49).

More broadly, our results suggest that coregulators of Pdx1, Ptf1a and Sox9 influence pancreas size, a global physical determinant linked to T1D and T2D susceptibility (9,50). Future efforts should not only involve identifying coregulators affecting transcription factor activity, but also the processes and factors that influence their recruitment to target loci. These would be expected to include post-translational modification mechanisms that positively or negatively affect transcription factor:coregulator interactions. For example, phosphorylation of the p53 transcription factor increases CBP/p300 histone acetyltransferase association, amplifying transcriptional activity (51).

T2D is ultimately caused by the inability of islet β cells to produce sufficient amounts of insulin to cause transport of blood glucose into insulin resistant tissues to maintain normoglycemia. A hallmark of this disease is an increase in the number of “empty” β cells, defined by their lack of insulin immunoreactivity (52). This was also a novel characteristic of βDKO β cells

(Figure 6) and associated with a lack of Pdx1 binding to the endogenous Ins2 gene enhancer.

These results are consistent with a recent report showing that DNA binding by the REST

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transcription factor relies on the remodeling activity of SWI/SNF in embryonic stem cells (53). In

contrast to Pdx1, there was no apparent change in Nkx2.2 transcription factor binding to the Ins2

gene nor Pdx1, Nkx2.2, and Nkx6.1 nuclear protein levels. In fact, MafA was the only other core

insulin regulator apparently absent in βDKO β cells (Figure 7). Because loss of MafA alone does

not abolish insulin production in either MafAΔpanc (34) or MafAΔβ (54) mice, insulin deficiencies in

βDKO “empty” β cells likely reflects the combined loss of the MafA protein and inability of Pdx1

to bind to the insulin enhancer. This proposal is supported by the ability of Pdx1 + MafA to

reprogram human islet α cells to β-like cells (55), or in transgenic mice, when combined with the

embryonic islet cell determination factor, Neurog3, to produce β-like cells in the intestine of mice

(56).

Using Circularized Chromosome Conformation Capture (i.e. 4C) and PDX1-binding

enhancer elements as anchor bait sites in the human EndoC-βH1 pancreatic β cell line (57,58),

the human INSULIN locus was found to physically contact many distinct genes affecting β cell

secretory processes. Knockdown of INSULIN mRNA levels in EndoC-βH1 cells demonstrated

that expression of 259 genes were affected, with 45 residing in 4C contact regions and ~40%

associated with metabolic pathways. Moreover, these investigators proposed that the

chromosomal interactions with the INSULIN locus were conjoined with the transcriptional

machinery at the various loci. If PDX1:Swi/Snf contributed to such control, we predicted some

overlap between the βDKO regulated genes and those identified in the human 4C INSULIN

knockdown analysis. However, not one of their 45 genes was differentially expressed in βDKO β

cells. Possible explanations for this difference could involve the unique variable number of tandem

repeats (VNTR) region upstream of the human INSULIN enhancer (39) and/or simply the

experimental context (i.e. human EndoC-βH1 cells versus the mouse βDKO model). Alternatively,

our ability to detect Nkx2.2 binding to the Ins2 enhancer in βDKO islets raises the possibility that

19 Diabetes Page 20 of 125

4C-detected interactions persist because they are regulated by transcription factors binding independently of Pdx1.

While Genome Wide Association studies have found numerous genomic loci linked to T2D

(59), the Swi/Snf subunits have not been associated directly to diabetes pathogenesis. Notably, our results suggest that only genetic variants leading to a complete loss of Swi/Snf activity would yield a βDKO diabetic phenotype. However, a recent study found that genomic deletions and rearrangements in Swi/Snf subunits exist in approximately one-third of pancreatic cancers containing alterations in known tumor-associated genes (e.g. MYC, KRAS, CDKN2A, TGFBR2,

MAP2K4 and SMAD4) (60). Specifically in regards to the ATPase subunits, heterozygous and homozygous mutations in the BRG1 or BRM genes occurs in 9.6% and 2.6%, respectively, of human pancreatic cancer samples. Moreover, while combined mutations in BRG1 and BRM were found in several pancreatic cancer cell lines, double mutations were absent from primary tumor samples, although the latter involved a limited sample number (60). Notably, ~80% of individuals with pancreatic cancer often present with either new-onset T2D or impaired glucose tolerance at diagnosis (61). Although these studies do not directly link the prevalence of Swi/Snf subunit mutations to pancreatic cancer-associated diabetes, loss of function mutations in BRG1 and BRM provide a potential intersection for pancreatic cancer and T2D, especially given the influence

Swi/Snf has on mature β cell function.

Functional heterogeneity within the β cell population was first described over two decades ago (62,63), with recent observations identifying distinct normal and T2D β cell populations that differ in their molecular composition and glucose-stimulated insulin secretion properties (64).

Interestingly, Pdx1, MafA and Nkx6.1 levels appear similar between these β cell subtypes, raising an intriguing possibility that variations in transcription factor:coregulator interactions could be effecting activity. This possibility is supported by our previous findings that Pdx1:Swi/Snf interactions were not observed in all healthy human islet β cells in the PLA (12), which adds

20 Page 21 of 125 Diabetes

another level of heterogeneity to a subpopulation of human β cells. Such observations emphasize

the importance of investigating how coregulator recruitment by endocrine-cell-enriched

transcription factors contribute to human β cell functional heterogeneity under normal

physiological conditions.

Collectively, our study provides fundamental insight into the role of Pdx1:Swi/Snf

complexes in pancreas organogenesis and in maintaining principal features of the mature β cell

state. The translational significance of our findings is underscored by the knowledge that, in

humans, a subset of T2D β cells lose their ability to produce insulin, and that overall pancreas

size, with otherwise normal cell-type proportional allocations, is a risk factor in the development

of diabetes. Furthermore, our findings that Swi/Snf activity is crucial for driving insulin expression

and Pdx1:Swi/Snf interactions are negatively affected in human T2D (12) indicate that therapies

that enhance such interactions are an attractive target in T2D. Upon broader consideration, we

propose that transcriptional coregulator recruitment is essential to the formation and function of

the other islet cell types (α, β, δ, ε and PP). In this context, our studies are currently focused on

additional Pdx1-interacting proteins, such as the multi-subunit Nucleosome Remodeler and

Deacetylase (NuRD) complex, the Myst2 histone acetyltransferase, and the Tif1β corepressor.

Author Contributions

JMS, J-HL, DP, MG, AO, FM, and NR designed, executed and analyzed experiments.

MH, MAM, AB, CVEW and RS designed and analyzed experiments. JMS and RS wrote the

manuscript that was reviewed by all the authors. RS is the guarantor of this work and, as such,

had full access to all the data in the study and takes responsibility for the integrity of the data and

the accuracy of the data analysis.

21 Diabetes Page 22 of 125

Acknowledgements

We thank Drs. Xin Tong and Emily Walker for critically reading the manuscript. This work was supported by grants from the NIH (R01DK050203 (RS), K01DK115633 (JMS),

R01CA172045 (MH)), and American Diabetes Association (1-16-PDF-109 (JMS)). We thank the

Vanderbilt Flow Cytometry Shared Resource (P30CA68485), Vanderbilt Technologies for

Advanced Genomics core (VANTAGE) (supported in part by CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30

EY08126), and NIH/NCRR (G20 RR030956)), and the Vanderbilt Hormone Assay and Analytical

Services Core (NIH DK020593) for core laboratory and technical assistance.

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Data and Resource Availability

Raw and analyzed RNA-Sequencing datasets have been deposited in GEO (accession number GSE128945). All non-commercially available resources generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

22 Page 23 of 125 Diabetes

References

1. Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for

pancreas development in mice. Nature. 1994 Oct 13;(371):606–9.

2. Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, et al. PDX-1 is

required for pancreatic outgrowth and differentiation of the rostral duodenum.

Development. 1996 Mar 1;122(3):983–95.

3. Stoffers D, Ferrer J, Clarke W, Habener J. Early-onset type-II diabetes mellitus (MODY4)

linked to IPF1. Nat Genet. 1997;17(2):138–9.

4. Krapp A, Knöfler M, Ledermann B, Bürki K, Berney C, Zoerkler N, et al. The bHLH protein

PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization

of the endocrine pancreas. Genes Dev. 1998;12:3752–63.

5. Seymour PA, Freude KK, Tran MN, Mayes EE, Jensen J, Kist R, et al. SOX9 is required

for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci.

2007;104(6):1865–1870.

6. Pan FC, Wright C. Pancreas organogenesis: From bud to plexus to gland. Dev Dyn. 2011

Mar;240(3):530–65.

7. Stanger BZ, Tanaka AJ, Melton DA. Organ size is limited by the number of embryonic

progenitor cells in the pancreas but not the liver. Nature. 2007 Feb 22;445(7130):886–91.

8. Saisho Y, Butler AE, Meier JJ, Monchamp T, Allen-Auerbach M, Rizza RA, et al. Pancreas

volumes in humans from birth to age one hundred taking into account sex, obesity, and

presence of type-2 diabetes. Clin Anat. 2007 Nov;20(8):933–42.

23 Diabetes Page 24 of 125

9. Campbell-Thompson M, Wasserfall C, Montgomery E, Atkinson M, Kaddis J. Pancreas

organ weight in individuals with disease-associated autoantibodies at risk for Type 1

Diabetes. 2012.

10. Guz Y, Montminy MR, Stein R, Leonard J, Gamer LW, Wright CV, et al. Expression of

murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas,

duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny.

Development. 1995 Jan 1;121(1):11–8.

11. Gao T, McKenna B, Li C, Reichert M, Nguyen J, Singh T, et al. Pdx1 maintains β cell

identity and function by repressing an α cell program. Cell Metab. 2014 Feb;19(2):259–71.

12. McKenna B, Guo M, Reynolds A, Hara M, Stein R. Dynamic recruitment of functionally

distinct Swi/Snf chromatin remodeling complexes modulates Pdx1 activity in islet β cells.

Cell Rep. 2015 Mar 31;10(12):2032–42.

13. Wang W, Cote J, Zhou S, Khavari PA, Biggar SR, Muchardt C, et al. Purification and

biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO. 1996

Oct;15(19):5370–5382.

14. Mani U, S AS, Goutham R N A, Mohan S S. SWI/SNF Infobase-An exclusive information

portal for SWI/SNF remodeling complex subunits. PloS One. 2017 Sep

29;12(9):e0184445–e0184445.

15. Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CVE. The role of the

transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet.

2002 Sep;32(1):128–34.

24 Page 25 of 125 Diabetes

16. Tamarina NA, Roe MW, Philipson L. Characterization of mice expressing Ins1 gene

promoter driven CreERT recombinase for conditional gene deletion in pancreatic β-cells.

Islets. 2014 Jan 14;6(1):e27685.

17. Sumi-Ichinose C, Ichinose H, Metzger D, Chambon P. SNF2beta-BRG1 is essential for the

viability of F9 murine embryonal carcinoma cells. Mol Cell Biol. 1997;17(10):5976–5986.

18. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and

high-throughput Cre reporting and characterization system for the whole mouse brain. Nat

Neurosci. 2010 Jan;13(1):133–40.

19. Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M. Altered control of cellular

proliferation in the absence of mammalian brahma (SNF2α). EMBO J. 1998;17(23):6979–

6991.

20. Spaeth JM, Hunter CS, Bonatakis L, Guo M, French CA, Slack I, et al. The FOXP1,

FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and

function in mice. Diabetologia. 2015 May 29;1–9.

21. Spaeth JM, Gupte M, Perelis M, Yang Y-P, Cyphert H, Guo S, et al. Defining a novel role

for the Pdx1 transcription factor in islet β-cell maturation and proliferation during weaning.

Diabetes. 2017 Nov 1;66(11):2830.

22. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence

data. Bioinformatics. 2014 Aug 1;30(15):2114–20.

23. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory

requirements. Nat Methods. 2015 Apr;12(4):357–60.

24. Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput

sequencing data. Bioinformatics. 2015 Jan 15;31(2):166–9.

25 Diabetes Page 26 of 125

25. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for

RNA-seq data with DESeq2. Genome Biol. 2014 Dec;15(12).

26. von Figura G, Fukuda A, Roy N, Liku ME, Morris IV JP, Kim GE, et al. The chromatin

regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and

pancreatic ductal adenocarcinoma. Nat Cell Biol. 2014 Feb 23;16(3):255–67.

27. Seymour PA. Sox9: A master regulator of the pancreatic program. Rev Diabet Stud.

2014;11(1):51–83.

28. Gradwohl G, Dierich A, LeMeur M, Guillemot F. neurogenin3 is required for the

development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci.

2000;97(4):1607–1611.

29. Brouwers B, de Faudeur G, Osipovich AB, Goyvaerts L, Lemaire K, Boesmans L, et al.

Impaired islet function in commonly used transgenic mouse lines due to human growth

hormone minigene expression. Cell Metab. 2014 Dec 2;20(6):979–90.

30. Taylor BL, Liu F-F, Sander M. Nkx6.1 Is essential for maintaining the functional state of

pancreatic beta cells. Cell Rep. 2013 Sep;4(6):1262–75.

31. Gutiérrez GD, Bender AS, Cirulli V, Mastracci TL, Kelly SM, Tsirigos A, et al. Pancreatic β

cell identity requires continual repression of non–β cell programs. J Clin Invest. 2016 Dec

12;127(1):244–59.

32. Mitchell RK, Nguyen-Tu M-S, Chabosseau P, Callingham RM, Pullen TJ, Cheung R, et al.

The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated

ATP synthesis, and Ca2+ dynamics in adult mice. J Biol Chem. 2017 May

26;292(21):8892–906.

26 Page 27 of 125 Diabetes

33. Pan FC, Brissova M, Powers AC, Pfaff S, Wright CVE. Inactivating the permanent neonatal

diabetes gene Mnx1 switches insulin-producing beta-cells to a delta-like fate and reveals a

facultative proliferative capacity in aged beta-cells. Development. 2015 Nov

1;142(21):3637–48.

34. Hang Y, Yamamoto T, Benninger RKP, Brissova M, Guo M, Bush W, et al. The MafA

transcription factor becomes essential to islet β-cells soon after birth. Diabetes. 2014 Jun

1;63(6):1994–2005.

35. Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene

lists using DAVID bioinformatics resources. Nat Protoc. 2009 Jan;4(1):44–57.

36. Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the

comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009

Jan;37(1):1–13.

37. Khoo C, Yang J, Weinrott SA, Kaestner KH, Naji A, Schug J, et al. Research resource: The

Pdx1 cistrome of pancreatic islets. Mol Endocrinol. 2012 Mar;26(3):521–33.

38. Fromont-Racine M, Bucchini D, Madsen O, Desbois P, Linde S, Nielsen JH, et al. Effect of

5′-flanking sequence deletions on expression of the human insulin gene in transgenic

mice. Mol Endocrinol. 1990 May;4(5):669–77.

39. Hay CW, Docherty K. Comparative analysis of insulin gene promoters: Implications for

diabetes research. Diabetes. 2006 Dec 1;55(12):3201–13.

40. Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the

insulin gene. EMBO J. 1993;12(11):4251.

27 Diabetes Page 28 of 125

41. Sander M, Neubuser A, Kalamaras J, Ee HC, Martin GR, German MS. Genetic analysis

reveals that PAX6 is required for normal transcription of pancreatic hormone genes and

islet development. Genes Dev. 1997 Jul 1;11(13):1662–73.

42. Cissell MA, Zhao L, Sussel L, Henderson E, Stein R. Transcription factor occupancy of the

insulin gene in vivo: Evidence for direct regulation by Nkx2.2. J Biol Chem. 2003 Jan

10;278(2):751–6.

43. Zhao L, Guo M, Matsuoka T -a., Hagman DK, Parazzoli SD, Poitout V, et al. The islet cell-

enriched MafA activator is a key regulator of insulin gene transcription. J Biol Chem. 2005

Mar 25;280(12):11887–94.

44. Watada H, Mirmira RG, Leung J, German MS. Transcriptional and translational regulation

of β-cell differentiation factor Nkx6.1. J Biol Chem. 2000 Nov 3;275(44):34224–30.

45. Mouchiroud L, Eichner LJ, Shaw RJ, Auwerx J. Transcriptional Coregulators: Fine-Tuning

Metabolism. Cell Metab. 2014 Jul;20(1):26–40.

46. Bultman S, Gebuhr T, Yee D, La Mantia C, Nicholson J, Gilliam A, et al. A Brg1 Null

Mutation in the Mouse Reveals Functional Differences among Mammalian SWI/SNF

Complexes. Mol Cell. 2000;6(6):1287–1295.

47. Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH-R, Harb G, et al. Charting cellular

identity during human in vitro β-cell differentiation. Nature. 2019 May;569(7756):368–73.

48. Hodges C, Kirkland JG, Crabtree GR. The Many Roles of BAF (mSWI/SNF) and PBAF

Complexes in Cancer. Cold Spring Harb Perspect Med. 2016 Aug;6(8):a026930.

49. Wei Z, Yoshihara E, He N, Hah N, Fan W, Pinto AFM, et al. Vitamin D Switches BAF

Complexes to Protect β Cells. Cell. 2018 May;173(5):1135-1149.e15.

28 Page 29 of 125 Diabetes

50. Philippe M-F, Benabadji S, Barbot-Trystram L, Vadrot D, Boitard C, Larger E. Pancreatic

volume and endocrine and exocrine functions in patients with diabetes. Pancreas. 2011

Apr;40(3):359–63.

51. Lambert PF, Kashanchi F, Radonovich MF, Shiekhattar R, Brady JN. Phosphorylation of

p53 serine 15 increases interaction with CBP. J Biol Chem. 1998 Dec 4;273(49):33048–53.

52. Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of β-

cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016

Mar;101(3):1044–54.

53. Barisic D, Stadler MB, Iurlaro M, Schübeler D. Mammalian ISWI and SWI/SNF selectively

mediate binding of distinct transcription factors. Nature. 2019 May;569(7754):136–40.

54. Scoville DW, Cyphert HA, Liao L, Xu J, Reynolds A, Guo S, et al. MLL3 and MLL4

methyltransferases bind to the MAFA and MAFB transcription factors to regulate islet β-cell

function. Diabetes. 2015;db150281.

55. Matsuoka T, Kawashima S, Miyatsuka T, Sasaki S, Shimo N, Katakami N, et al. Mafa

enables Pdx1 to effectively convert pancreatic islet progenitors and committed islet α-cells

into β-cells in vivo. Diabetes. 2017 May;66(5):1293–300.

56. Chen Y-J, Finkbeiner SR, Weinblatt D, Emmett MJ, Tameire F, Yousefi M, et al. De novo

formation of insulin-producing “Neo-β Cell Islets” from intestinal crypts. Cell Rep. 2014

Mar;6(6):1046–58.

57. Jian X, Felsenfeld G. Insulin promoter in human pancreatic β cells contacts diabetes

susceptibility loci and regulates genes affecting insulin metabolism. Proc Natl Acad Sci.

2018 May 15;115(20):E4633–41.

29 Diabetes Page 30 of 125

58. Xu Z, Wei G, Chepelev I, Zhao K, Felsenfeld G. Mapping of INS promoter interactions

reveals its role in long-range regulation of SYT8 transcription. Nat Struct Amp Mol Biol.

2011 Feb 20;18:372.

59. Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-

mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-

density imputation and islet-specific epigenome maps. bioRxiv. 2018 Jan 9; Available from:

http://biorxiv.org/lookup/doi/10.1101/245506

60. Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, et al.

Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF)

chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc

Natl Acad Sci U S A. 2012 Jan 31;109(5):E252–9.

61. Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and

pancreatic cancer. Mol Cancer. 2003 Jan 6;2:4–4.

62. Giordano E, Bosco D, Cirulli V, Meda P. Repeated glucose stimulation reveals distinct and

lasting secretion patterns of individual rat pancreatic B cells. J Clin Invest. 1991 Jun

1;87(6):2178–85.

63. Kiekens R, In ’t Veld P, Mahler T, Schuit F, Van De Winkel M, Pipeleers D. Differences in

glucose recognition by individual rat pancreatic B cells are associated with intercellular

differences in glucose-induced biosynthetic activity. J Clin Invest. 1992 Jan 1;89(1):117–

25.

64. Dorrell C, Schug J, Canaday PS, Russ HA, Tarlow BD, Grompe MT, et al. Human islets

contain four distinct subtypes of β cells. Nat Commun. 2016 Jul 11;7:11756.

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Figure Legends

Figure 1: Pancreas size is reduced upon embryonic deletion of the mouse Brg1 Swi/Snf

ATPase subunit. (A) Schematic illustrating the composition of the mammalian Swi/Snf complex,

with the core of the coregulator containing either the Brg1 or Brm ATPase and the BAF47, BAF155

and BAF170 subunits (white font). Swi/Snf complexes also contain 8 - 10 other BAFs (Brm or

Brg1-associated factors) and accessory subunits, which vary depending on the tissue and

developmental stage (14). (B) Representative image of the pancreas, stomach, spleen and

duodenum in P1 control, Brg1Δpanc, Brm-/-, and DKOΔpanc mice. panc = pancreas; st = stomach; sp

= spleen; duod = duodenum.

Figure 2: Pdx1, but not Sox9 or Ptf1a, interacts with Brg1 and Brm in wild type e12.5

pancreatic epithelium. PLA was performed with antibodies specific for (A) Brg1 or (B) Brm and

either Sox9, Ptf1a or Pdx1. Distinct fluorescence PLA signals were easily visible in the Pdx1:Brg1

and Pdx1:Brm experiments, but were nearly absent in the Brg1:Sox9, Brg1:Ptf1a, Brm:Sox9 and

Brm:Ptf1a assays. The yellow square demarks the magnified area displayed below, while the

dashed yellow marks outline the pancreatic epithelium. RBC = Red Blood Cell. Scale bars =

10µm.

Figure 3: All pancreatic cell lineages are reduced in e15.5 Brg1Δpanc and DKOΔpanc

epithelium. Control, Brg1Δpanc and DKOΔpanc mutant embryos were stained with antibodies specific

for (A) E-Cadherin and Sox9, (B) E-Cadherin and Neurogenin 3 (Neurog3), (C) Insulin (Ins),

Somatostatin (Sst) and Glucagon (Gcg), or (D) Cpa1. The yellow square in (B) marks the

magnified area in the panel; DAPI nuclear staining is also provided in (C) and (D). Cell type

31 Diabetes Page 32 of 125

counting was performed on sections 90 µm apart that spanned the entire pancreatic region (n=3).

*, p < 0.05. **, p < 0.01. ***, p < 0.001. n.s. = not significant. Scale bars = 50 µm.

Figure 4: MPC proliferation is dependent on the Brg1 ATPase subunit of Swi/Snf. (A) A representative immunostaining image of Sox9+ and Pdx1+ cells in control, Brg1Δpanc and DKOΔpanc pancreata at e12.5. Sox9+Pdx1+ MPCs numbers were determined in sections obtained every 60

µm of the entire pancreatic region. (B) E-Cadherin, Brg1 and BrdU staining of pregnant dams injected with BrdU 30 minutes prior to harvesting the e12.5 embryos. Also provided is the percentage of Brg1+ (Yellow arrowheads) or Brg1- (Blue arrowheads) cells that incorporated BrdU

(n=3). The yellow square illustrates the magnified area displayed in the panels on the right. *, p

< 0.05. Scale bars = 20µm. DAPI nuclear staining is shown in (A) and (B).

Figure 5: Severe defects in adult islet β cell function are only produced in βDKO mice.

Control, Brg1Δβ/+;Brm-/-, Brg1Δβ;Brm+/-, and βDKO mice were subjected to testing 2 weeks after the last TM treatment. All statistical comparisons are to controls. (A) Fasting blood glucose and glucose tolerance was specifically compromised in βDKO mice in intraperitoneal glucose tolerance tests (IPGTT). (B) Serum insulin levels were also only reduced in ad lib fed or fasted

βDKO animals. n = 5 - 9. *, p < 0.05; **, p < 0.01. (C) Glucose (G)-induced insulin secretion was reduced in βDKO islets, and not Brg1Δβ/+;Brm-/- or Brg1Δβ;Brm+/-. Data is displayed as secreted insulin per islet insulin content. n = 3 - 6. (D) Islet insulin content is only decreased in the βDKO mutant. Data is displayed as nanogram (ng) of insulin per mL per islet (n = 4 - 8).

Figure 6: βDKO β cells have very reduced insulin protein levels yet retain Nkx6.1 and Pdx1.

(A) Representative confocal images of lineage labeled control and βDKO Tomato+ and insulin+

32 Page 33 of 125 Diabetes

stained islet cells. Most Tomato+ βDKO cells are insulinLo or insulin- as illustrated in the lower

panels by the yellow arrowheads of the magnified squared field. The graph depicts the percent of

Tomato+ insulin- or insulin+ cells to the total number of Tomato+ cells. (B) Islet β cell enriched Pdx1

and Nkx6.1 are present in control and βDKO Tomato+ cells, whereas MafA is absent. Scale bars

= 20µm. The graph illustrates the percent of Tomato+ transcription factor- or transcription factor+

cells to the total number of Tomato+ cells.

Figure 7: Swi/Snf affects a broad range of metabolic processes in islet β cells. (A) Top:

Volcano plot showing the most differentially expressed genes in βDKO β cells. Bottom: The most

significant biological pathways identified by gene ontology analysis. Swi/Snf contributed to very

divergent regulatory processes, varying from cell adhesion (most significant) to ion transport, cell

migration and carbohydrate metabolism (least significant). Expression of Swi/Snf subunits

BAF250A (Arid1a), BAF53B (Actl6b) and BAF60C (Smarcd3) were increased in βDKO β cells by

2.11-, 2.08-, and 10.3-fold, respectively. (B) qPCR analysis from FACS purified Tomato+ β cells

of various βDKO genes upregulated in the RNA-Seq. n = 3, *, p < 0.05; **, p < 0.01.

Figure 8: Pdx1:Swi/Snf controls genes essential to islet β cell function. (A) Left: Venn

diagram of upregulated and downregulated βDKO genes overlaid with Pdx1 bound genes

obtained from ChIP experimentation of primary mouse islets (37). Right: Most of the pathways

identified by gene ontology analysis of the 507 genes that were Pdx1 bound and upregulated in

βDKO β cells were associated with cell adhesion and neuromuscular functions, while the 917

genes that were Pdx1 bound and downregulated in βDKO β cells were associated with β cell

function, like glucose homeostasis and insulin secretion. (B) Expression of a key subset of islet β

cell regulators identified in βDKO RNA-Seq and Pdx1 ChIP studies were confirmed upon qPCR

33 Diabetes Page 34 of 125

of FACS purified Tomato+ β cells. *, p < 0.05; **, p < 0.01; ***, p < 0.001. (C) Pdx1 ChIP binding to the Ins2 enhancer was decreased in βDKO compared to control islets, whereas there was no impact on binding to the Nkx6.1 enhancer. Nkx2.2 binding to the Ins2 and Nkx6.1 enhancer was unchanged between βDKO and control islets. Dotted line represents IgG enrichment on target gene following normalization to β-actin. n = 3. *, p < 0.05.

34 FigurePage 35 of 1251 Diabetes A. BAF45A,B,C Bcl7A,B,C

BAF47 Brg1/Brm BAF170 BAF155 BAF250A,B,C BAF57 SS18 BAF53A,B

Bcl11A,B BAF200 BAF60A,B,C BAF180 β actin B. Control Brg1panc Brm-/- DKOpanc

st sp st st st sp sp panc sp

panc panc panc duod duod duod duod Figure 2 Diabetes Page 36 of 125

DAPI PLA DAPI PLA DAPI PLA A. (Sox9:Brg1) (Ptf1a:Brg1) (Pdx1:Brg1)

RBC

RBC RBC

RBC

DAPI PLA DAPI PLA DAPI PLA B. (Sox9:Brm) (Ptf1a:Brm) (Pdx1:Brm)

RBC RBC FigurePage 37 of 1253 Diabetes Control Brg1panc A. Control Brg1panc DKOpanc * 6000 * Sox9 n.s. 4000 cells/embryo

+ 2000 Cadherin - E Sox9 0 B. 500 ** 400 * n.s. 300 Neurog3 cells/embryo

+ 200

Cad 100 -

E 0 50µM 50µM Neurog3 C. * 500 * * 400 ** DAPI n.s. 300 Gcg

cells/embryo n.s.

+ 200 *

Sst ** 100 n.s. Ins 0 Hormone D.

8000 *** ** DAPI 6000 n.s. 4000 cells/embryo Cpa1 + 2000

Cpa1 0 Figure 4 Diabetes Page 38 of 125

A. Control Brg1panc DKOpanc * 2000 * n.s. DAPI 1000 Sox9 Sox9 (per embryo) (per MPC MPC number 0 Pdx1

B. Control Brg1 BrdU Control Brg1panc DAPI DKOpanc - BrdU 40

BrdU * * Brg1 E-Cadherin DAPI 30 or Brg1 + 20 positive for positive

Cadherin Cadherin 10 - E % of % of Brg1 0 MPCs

Brg1panc Brg1 BrdU DAPI BrdU Brg1-BrdU+

Brg1 + + E-Cadherin DAPI Brg1 BrdU Cadherin Cadherin - E FigurePage 39 of 1255 Diabetes

A. Control B. Control β/+ -/- ) Brg1β/+;Brm-/- Brg1 ;Brm

dL Brg1β;Brm+/- Brg1β;Brm+/- βDKO 600 1.0 βDKO * ** 400 ** * 0.5 200 * (ng/mL) * * 0 insulin Serum 0.0 Blood glucose (mg/ glucoseBlood 0 30 60 90 120 ad lib Fed Fasted Minutes post glucose C. D.

4.0 400.0 3.0 2.0 * 200.0 1.0 *** (ng/mL/islet) Insulin contentInsulin 0.0 - - - - 0.0 / / - - +/ +/ Fold change in GSIS GSIS in change Fold (16.7mMG / 2.8mMG) / (16.7mMG DKO DKO Brm Brm Brm β ; Brm β ; ; ; Control β /+ Control β /+

β 

β    Brg1 Brg1 Brg1 Brg1 Figure 6 Diabetes Page 40 of 125

A. Tom Ins DAPI Tomato Insulin

Control Control βDKO

100 *** cells cells (%) DKO + 50 β *** Tomato 0

B. Nkx6.1 Tomato Pdx1 Tomato MafA Tomato

Control βDKO Control 100 *** 80 60 cells cells (%)

+ 40 20 *** DKO

Tomato 0 β FigurePage 41 of 1257 Diabetes

1789 downregulated 1273 upregulated A. B. Control MafA Ucn3 Gucy1b3 βDKO 300 Slc2a2 Slc30a8 ) 250 60 ** 200

(FDR Creg1 40

10 150 Ins1 Scg3 Gucy1a3 **

log 100

Nkx6.1 * - Ins2 20 50 Pdx1 * 0 0 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

-log2(Fold Change) Change Fold Relative

carbohydrate metabolic process immune system process negative regulation of cell proliferation positive regulation of cell migration cell differentiation potassium ion transport GO Terms Terms GO ion transport cell adhesion

(Biological Processes) (Biological 0.0 10.0 20.0

-log10(p-value) Figure 8 Diabetes Page 42 of 125

A. GO Terms (Biological Processes) protein dephosphorylation nervous system development locomotory behavior Upregulated axon guidance genes in βDKO neuromuscular process controlling balance β cells positive regulation of synapse assembly Pdx1 bound 766 cell adhesion genes in primary homophilic cell adh. via plasma membrane molecules 507507 mouse islets 0 5 10 -log10(p-value) 6480 917 872 potassium ion transport Downregulated cell adhesion genes in βDKO ion transport response to glucose β cells negative regulation of cell proliferation glucose homeostasis positive regulation of insulin secretion regulation of insulin secretion 0 5 10 -log10(p-value)

B. C. Control βDKO Control βDKO Pdx1 ChIP Nkx2.2 ChIP 1.5 4.0 12.0 1 8.0 2.0 * 0.5 4.0 ** ** * 0 *** ** ** 0.0 0.0 Fold enrichment Fold Fold enrichment Fold Relative Fold Change Fold Relative Page 43 of 125 Diabetes

Supplemental Figure Legends:

Supplemental Figure 1: Brg1 is not upregulated in e12.5 Brm-/- or DKOΔpanc pancreatic

epithelium. Brg1 and E-Cadherin staining of control, Brg1Δpanc, Brm-/- and DKOΔpanc pancreata

illustrates that Brg1 is removed from ~50% of cells. Brg1 levels are not induced in Brm-/- pancreata

- compare Brg1 levels between Control and Brm-/-. The yellow square demarks the magnified

area displayed in the panels on the right. Scale bars = 20 µm.

Supplemental Figure 2: Brm levels are not elevated in e12.5 Brg1Δpanc pancreata. Staining of

e12.5 control, Brg1Δpanc, Brm-/- and DKOΔpanc pancreatic epithelium shows that Brm levels are

similar within control and Brg1Δpanc cells. The yellow square mark the magnified area displayed in

the panels on the right. Scale bars = 20µm.

Supplemental Figure 3: Brg1 is absent in most pancreas P1 Brg1Δpanc Cpa1+ cells but

present in hormone+ cells. Staining for Brg1 and either (A) Cpa1 and E-Cadherin or (B) insulin

and glucagon. The yellow square mark the magnified area shown to the right. Scale bars = 20µm.

Supplemental Figure 4: Ductal branching is less expansive in e15.5 Brg1Δpanc and DKOΔpanc

embryos. E-cadherin, Muc1, and DAPI analysis of e15.5 control, Brg1Δpanc, and DKOΔpanc

embryos. Note the less extensive Muc1 ductal staining pattern in the Brg1Δpanc and DKOΔpanc

mutants compared to control. Scale bars = 50µm.

1 Diabetes Page 44 of 125

Supplemental Figure 5: Most Tomato-lineage labeled βDKO β cells lack Brg1. (A) Loxp sites

(Red arrowheads) surround exons (Ex) 17 and 18 of the Brg1 (Brg1f) gene and the stop codon in

R26LSL-tdTomato lineage reporter. Brm Ex4 is replaced with Neomycin in the Brm null allele (Brm-).

Tamoxifen inducible MIP-CreERT was used to remove the Loxp sites from Brg1f/f and the R26LSL- tdTomato lineage reporter specifically in islet β cells of 4 week old Brg1Δβ;Brm+/- (MIP-CreERT; R26LSL- tdTomato; Brg1f/f; Brm+/-), and βDKO (MIP-CreERT; R26LSL-tdTomato; Brg1f/f; Brm-/-) mice. (B)

Approximately 70% of Control (i.e. MIP-CreERT; Brg1f/+; Brm+/-; R26LSL-tdTomato) Tomato+ cells are insulin+. (C) Approximately 90% of Tomato+ cells in βDKO islets lack Brg1. Scale bars = 20µm.

Supplemental Figure 6: Male and female βDKO mice appear to have similar glucose intolerant phenotypes, the properties of which are not changed by aging. Control and mutant mice were subjected to an IPGTT at 2, 6 or 12 weeks from the last TM treatment. The

βDKO pattern is not dependent upon the sex of the animal or length of time without Swi/Snf activity. n = 4 - 9, *, p < 0.05; **, p < 0.01, comparing βDKO to control animals.

Supplemental Figure 7: Tomato-labeled Brm- or Brg1- β cells have normal insulin, Ucn3 and MafA levels. Control, Brg1Δβ/+;Brm-/- and Brg1Δβ;Brm+/- pancreas sections stained with

Insulin, Ucn3 and MafA antibodies. Scale bars = 20µm.

Supplemental Figure 8: Tomato-labeled βDKO β cells retain Nkx2.2, Pax6 and Mnx1 expression and do not express other islet hormones. Control and βDKO pancreas stained for

Nkx2.2, Pax6, Mnx1, glucagon and somatostatin. Note that the Tomato+ islet cells produce these transcription factors and are not glucagon+ or somatostatin+. Scale bars = 20µm. The islet

2 Page 45 of 125 Diabetes

glucagon+ or somatostatin+ cell area did not change in the βDKO mutant, which was calculated

by determining the percentage of hormone+ area within the pancreatic area.

Supplemental Figure 9: Tomato-labeled βDKO β cells have reduced Ucn3 and Glut2 levels.

Control and βDKO pancreas stained with Ucn3 and Glut2 specific antibodies. Note the severe

reductions in both Ucn3 and Glut2 levels in βDKO Tomato+ cells.

Supplemental Figure 10: Candidate gene expression analysis in Brg1Δβ/+;Brm-/- and

Brg1Δβ;Brm+/- islets. qPCR analysis of various β cell enriched gene products in control,

Brg1Δβ/+;Brm-/- and Brg1Δβ;Brm+/- islets. n = 3-5.

Supplemental Table 1: List of antibodies used for immunofluorescence.

Supplemental Table 2: List of DNA primers used for qPCR and ChIP-qPCR studies.

Supplemental Table 3: List of genes differentially expressed between βDKO and control β cells

using a ± 2-fold cut-off and FDR < 0.05. These 3062 differentially expressed genes are classified

by Gene Ontology enrichment analysis into an array of biological pathways, including cell

adhesion, ion transport, cell differentiation, cell proliferation and carbohydrate metabolic

processes.

3 Diabetes Page 46 of 125

Supplemental Table 4: List of genes bound by Pdx1 in primary mouse islets and either upregulated or downregulated in βDKO β cells. The 507 upregulated and Pdx1 bound genes resided in pathways linked to cell adhesion and neuromuscular functions. In contrast, the 917 downregulated and Pdx1 bound genes were more aligned with β cell function, including insulin secretion, glucose homeostasis and ion transport.

Supplemental Table 5: Human RNA-Sequencing expression data of SWI/SNF subunit genes from in vitro produced Stage 5 NKX6.1+ pancreatic progenitor cells and Stage 6 β-like cells derived during human embryonic stem cell differentiation (47). Notably, BRM (SMARCA2) levels increased ~17-fold in β-like cells, with a much more modest change in other SWI/SNF subunits.

4 SupplementalPage 47 of 125 Figure 1 Diabetes

E-Cadherin Brg1 E-Cadherin Brg1 Brg1 Control panc

 Brg1 - / - Brm panc

 DKO Supplemental Figure 2 Diabetes Page 48 of 125

E-Cadherin Brm E-Cadherin Brm Brm Control panc

 Brg1 - / - Brm panc

 DKO SupplementalPage 49 of 125 Figure 3 Diabetes

A. Brg1 E-Cad Cpa1 DAPI Brg1 E-Cadherin Cpa1 Control panc

 Brg1

B. Ins Gcg Brg1 DAPI Brg1 Glucagon Insulin Control panc

 Brg1 Supplemental Figure 4 Diabetes Page 50 of 125

Control Brg1panc DKOpanc DAPI Muc1 Cadherin Cadherin - E Muc1 SupplementalPage 51 of 125 Figure 5 Diabetes

4W 5W A. Brg1β Brg1f Ex17 Ex18 Tamoxifen 4mg/dose (x3)

ERT R26LSL-tdTomato STOP Tomato MIPCre + Tamoxifen Tomato

Brm+ Ex3 Ex4 Ex5

Brm- Ex3 NeoR Ex5

B. Tom Ins DAPI Tomato Insulin 80 60 cells + 40 20 % Insulin Control 0

C. Tom Brg1 DAPI Tomato Brg1 Control βDKO 100 cells + 50 DKO

% Tomato % 0 β Supplemental Figure 6 Diabetes Page 52 of 125

Control Brg1β/+;Brm-/- Brg1β;Brm+/- βDKO

Female, 2 weeks post TM Male, 2 weeks post TM

) 600 600 dL ** 500 500 * ** 400 *** 400 ** 300 300 * 200 ** 200 * 100 100

Blood glucose (mg/ glucose Blood 0 0 0 30 60 90 120 0 30 60 90 120

Female, 6 weeks post TM Male, 6 weeks post TM )

dL 600 *** 600 *** 500 500 *** 400 ** 400 ** 300 300 200 ** 200** 100 100

Blood glucose (mg/ glucose Blood 0 0 0 30 60 90 120 0 30 60 90 120

Female, 12 weeks post TM Male, 12 weeks post TM ) 600 600 dL * ** *** 500 ** 500 ** 400 * 400 300 300 * ** * 200* 200 100 100

Blood glucose (mg/ glucose Blood 0 0 0 30 60 90 120 0 30 60 90 120 Minutes post glucose Minutes post glucose SupplementalPage 53 of 125 Figure 7 Diabetes

Tomato Insulin Tomato Ucn3 Tomato MafA Control - / - Brm ; /+ β

 Brg1 - +/ Brm ; β

 Brg1 Supplemental Figure 8 Diabetes Page 54 of 125

Nkx2.2 Tomato Pax6 Tomato Mnx1 Tomato Control DKO β

Somatostatin Glucagon Tomato Tomato

0.10 area area

+ 0.05

0.00 Control Glucagon (% pancreas area) pancreas (%

0.10 area area + 0.05 DKO β 0.00 (% pancreas area) pancreas (% Somatostatin SupplementalPage 55 of 125 Figure 9 Diabetes

Ucn3 Tomato Glut2 Tomato Control DKO β Supplemental Figure 10 Diabetes Page 56 of 125

Control Brg1β/+;Brm-/- Brg1β;Brm+/- 2

1.5

1

0.5

0 Relative Fold Change Fold Relative Page 57 of 125 Diabetes

Antibody Company Catalog number Concentration Insulin Dako A056401-2 1:1000 Cryo/Paraffin Glucagon Sigma G2654 1:2000 Cryo/Paraffin Somatostatin Santa Cruz SC-7819 1:1000 Cryo/Paraffin Brdu Bio-Rad OBT0030G 1:500 Paraffin Brg1 Santa Cruz SC-10768 1:400 Cryo/Paraffin Brg1 R & D Systems AF5738 1:500 Cryo/Paraffin Brm Abcam AB1559 1:500 Cryo/Paraffin Brm Cell Signaling 72182 1:500 Cryo/Paraffin E-cadherin BD Bioscience 610181 1:500 Paraffin Sox9 EMD Millipore AB5535 1:500 Paraffin Cpa1 R & D Systems AF2765 1:500 Paraffin Muc1 Fisher HM-1630-P 1:500 Paraffin MafA Novus Biologicals NBP1-00121 1:500 Cryo MafA Cell Signaling 79737 1:10000 Cryo Nkx6.1 Novus Biologicals NBP1-49672 1:500 Cryo Glut2 Santa Cruz SC-7580 1:500 Cryo Ucn3 Phoenix Pharmaceuticals H-019-29 1:1000 Cryo Pax6 Covance PRB-278P 1:1000 Cryo Pdx1 Abcam AB47383 1:20,000 Cryo/Paraffin Mnx1 gift from Samuel Pfaff (Salk) 1:5000 Cryo gift from Guoqiang Gu Ngn3 1:500 Paraffin (Vanderbilt) Diabetes Page 58 of 125

Gene Sequence Use Ins1_Forward CACTTCCTACCCCTGCTGG qPCR Ins1_Reverse ACCACAAAGATGCTGTTTGACA qPCR pre-Ins2_Forward GGGGAGCGTGGCTTCTTCTA qPCR pre-Ins2_Reverse GGGGACAGAATTCAGTGGCA qPCR Ins2_Forward CCACCCAGGCTTTTGTCAAA qPCR Ins2-Reverse CCCAGCTCCAGTTGTTCCAC qPCR Ucn3_Forward AGCACCCGGTACAGATACCAA qPCR Ucn3_Reverse GGCCTTGTCGATGTTGAAGAG qPCR Slc2a2_Forward CAGTTCGGCTATGACATCGGT qPCR Slc2a2_Reverse GTTAATGGCAGCTTTCCGGTC qPCR Slc30A8_Forward AGCTTCCTGTGTTTCCTAGGCCAT qPCR Slc30A8_Reverse AATCTATTCCGACGGCTGCCTCAT qPCR MafA_Forward CCTGTAGAGGAAGCCGAGGAA qPCR MafA_Reverse CCTCCCCCAGTCGAGTATAGC qPCR Pdx1_Forward CGGCTGAGCAAGCTAAGGTT qPCR Pdx1_Reverse TGGAAGAAGCGCTCTCTTTGA qPCR Nkx6.1_Forward CCTCTGGCCCGAACTCTGA qPCR Nkx6.1_Reverse GCTGCCACCGCTCGATT qPCR Gucy1a3_Forward CCATCCTGCAGCTGGGTAAC qPCR Gucy1a3_Reverse CGTCCTGTGAAATCTTCCAGCC qPCR Gucy1b3_Forward GTGAGTGGCTTGCCAGAACC qPCR Gucy1b3_Reverse CTGTGGTTTCTGTCCTGCTTGTG qPCR Scg3_Forward CCGGCTCTTGGATACTGGTGTTG qPCR Scg3_Reverse ATCTTGTCTGCCTCTGCCTCAGCG qPCR Creg1_Forward CCACAATAAAGGAGGTGCGCG qPCR Creg1_Reverse GCGTAGCCTCTGGATTTTCCTGC qPCR G6PC2_Forward ACCTGGTCCTTTCTGTGGAGTGTT qPCR G6PC2_Reverse TTCAAAGGCCTCGGCTACTAGCAT qPCR GAPDH_Forward AACTTTGGCATTGTGGAAGG qPCR GAPDH_Reverse GGATGCAGGGATGATGTTCT qPCR 18s_Forward AGTCCCTGCCCTTTGTACACA qPCR 18s_Reverse GATCCGAGGGCCTCACTAAAC qPCR

Ins2_ChIP_Forward CCCCTGGACTTTGCTGTTT ChIP-qPCR Ins2_ChIP_Reverse GCCATCTGCTGACCTACCC ChIP-qPCR Nkx6.1_enhancer_ChIP_Forward CTGTTAGGTTTAGACACCACGC ChIP-qPCR Nkx6.1_enhancer_ChIP_Reverse CCCTTCACCATCTTTCCGTCTCC ChIP-qPCR Beta-actin_ChIP_Forward AAAGCCGTATTAGGTCCATCTTGA ChIP-qPCR Beta-actin_ChIP_Reverse GGCCATTGAGGCGTGATC ChIP-qPCR Page 59 of 125 Diabetes

Log fold-change: βDKO Gene symbol Source Species p-value (FDR) vs. Control Lactbl1 UCSC Mus musculus -10.60362187 1.91E-15 Slc26a3 UCSC Mus musculus -10.21698794 3.92E-06 Slc14a2 UCSC Mus musculus -10.21167795 1.42E-15 Aldob UCSC Mus musculus -9.925742068 2.59E-18 Gm3772 UCSC Mus musculus -9.879299845 4.94E-14 Wdr86 UCSC Mus musculus -9.813074782 5.67E-12 S100a4 UCSC Mus musculus -9.690473893 8.04E-14 Trpm5 UCSC Mus musculus -9.413853859 4.98E-110 4931431B13Rik UCSC Mus musculus -9.171392515 1.07E-11 Pdlim4 UCSC Mus musculus -9.158627357 6.95E-06 Gm14085 UCSC Mus musculus -9.023921111 2.91E-10 Hr UCSC Mus musculus -9.018213296 9.75E-12 Spic UCSC Mus musculus -8.868918271 1.20E-14 Foxn1 UCSC Mus musculus -8.867122751 2.66E-11 Ugt1a6a UCSC Mus musculus -8.647474631 1.86E-19 Gm4791 UCSC Mus musculus -8.598501506 3.67E-11 S100a6 UCSC Mus musculus -8.462730554 2.38E-09 9430069I07Rik UCSC Mus musculus -8.456366797 6.52E-20 Gm19510 UCSC Mus musculus -8.39753241 1.37E-09 Angptl7 UCSC Mus musculus -8.352656098 6.64E-50 Tmem40 UCSC Mus musculus -8.213424436 5.46E-09 Fam71a UCSC Mus musculus -8.202479343 2.27E-08 Rbp3 UCSC Mus musculus -8.116978551 9.00E-09 Kirrel3 UCSC Mus musculus -8.001368721 2.62E-65 Mmp12 UCSC Mus musculus -7.980400379 3.44E-06 Cox6a2 UCSC Mus musculus -7.923394441 1.83E-39 Cxcl11 UCSC Mus musculus -7.917483161 1.18E-08 Adtrp UCSC Mus musculus -7.808839933 2.79E-07 Gbp11 UCSC Mus musculus -7.789399779 4.33E-35 Ffar1 UCSC Mus musculus -7.781628511 2.94E-115 Pbk UCSC Mus musculus -7.775552716 1.11E-18 Prr29 UCSC Mus musculus -7.758428838 2.28E-07 Kif18b UCSC Mus musculus -7.711311342 1.63E-07 Defb1 UCSC Mus musculus -7.695237931 4.55E-108 C030029H02Rik UCSC Mus musculus -7.683220143 1.08E-06 2200002J24Rik UCSC Mus musculus -7.66036291 6.04E-08 Gm4598 UCSC Mus musculus -7.597752043 2.21E-07 Serpina3i UCSC Mus musculus -7.58162884 1.66E-05 Ngfr UCSC Mus musculus -7.548970968 9.84E-15 Apob UCSC Mus musculus -7.516539211 8.20E-08 Gsdma UCSC Mus musculus -7.49054956 7.37E-68 Gbp3 UCSC Mus musculus -7.489087512 7.93E-07 Speer2 UCSC Mus musculus -7.480928905 1.86E-06 Adgre1 UCSC Mus musculus -7.450430369 1.98E-05 Gm4262 UCSC Mus musculus -7.447993885 1.53E-07 Hsd3b2 UCSC Mus musculus -7.42872399 3.05E-06 4930470P17Rik UCSC Mus musculus -7.404433821 1.14E-06 Lgals3 UCSC Mus musculus -7.386753268 2.73E-06 Hmmr UCSC Mus musculus -7.373506601 1.40E-12 T2 UCSC Mus musculus -7.311978121 4.04E-21 Bmpr1b UCSC Mus musculus -7.304551605 3.00E-06 Diabetes Page 60 of 125

Oas2 UCSC Mus musculus -7.260228871 2.37E-07 Endou UCSC Mus musculus -7.257652894 8.34E-05 4930404H11Rik UCSC Mus musculus -7.236547783 1.61E-05 5330411J11Rik UCSC Mus musculus -7.163876372 3.12E-07 1500017E21Rik UCSC Mus musculus -7.159610357 9.08E-09 Akr1d1 UCSC Mus musculus -7.142389282 3.86E-06 Krtap13-1 UCSC Mus musculus -7.13398796 8.68E-09 Mir344i UCSC Mus musculus -7.133457735 4.60E-06 Dppa1 UCSC Mus musculus -7.101974732 6.23E-06 Rptoros UCSC Mus musculus -7.090675977 9.35E-09 Plau UCSC Mus musculus -7.006960432 0.000110981 1700011H14Rik UCSC Mus musculus -7.00043339 2.64E-06 Krt80 UCSC Mus musculus -6.971349419 7.53E-20 Npy UCSC Mus musculus -6.939567159 1.40E-12 Cbs UCSC Mus musculus -6.930350119 3.70E-170 Itga2 UCSC Mus musculus -6.930006627 4.23E-08 Tmprss4 UCSC Mus musculus -6.9132894 4.99E-81 Platr26 UCSC Mus musculus -6.90746063 1.46E-05 Ntrk3 UCSC Mus musculus -6.888524236 3.30E-05 Pla1a UCSC Mus musculus -6.870674705 2.23E-06 Plcz1 UCSC Mus musculus -6.850341519 6.26E-08 Lgals9 UCSC Mus musculus -6.849186298 0.000559548 Cd72 UCSC Mus musculus -6.846427046 0.000539925 Ffar3 UCSC Mus musculus -6.836595743 5.05E-46 P2ry14 UCSC Mus musculus -6.809186784 4.25E-08 4930592I03Rik UCSC Mus musculus -6.804808107 2.42E-06 5830416P10Rik UCSC Mus musculus -6.79396334 0.000170007 Gm10768 UCSC Mus musculus -6.788560173 0.000135602 Cxcl2 UCSC Mus musculus -6.785479033 0.00013241 Col6a3 UCSC Mus musculus -6.779132236 1.43E-54 Lilrb4a UCSC Mus musculus -6.738133614 1.94E-05 Ggta1 UCSC Mus musculus -6.721533817 4.69E-05 Cfb UCSC Mus musculus -6.697626649 0.000761166 Meox1 UCSC Mus musculus -6.686820706 1.54E-52 Slc26a1 UCSC Mus musculus -6.67993477 0.001614011 Gm29684 UCSC Mus musculus -6.677269018 0.000134851 Slc12a1 UCSC Mus musculus -6.642260744 6.23E-05 Zp2 UCSC Mus musculus -6.627848791 1.01E-07 Gbp4 UCSC Mus musculus -6.624306388 9.07E-29 1700063D05Rik UCSC Mus musculus -6.590907193 0.000206194 Hcar2 UCSC Mus musculus -6.572786342 2.41E-22 Mpeg1 UCSC Mus musculus -6.554085342 1.07E-07 4933440M02Rik UCSC Mus musculus -6.535143974 4.95E-05 Gstm2 UCSC Mus musculus -6.516542879 1.55E-33 4933417E11Rik UCSC Mus musculus -6.493861884 8.48E-11 Nupr1 UCSC Mus musculus -6.483216907 2.83E-40 Ugt2b34 UCSC Mus musculus -6.449852642 1.22E-19 2210011C24Rik UCSC Mus musculus -6.443104741 1.60E-05 Fcer1g UCSC Mus musculus -6.420939245 6.77E-25 Cd93 UCSC Mus musculus -6.413477132 1.04E-27 Adh7 UCSC Mus musculus -6.40843912 0.0002078 Cib3 UCSC Mus musculus -6.390748137 1.54E-19 Casc5 UCSC Mus musculus -6.389846023 0.000107739 Page 61 of 125 Diabetes

Areg UCSC Mus musculus -6.382770228 0.00039992 Abca8a UCSC Mus musculus -6.371155572 0.000249227 Tubb6 UCSC Mus musculus -6.363840154 8.04E-11 Mroh2a UCSC Mus musculus -6.355581155 1.86E-07 Prdm14 UCSC Mus musculus -6.34373659 0.001278169 Hcar1 UCSC Mus musculus -6.341714673 9.48E-10 Prok1 UCSC Mus musculus -6.336334894 2.50E-18 Cym UCSC Mus musculus -6.330840195 6.63E-13 Slit1 UCSC Mus musculus -6.330774672 5.18E-06 Depdc1b UCSC Mus musculus -6.329679798 0.000596599 Chrna4 UCSC Mus musculus -6.328100694 0.000753238 Rasd1 UCSC Mus musculus -6.298562142 5.30E-171 Tlr12 UCSC Mus musculus -6.289295275 0.001018623 Olfr330 UCSC Mus musculus -6.286170024 0.000955566 Bub1 UCSC Mus musculus -6.27887747 7.04E-07 Fcgr3 UCSC Mus musculus -6.275371414 0.001313787 Aqp7 UCSC Mus musculus -6.269363432 4.26E-10 Emid1 UCSC Mus musculus -6.246437419 1.96E-32 Icam1 UCSC Mus musculus -6.24569404 0.000280481 BC024139 UCSC Mus musculus -6.240722202 0.000481148 Kcnk16 UCSC Mus musculus -6.235791518 2.00E-143 Gp9 UCSC Mus musculus -6.228698481 0.009854361 Cldn2 UCSC Mus musculus -6.218072665 2.27E-10 Gm6484 UCSC Mus musculus -6.21293922 1.18E-08 Gm572 UCSC Mus musculus -6.212327545 6.43E-159 Bcat1 UCSC Mus musculus -6.202418953 7.39E-05 Lhx6 UCSC Mus musculus -6.191130365 0.011054519 Trpm1 UCSC Mus musculus -6.187673101 4.80E-17 Ppp1r1b UCSC Mus musculus -6.163705416 0.011713033 Tgfbi UCSC Mus musculus -6.162015366 2.86E-14 Mx1 UCSC Mus musculus -6.144355932 0.001097702 Kcnj13 UCSC Mus musculus -6.110954321 0.001198364 Pif1 UCSC Mus musculus -6.105346804 0.000649184 Serpine1 UCSC Mus musculus -6.095037169 9.46E-05 Fcgr1 UCSC Mus musculus -6.093632629 0.0140902 C1qb UCSC Mus musculus -6.073458596 7.36E-09 Clec12b UCSC Mus musculus -6.07099558 7.35E-21 Pigr UCSC Mus musculus -6.066908768 1.54E-16 Pklr UCSC Mus musculus -6.062625349 9.01E-96 Serpina7 UCSC Mus musculus -6.045650729 1.07E-06 Serpina10 UCSC Mus musculus -6.029959146 4.04E-30 Gm11665 UCSC Mus musculus -6.028484763 0.00110827 Crybb1 UCSC Mus musculus -6.025934766 9.51E-06 Ly6g6d UCSC Mus musculus -6.001624154 0.01725232 Kcnf1 UCSC Mus musculus -5.994597388 1.15E-27 Slamf7 UCSC Mus musculus -5.988732559 0.002301634 Fcer2a UCSC Mus musculus -5.979560991 0.016204822 Lvrn UCSC Mus musculus -5.979154785 0.002445949 Sult1c2 UCSC Mus musculus -5.974018674 1.07E-17 E2f8 UCSC Mus musculus -5.96882744 1.46E-05 Lilr4b UCSC Mus musculus -5.963771661 0.003948292 Ces1d UCSC Mus musculus -5.961651495 0.000425122 Clec1b UCSC Mus musculus -5.953529811 0.000162076 Diabetes Page 62 of 125

Cxcl10 UCSC Mus musculus -5.938119152 3.34E-07 Tmem252 UCSC Mus musculus -5.935153208 0.007151897 Tchh UCSC Mus musculus -5.934127134 0.00340777 4831407H17Rik UCSC Mus musculus -5.93311279 0.002034002 Fam64a UCSC Mus musculus -5.925443221 7.68E-08 Pla2g2d UCSC Mus musculus -5.91990293 1.13E-17 Hils1 UCSC Mus musculus -5.919743983 0.000378387 Dnase2b UCSC Mus musculus -5.907809162 0.002799461 Gbp10 UCSC Mus musculus -5.90315712 0.000286531 Trem2 UCSC Mus musculus -5.89923509 0.008696845 Tyrobp UCSC Mus musculus -5.898197999 0.007037763 Slco1a6 UCSC Mus musculus -5.88493087 1.09E-05 9530053A07Rik UCSC Mus musculus -5.88127552 0.002365 Rnu12 UCSC Mus musculus -5.88127552 0.002365 Anln UCSC Mus musculus -5.862881558 2.61E-12 Arhgdib UCSC Mus musculus -5.859985647 0.003023754 Mki67 UCSC Mus musculus -5.843002051 1.53E-49 Mgst1 UCSC Mus musculus -5.838535259 5.28E-05 Csf3r UCSC Mus musculus -5.834619687 0.035555598 Mafa UCSC Mus musculus -5.834508335 0 Glipr1 UCSC Mus musculus -5.832409302 0.008251001 Cx3cr1 UCSC Mus musculus -5.821677684 0.007943805 Vcam1 UCSC Mus musculus -5.810600718 0.027910621 Glod5 UCSC Mus musculus -5.805045695 0.003706788 F13a1 UCSC Mus musculus -5.7903865 1.82E-07 Spon2 UCSC Mus musculus -5.788844242 4.85E-39 Gm5547 UCSC Mus musculus -5.777224738 0.000355167 Mab21l1 UCSC Mus musculus -5.771980084 0.006547904 Slc5a10 UCSC Mus musculus -5.771009091 2.28E-24 Rab17 UCSC Mus musculus -5.763142109 1.57E-05 Anxa2 UCSC Mus musculus -5.761237619 0.000176111 Hk2 UCSC Mus musculus -5.742698746 0.033255586 Vim UCSC Mus musculus -5.740219765 2.83E-05 Ms4a7 UCSC Mus musculus -5.739624832 0.001019369 Klra2 UCSC Mus musculus -5.737726188 0.02911027 9230117E06Rik UCSC Mus musculus -5.731356727 0.009185371 Ly86 UCSC Mus musculus -5.716736834 0.030662319 2810417H13Rik UCSC Mus musculus -5.711557192 4.02E-06 Fmo2 UCSC Mus musculus -5.711239156 1.75E-44 Slc2a2 UCSC Mus musculus -5.709387966 0 Unc13c UCSC Mus musculus -5.708159757 0.000836964 A930001C03Rik UCSC Mus musculus -5.686263185 0.001105893 Asb11 UCSC Mus musculus -5.676799381 2.90E-19 F2 UCSC Mus musculus -5.666251843 1.66E-05 Ube2c UCSC Mus musculus -5.652766876 2.48E-11 P2ry12 UCSC Mus musculus -5.640585711 2.03E-32 Esco2 UCSC Mus musculus -5.6359206 1.19E-06 Ugt1a9 UCSC Mus musculus -5.633758287 0.00945005 H2-Ea-ps UCSC Mus musculus -5.620762435 0.009644697 2310061N02Rik UCSC Mus musculus -5.608306136 0.015188522 Svopl UCSC Mus musculus -5.60582926 5.31E-09 1810008I18Rik UCSC Mus musculus -5.592942326 5.25E-63 Chp2 UCSC Mus musculus -5.586073282 1.27E-15 Page 63 of 125 Diabetes

Anxa13 UCSC Mus musculus -5.576763493 0.000907614 Tnfrsf26 UCSC Mus musculus -5.571598413 0.003634774 Anks4b UCSC Mus musculus -5.56999161 6.24E-82 S100a3 UCSC Mus musculus -5.56561921 0.041056032 Tshb UCSC Mus musculus -5.565364806 0.044298948 Gldc UCSC Mus musculus -5.557921621 9.74E-14 Rhod UCSC Mus musculus -5.557803676 0.004644452 AI427809 UCSC Mus musculus -5.55707556 5.46E-08 Ddit4l UCSC Mus musculus -5.55424453 1.30E-06 Rfx4 UCSC Mus musculus -5.53601306 0.012881471 Rxfp2 UCSC Mus musculus -5.531489797 6.13E-05 Igfbp4 UCSC Mus musculus -5.530027202 0.003041821 Dgkeos UCSC Mus musculus -5.51780526 0.001995192 Ccr5 UCSC Mus musculus -5.503581821 0.024418288 Aplnr UCSC Mus musculus -5.492117967 0.000326536 Fcna UCSC Mus musculus -5.488910437 0.0161005 Slc30a8 UCSC Mus musculus -5.481559132 0 Cd96 UCSC Mus musculus -5.474576811 2.85E-14 Gm10804 UCSC Mus musculus -5.474017459 0.015086132 Clec7a UCSC Mus musculus -5.433430484 0.031551743 C4bp UCSC Mus musculus -5.430573603 0.012865908 Hist1h3c UCSC Mus musculus -5.430189117 0.011492704 Aif1 UCSC Mus musculus -5.41186394 0.006872168 Fmo1 UCSC Mus musculus -5.408843772 2.10E-134 4921525O09Rik UCSC Mus musculus -5.40690232 3.19E-16 Tnf UCSC Mus musculus -5.404459816 0.000171777 Runx1 UCSC Mus musculus -5.394003213 0.000197823 Rgs1 UCSC Mus musculus -5.383073066 1.25E-06 Slc15a3 UCSC Mus musculus -5.370715035 0.002595112 Comp UCSC Mus musculus -5.369807911 0.025913707 Serpina3n UCSC Mus musculus -5.364293546 0.010750878 Otoa UCSC Mus musculus -5.35451198 2.23E-28 Itih1 UCSC Mus musculus -5.348990534 4.60E-09 Gm5936 UCSC Mus musculus -5.34127924 0.028803899 Aurkb UCSC Mus musculus -5.336558046 1.73E-08 Msln UCSC Mus musculus -5.335517106 1.20E-62 Dram1 UCSC Mus musculus -5.333392888 0.036574981 Cybb UCSC Mus musculus -5.331570122 0.00083318 Ifit1bl1 UCSC Mus musculus -5.330773942 0.029344523 D030025P21Rik UCSC Mus musculus -5.325211527 0.0158243 Cplx3 UCSC Mus musculus -5.324617535 0.026975601 C1qa UCSC Mus musculus -5.321857179 3.83E-110 Fgf1 UCSC Mus musculus -5.320113316 9.76E-10 Tmigd3 UCSC Mus musculus -5.316042354 6.04E-51 Cd79a UCSC Mus musculus -5.310604756 3.54E-30 Nlrc4 UCSC Mus musculus -5.29914499 0.004033403 5830473C10Rik UCSC Mus musculus -5.295398043 3.47E-06 Arhgap22 UCSC Mus musculus -5.295101046 0.003389239 Cngb3 UCSC Mus musculus -5.294036208 1.68E-05 Cilp UCSC Mus musculus -5.290593292 5.13E-21 Tmem207 UCSC Mus musculus -5.286123988 0.023411705 Lyve1 UCSC Mus musculus -5.28300393 5.38E-06 Dlgap5 UCSC Mus musculus -5.277488456 4.83E-08 Diabetes Page 64 of 125

4933432K03Rik UCSC Mus musculus -5.274766291 0.000379175 Top2a UCSC Mus musculus -5.271226868 1.45E-30 8030443G20Rik UCSC Mus musculus -5.268322786 0.030166814 Megf10 UCSC Mus musculus -5.262994569 0.000259825 Slc17a4 UCSC Mus musculus -5.262341992 2.25E-13 Rab7b UCSC Mus musculus -5.258217452 0.006728565 Acvrl1 UCSC Mus musculus -5.254337202 0.005180025 A930019D19Rik UCSC Mus musculus -5.253536167 1.91E-08 Igfals UCSC Mus musculus -5.248548654 1.25E-27 Smim6 UCSC Mus musculus -5.247635781 2.80E-13 Gstt3 UCSC Mus musculus -5.2284213 0.004271996 St6gal1 UCSC Mus musculus -5.227276519 3.59E-136 Folr1 UCSC Mus musculus -5.226408052 8.99E-39 Syndig1 UCSC Mus musculus -5.222469246 1.12E-18 Foxf1 UCSC Mus musculus -5.220055716 0.022355204 5530401A14Rik UCSC Mus musculus -5.207861837 1.69E-08 Sgca UCSC Mus musculus -5.202647567 0.005670297 Penk UCSC Mus musculus -5.195568886 5.99E-11 Cdk15 UCSC Mus musculus -5.194174015 3.82E-06 Pld4 UCSC Mus musculus -5.189819251 0.000664197 Irf5 UCSC Mus musculus -5.187472208 0.011462413 Gpbar1 UCSC Mus musculus -5.18652899 0.029790148 Fblim1 UCSC Mus musculus -5.168566078 0.029864657 D930007P13Rik UCSC Mus musculus -5.159970158 0.024443134 Scube2 UCSC Mus musculus -5.158705422 2.36E-21 2410021H03Rik UCSC Mus musculus -5.134702747 9.41E-11 1810011O10Rik UCSC Mus musculus -5.125093904 3.41E-15 Chil1 UCSC Mus musculus -5.122366637 0.004698524 Fam179a UCSC Mus musculus -5.119260251 8.72E-33 Col28a1 UCSC Mus musculus -5.11507065 8.77E-12 Sema4a UCSC Mus musculus -5.106633906 2.70E-149 Alb UCSC Mus musculus -5.106415649 0.033611088 1700016L21Rik UCSC Mus musculus -5.097080932 0.035830117 Itk UCSC Mus musculus -5.091370464 2.29E-13 Ucn3 UCSC Mus musculus -5.088034953 0 Ccnjl UCSC Mus musculus -5.084683415 0.004882474 Ano3 UCSC Mus musculus -5.082956782 0.000569042 B830017H08Rik UCSC Mus musculus -5.082561144 1.31E-170 Adam32 UCSC Mus musculus -5.082453398 6.34E-24 Col15a1 UCSC Mus musculus -5.082276232 0.03251474 Gast UCSC Mus musculus -5.079597343 0.008165345 Notch1 UCSC Mus musculus -5.069774267 2.45E-117 Gm4265 UCSC Mus musculus -5.0602495 0.037428328 Rph3a UCSC Mus musculus -5.059582865 9.86E-25 Tmem37 UCSC Mus musculus -5.056954442 0.003629163 Lcat UCSC Mus musculus -5.050279669 0.011382621 Dio1 UCSC Mus musculus -5.0227431 4.12E-22 Cldn11 UCSC Mus musculus -5.021820261 4.23E-05 Lrrc55 UCSC Mus musculus -5.020727596 1.07E-22 9530036O11Rik UCSC Mus musculus -5.018867008 0.038891537 A930031H19Rik UCSC Mus musculus -5.012825957 0.006278744 Il22 UCSC Mus musculus -4.983433327 0.04155709 Tnni3k UCSC Mus musculus -4.973594444 0.04144559 Page 65 of 125 Diabetes

Fxyd3 UCSC Mus musculus -4.965235388 2.04E-11 Th UCSC Mus musculus -4.962379394 9.30E-102 Vwa5b1 UCSC Mus musculus -4.955383307 2.37E-22 Gm12530 UCSC Mus musculus -4.953850339 0.046027188 Gm7616 UCSC Mus musculus -4.952283446 0.036636794 Ins1 UCSC Mus musculus -4.95122441 8.36E-126 Slco2b1 UCSC Mus musculus -4.946176041 0.014725939 1810007C17Rik UCSC Mus musculus -4.943627342 0.04413851 Ffar2 UCSC Mus musculus -4.937088618 2.94E-107 Melk UCSC Mus musculus -4.926241033 5.87E-06 Hck UCSC Mus musculus -4.924801092 0.048177258 Acot3 UCSC Mus musculus -4.923155342 0.049101014 A2m UCSC Mus musculus -4.913790112 0.013532293 C3ar1 UCSC Mus musculus -4.913788405 0.013523708 Tmem173 UCSC Mus musculus -4.912537471 0.048924131 Il1b UCSC Mus musculus -4.904660831 0.000119246 Plbd1 UCSC Mus musculus -4.902074595 0.042988537 Ankrd22 UCSC Mus musculus -4.891398841 0.042064655 Ccl3 UCSC Mus musculus -4.887851161 0.000485672 Hapln1 UCSC Mus musculus -4.883742811 7.30E-06 Parvb UCSC Mus musculus -4.881471499 8.03E-07 Cxcl1 UCSC Mus musculus -4.879405202 0.001296557 Adora3 UCSC Mus musculus -4.879094611 0.006059631 Ckap2l UCSC Mus musculus -4.87514512 2.56E-11 Gbp9 UCSC Mus musculus -4.870150857 1.48E-29 Mis18bp1 UCSC Mus musculus -4.845892294 4.01E-07 Foxq1 UCSC Mus musculus -4.84181587 0.021643916 Zan UCSC Mus musculus -4.841233459 1.09E-06 Xdh UCSC Mus musculus -4.840085997 7.84E-06 Msn UCSC Mus musculus -4.836338655 5.14E-07 Hmga2-ps1 UCSC Mus musculus -4.82396675 0.001079768 H2-Ab1 UCSC Mus musculus -4.801803583 3.80E-11 Car15 UCSC Mus musculus -4.750687345 3.28E-129 Mafb UCSC Mus musculus -4.7448266 2.28E-62 3425401B19Rik UCSC Mus musculus -4.740873171 4.84E-07 Trpv6 UCSC Mus musculus -4.739771407 0.028637348 Cyp4f39 UCSC Mus musculus -4.729090606 1.91E-29 Fbln5 UCSC Mus musculus -4.722200745 7.74E-05 Lrrc14b UCSC Mus musculus -4.718654788 2.56E-12 Pdyn UCSC Mus musculus -4.678054735 2.99E-06 Atf3 UCSC Mus musculus -4.674111418 1.52E-57 Tmem154 UCSC Mus musculus -4.653392916 5.36E-19 A630023P12Rik UCSC Mus musculus -4.65230838 0.020264467 Hgfac UCSC Mus musculus -4.644712036 4.12E-115 Slco5a1 UCSC Mus musculus -4.644406613 0.002958166 Pde4c UCSC Mus musculus -4.641109911 7.94E-62 6430562O15Rik UCSC Mus musculus -4.638820611 7.09E-10 2210019I11Rik UCSC Mus musculus -4.631079059 3.93E-104 Fibin UCSC Mus musculus -4.628346487 1.30E-07 Grip2 UCSC Mus musculus -4.625416661 0.000219951 Spon1 UCSC Mus musculus -4.623684769 2.40E-05 Glipr2 UCSC Mus musculus -4.614242907 1.70E-06 C1qc UCSC Mus musculus -4.614009855 1.49E-05 Diabetes Page 66 of 125

Tlr13 UCSC Mus musculus -4.612860347 0.027644401 2010107G12Rik UCSC Mus musculus -4.606165863 5.44E-20 Myo1g UCSC Mus musculus -4.600325305 0.020662563 Ndc80 UCSC Mus musculus -4.598742334 1.73E-08 Wfdc16 UCSC Mus musculus -4.596602794 8.15E-16 Ddc UCSC Mus musculus -4.595832829 7.31E-217 Grhl2 UCSC Mus musculus -4.593916663 0.02228706 Mgam UCSC Mus musculus -4.591519058 1.40E-05 Cd74 UCSC Mus musculus -4.580548813 3.24E-17 Sertm1 UCSC Mus musculus -4.580089462 1.39E-06 Gm10432 UCSC Mus musculus -4.579116699 1.29E-06 LOC105246506 UCSC Mus musculus -4.574942401 0.000606643 Lyz2 UCSC Mus musculus -4.573318831 1.61E-05 Wdfy4 UCSC Mus musculus -4.569429295 0.028514656 Acp5 UCSC Mus musculus -4.564626195 0.005674011 Dab2 UCSC Mus musculus -4.563179058 0.00531523 Neurl3 UCSC Mus musculus -4.562167294 4.15E-06 Sfrp5 UCSC Mus musculus -4.543782597 1.81E-12 Kcnab1 UCSC Mus musculus -4.539929305 0.014499659 Prss23 UCSC Mus musculus -4.517704507 2.58E-19 Mylk UCSC Mus musculus -4.5109612 1.88E-13 Nptx2 UCSC Mus musculus -4.509619935 2.93E-25 3930402G23Rik UCSC Mus musculus -4.504612672 5.89E-07 Gm5860 UCSC Mus musculus -4.50031831 7.54E-13 4933428C19Rik UCSC Mus musculus -4.487866344 1.12E-07 Rab37 UCSC Mus musculus -4.487576616 1.76E-78 Hspb8 UCSC Mus musculus -4.486826549 2.25E-15 Cuzd1 UCSC Mus musculus -4.480357334 0.028049409 Abcc2 UCSC Mus musculus -4.478333895 6.94E-07 Cebpa UCSC Mus musculus -4.478087494 4.08E-11 Gpx2 UCSC Mus musculus -4.47768974 7.39E-39 Slc6a19 UCSC Mus musculus -4.476953582 2.83E-10 Dpys UCSC Mus musculus -4.475808915 0.001225763 Krt19 UCSC Mus musculus -4.465115168 0.000123999 Rdh1 UCSC Mus musculus -4.462572556 2.40E-05 Adam19 UCSC Mus musculus -4.460813962 0.037420815 Gdf15 UCSC Mus musculus -4.459955607 5.36E-18 H2-Aa UCSC Mus musculus -4.442396474 8.37E-11 Barx2 UCSC Mus musculus -4.433885373 0.003092485 Aldh1a1 UCSC Mus musculus -4.420155553 0.0020989 E230013L22Rik UCSC Mus musculus -4.41752016 1.23E-16 Slc5a9 UCSC Mus musculus -4.41059299 3.11E-07 Ccdc141 UCSC Mus musculus -4.406009972 2.64E-16 Sult1d1 UCSC Mus musculus -4.40290199 1.56E-40 Tpx2 UCSC Mus musculus -4.398666815 1.88E-19 1-Mar UCSC Mus musculus -4.397511715 0.017493773 Cxcr4 UCSC Mus musculus -4.393984326 0.039922578 Rgs8 UCSC Mus musculus -4.384353122 0.000237555 Uox UCSC Mus musculus -4.382676636 1.75E-09 Hspa1b UCSC Mus musculus -4.379861863 1.99E-14 Cd53 UCSC Mus musculus -4.370263036 0.01270895 D630024D03Rik UCSC Mus musculus -4.367501305 1.98E-81 Kcnmb1 UCSC Mus musculus -4.357916249 5.82E-06 Page 67 of 125 Diabetes

Izumo1 UCSC Mus musculus -4.356051636 0.047512509 Gbp8 UCSC Mus musculus -4.354791347 7.73E-46 Bche UCSC Mus musculus -4.350008488 0.001351862 Cd300a UCSC Mus musculus -4.333564895 0.019963973 Stx11 UCSC Mus musculus -4.325572611 0.004919833 Tat UCSC Mus musculus -4.324354873 3.17E-44 Gm5640 UCSC Mus musculus -4.318684038 0.005849732 Iapp UCSC Mus musculus -4.315765109 1.21E-61 Adh1 UCSC Mus musculus -4.303979443 5.45E-13 Agt UCSC Mus musculus -4.30013051 2.27E-45 Ces5a UCSC Mus musculus -4.276128457 6.37E-08 Apof UCSC Mus musculus -4.275307605 0.001046777 Cartpt UCSC Mus musculus -4.263583275 1.66E-05 Rtn4r UCSC Mus musculus -4.245535249 0.003948292 Fam151a UCSC Mus musculus -4.233694153 9.72E-198 Srgn UCSC Mus musculus -4.230634989 0.003338744 Slc7a7 UCSC Mus musculus -4.226235643 2.48E-22 Gbp6 UCSC Mus musculus -4.219958754 3.56E-19 Gbp2 UCSC Mus musculus -4.197837492 4.68E-05 Kcnj4 UCSC Mus musculus -4.184341667 4.52E-05 Ctgf UCSC Mus musculus -4.175406295 0.0078505 Grm4 UCSC Mus musculus -4.172752664 0.002211682 Iqgap3 UCSC Mus musculus -4.165621891 6.91E-12 Gm15326 UCSC Mus musculus -4.156120607 5.11E-05 Ccnb1 UCSC Mus musculus -4.155241439 6.04E-14 C2cd4b UCSC Mus musculus -4.149185077 6.95E-112 Rerg UCSC Mus musculus -4.135755364 3.02E-26 Axl UCSC Mus musculus -4.123615455 4.27E-05 Ctss UCSC Mus musculus -4.1151398 1.81E-06 Edn2 UCSC Mus musculus -4.113491003 5.76E-09 9130230L23Rik UCSC Mus musculus -4.111534792 4.57E-14 Tph1 UCSC Mus musculus -4.069049966 4.16E-05 Il1a UCSC Mus musculus -4.058816 0.003278956 Depdc1a UCSC Mus musculus -4.047155654 0.013533617 Neil3 UCSC Mus musculus -4.036543054 1.50E-10 Plk5 UCSC Mus musculus -4.030503162 6.86E-07 Dtl UCSC Mus musculus -4.023707692 9.44E-08 Sparcl1 UCSC Mus musculus -4.020415755 0.000229507 Ccl4 UCSC Mus musculus -4.011657301 0.002890724 Kif2c UCSC Mus musculus -3.995031438 3.49E-05 Smtn UCSC Mus musculus -3.994747636 0.000211541 Chil6 UCSC Mus musculus -3.989230995 1.72E-09 Wnt4 UCSC Mus musculus -3.977724218 1.53E-94 5330439B14Rik UCSC Mus musculus -3.971473243 0.012026149 Itgax UCSC Mus musculus -3.97068908 0.011058808 Rprml UCSC Mus musculus -3.965478711 1.70E-07 Rdh9 UCSC Mus musculus -3.960619421 3.53E-07 Cp UCSC Mus musculus -3.955836954 0.001867215 Tnfsf10 UCSC Mus musculus -3.954993944 7.76E-15 Ska1 UCSC Mus musculus -3.945318959 0.002138616 Fmo4 UCSC Mus musculus -3.944708701 1.62E-30 Gm9767 UCSC Mus musculus -3.940034125 0.032559308 Hhatl UCSC Mus musculus -3.895103214 1.13E-05 Diabetes Page 68 of 125

Scnn1b UCSC Mus musculus -3.89414964 9.48E-152 Pcsk9 UCSC Mus musculus -3.890359641 5.55E-82 Adra2a UCSC Mus musculus -3.886227679 1.23E-265 Slc6a20a UCSC Mus musculus -3.885886832 7.49E-08 Cldn8 UCSC Mus musculus -3.885608113 5.75E-40 Pbld1 UCSC Mus musculus -3.882676901 1.20E-05 Ckb UCSC Mus musculus -3.877789772 4.42E-11 Tmem176b UCSC Mus musculus -3.872548546 1.13E-76 Avpr1b UCSC Mus musculus -3.87055251 0.003528273 Cyba UCSC Mus musculus -3.866598782 0.001446936 Spag5 UCSC Mus musculus -3.866122035 2.62E-13 Fbln7 UCSC Mus musculus -3.863516728 0.003014101 Gpr142 UCSC Mus musculus -3.860640348 2.81E-45 Csf2rb UCSC Mus musculus -3.860426736 2.67E-07 Plb1 UCSC Mus musculus -3.857778614 0.00784905 8430426J06Rik UCSC Mus musculus -3.855339385 0.00385081 Nuf2 UCSC Mus musculus -3.852997637 9.79E-09 Gipr UCSC Mus musculus -3.850307464 6.59E-94 AB124611 UCSC Mus musculus -3.835446087 0.011493825 Plxnb3 UCSC Mus musculus -3.832599629 0.028039442 Il1rn UCSC Mus musculus -3.824402974 0.048914655 Crym UCSC Mus musculus -3.82162589 0.008994089 BC089597 UCSC Mus musculus -3.821150347 1.83E-19 Adgrg6 UCSC Mus musculus -3.816699811 2.71E-27 Pappa UCSC Mus musculus -3.814448345 9.27E-07 Pcp4l1 UCSC Mus musculus -3.813801082 3.18E-09 Ccl28 UCSC Mus musculus -3.81115866 0.000162805 Rgs16 UCSC Mus musculus -3.806578313 2.31E-14 Shcbp1 UCSC Mus musculus -3.801370325 1.25E-05 4930550C14Rik UCSC Mus musculus -3.779577841 4.22E-25 Krtap17-1 UCSC Mus musculus -3.778859467 0.000288343 Proc UCSC Mus musculus -3.772397949 2.40E-09 Slfn8 UCSC Mus musculus -3.772344754 0.004130754 Pnma2 UCSC Mus musculus -3.771457722 4.27E-07 Sstr3 UCSC Mus musculus -3.767493698 1.07E-294 Clspn UCSC Mus musculus -3.767204064 1.34E-07 Kif4 UCSC Mus musculus -3.764538817 1.86E-05 Mycn UCSC Mus musculus -3.761128562 3.54E-07 Celsr1 UCSC Mus musculus -3.758631326 8.66E-32 Ccnb2 UCSC Mus musculus -3.751750576 4.21E-12 4931409K22Rik UCSC Mus musculus -3.743367 0.025957449 Espl1 UCSC Mus musculus -3.728188416 1.33E-12 Thbd UCSC Mus musculus -3.726593034 1.67E-35 Klf2 UCSC Mus musculus -3.725975955 7.34E-16 Mesp1 UCSC Mus musculus -3.724741601 6.24E-09 Ahnak UCSC Mus musculus -3.719783461 7.06E-07 Ttr UCSC Mus musculus -3.713780516 2.57E-57 Fam107a UCSC Mus musculus -3.709634611 6.23E-06 Gm19461 UCSC Mus musculus -3.705667033 1.32E-22 Capn9 UCSC Mus musculus -3.696039029 2.62E-24 Alox12b UCSC Mus musculus -3.692997229 0.040911873 Glis1 UCSC Mus musculus -3.692364142 5.06E-06 Hsd17b13 UCSC Mus musculus -3.685689269 0.003965115 Page 69 of 125 Diabetes

Pbxip1 UCSC Mus musculus -3.678222766 1.53E-87 Tldc2 UCSC Mus musculus -3.673640141 0.002944594 Rbm20 UCSC Mus musculus -3.672553551 5.08E-27 Prr5l UCSC Mus musculus -3.668558764 3.67E-05 Adm2 UCSC Mus musculus -3.65457552 9.82E-09 Apobr UCSC Mus musculus -3.647100187 0.01853867 Nusap1 UCSC Mus musculus -3.644517944 5.96E-09 Tmem140 UCSC Mus musculus -3.641182037 4.79E-17 Uba7 UCSC Mus musculus -3.64072021 4.86E-47 Insrr UCSC Mus musculus -3.636691755 1.61E-114 Fgfr2 UCSC Mus musculus -3.63106853 6.96E-05 Ncaph UCSC Mus musculus -3.620875201 2.39E-05 Gm5105 UCSC Mus musculus -3.618023283 1.16E-09 Uckl1os UCSC Mus musculus -3.616488478 1.18E-06 Scarf2 UCSC Mus musculus -3.613666458 1.25E-44 Trh UCSC Mus musculus -3.613273674 0.046424937 Ptger3 UCSC Mus musculus -3.611889593 1.04E-16 Hrh3 UCSC Mus musculus -3.610907026 0.012165306 Lif UCSC Mus musculus -3.608122526 0.046974148 Kcnj3 UCSC Mus musculus -3.594977344 0.000343656 Artn UCSC Mus musculus -3.592513589 1.53E-05 A430105I19Rik UCSC Mus musculus -3.576970321 1.88E-108 Ldha UCSC Mus musculus -3.576301284 0.023374539 Abcc3 UCSC Mus musculus -3.566608524 1.81E-07 Ska3 UCSC Mus musculus -3.56291449 0.000278132 Cdc25c UCSC Mus musculus -3.548106486 0.000794976 Tdo2 UCSC Mus musculus -3.536785788 8.63E-07 Col5a2 UCSC Mus musculus -3.528557982 5.50E-07 9630028I04Rik UCSC Mus musculus -3.510690418 3.45E-12 Lats2 UCSC Mus musculus -3.509035203 1.41E-06 Blnk UCSC Mus musculus -3.507189794 0.032326528 Sox11 UCSC Mus musculus -3.500726036 0.005388438 Laptm5 UCSC Mus musculus -3.495980719 8.48E-05 Fanca UCSC Mus musculus -3.494471007 8.60E-05 Crispld2 UCSC Mus musculus -3.470993321 0.000108906 Ppp1r1a UCSC Mus musculus -3.470174694 1.20E-193 Fstl1 UCSC Mus musculus -3.466990521 0.010768259 Oit1 UCSC Mus musculus -3.46435392 5.51E-08 S100z UCSC Mus musculus -3.45563452 3.50E-10 D17H6S56E-5 UCSC Mus musculus -3.452509457 2.48E-05 Cited4 UCSC Mus musculus -3.450274069 1.09E-46 Plaur UCSC Mus musculus -3.449299055 0.014360172 Vipr1 UCSC Mus musculus -3.437210751 6.07E-45 Dct UCSC Mus musculus -3.434715473 2.19E-22 G6pc2 UCSC Mus musculus -3.431155655 3.77E-219 Procr UCSC Mus musculus -3.430865626 0.002375739 Cldn4 UCSC Mus musculus -3.428958202 6.12E-23 Gpr183 UCSC Mus musculus -3.422696192 0.015119791 Cd14 UCSC Mus musculus -3.422459568 0.00272211 Hspa1a UCSC Mus musculus -3.413610779 3.69E-08 Fgfr3 UCSC Mus musculus -3.411204899 0.002094008 Hhipl1 UCSC Mus musculus -3.40608169 0.013990158 Fam163a UCSC Mus musculus -3.404749053 2.15E-25 Diabetes Page 70 of 125

Gem UCSC Mus musculus -3.400417785 4.31E-39 Selenbp1 UCSC Mus musculus -3.400145417 0.001259645 Adamtsl4 UCSC Mus musculus -3.399384731 1.24E-08 Rai14 UCSC Mus musculus -3.397281468 0.014360172 Plk1 UCSC Mus musculus -3.392066599 3.56E-12 Birc5 UCSC Mus musculus -3.391170221 7.72E-07 Pik3cg UCSC Mus musculus -3.386131256 7.36E-05 Mir6236 UCSC Mus musculus -3.378367141 1.17E-16 Fbxo40 UCSC Mus musculus -3.372223884 0.035994469 Cd83 UCSC Mus musculus -3.371699086 0.000160397 Trim34b UCSC Mus musculus -3.370683073 0.000756713 Adamtsl5 UCSC Mus musculus -3.369139239 0.026814082 Bik UCSC Mus musculus -3.361921189 2.34E-11 Ehf UCSC Mus musculus -3.358121166 3.09E-57 Glp1r UCSC Mus musculus -3.356757717 9.81E-93 Tmem176a UCSC Mus musculus -3.353272225 1.65E-35 Gadd45b UCSC Mus musculus -3.351873626 5.38E-43 Sh2d4b UCSC Mus musculus -3.347418185 0.022092655 Actc1 UCSC Mus musculus -3.346209433 0.015016743 Cpne5 UCSC Mus musculus -3.342546557 3.19E-05 Piwil4 UCSC Mus musculus -3.342150802 0.008381786 Angptl2 UCSC Mus musculus -3.333240068 0.01503846 Fbxw15 UCSC Mus musculus -3.329512571 1.19E-07 Cd36 UCSC Mus musculus -3.328930584 0.019156635 Cep55 UCSC Mus musculus -3.328334466 5.92E-06 Aldh1a3 UCSC Mus musculus -3.326068317 0.005121089 Gm2447 UCSC Mus musculus -3.321708091 1.31E-08 Adgrf1 UCSC Mus musculus -3.316113748 0.001766554 Strip2 UCSC Mus musculus -3.306253666 8.35E-09 Mcm3 UCSC Mus musculus -3.30488366 7.31E-09 Ltbp2 UCSC Mus musculus -3.304220564 1.11E-07 Stac2 UCSC Mus musculus -3.303261392 0.019642804 Irx1 UCSC Mus musculus -3.303244482 2.29E-07 Fkbp1b UCSC Mus musculus -3.302390748 5.83E-101 Epha2 UCSC Mus musculus -3.301988006 0.041222122 Inpp5d UCSC Mus musculus -3.2990921 0.044031236 Sapcd2 UCSC Mus musculus -3.296536856 5.85E-07 8430408G22Rik UCSC Mus musculus -3.295340411 1.33E-41 Hcls1 UCSC Mus musculus -3.28996685 0.004928537 Kcnj5 UCSC Mus musculus -3.288582558 2.12E-26 P2rx6 UCSC Mus musculus -3.285374029 0.011766498 Aspm UCSC Mus musculus -3.281806834 1.55E-05 Trim12c UCSC Mus musculus -3.28020663 2.19E-16 Aldh3b1 UCSC Mus musculus -3.267439996 7.94E-14 Lyn UCSC Mus musculus -3.267219144 9.15E-15 Fut1 UCSC Mus musculus -3.257021117 4.18E-07 Abcb1b UCSC Mus musculus -3.256402129 3.36E-05 Luzp2 UCSC Mus musculus -3.255648936 6.35E-05 Cldn15 UCSC Mus musculus -3.255290564 0.008418525 Chrnb4 UCSC Mus musculus -3.253730151 3.35E-05 Cxcl16 UCSC Mus musculus -3.253171407 2.29E-06 Rasl11a UCSC Mus musculus -3.251229483 0.002769301 H2-Eb1 UCSC Mus musculus -3.250736876 0.000169768 Page 71 of 125 Diabetes

S100a16 UCSC Mus musculus -3.250662654 0.03676898 Ppp1r3fos UCSC Mus musculus -3.24828146 0.000556607 Exo1 UCSC Mus musculus -3.244366605 0.003780217 Prc1 UCSC Mus musculus -3.240051239 4.57E-15 Tmed6 UCSC Mus musculus -3.233246966 3.17E-22 Ttk UCSC Mus musculus -3.225070267 0.00019343 Stc1 UCSC Mus musculus -3.22496398 0.007450982 Rhoj UCSC Mus musculus -3.222326198 0.004663029 Necab2 UCSC Mus musculus -3.221996382 2.86E-17 Cyp4f16 UCSC Mus musculus -3.220751653 1.42E-51 Cdc42ep1 UCSC Mus musculus -3.218007557 0.038315459 Gcg UCSC Mus musculus -3.208485066 5.86E-11 A1cf UCSC Mus musculus -3.207945817 2.78E-19 Hyal1 UCSC Mus musculus -3.206416185 4.61E-07 Crybb3 UCSC Mus musculus -3.196768979 0.002037398 Podxl UCSC Mus musculus -3.187566025 0.005992464 Mir7662 UCSC Mus musculus -3.18220044 0.024097608 Stab2 UCSC Mus musculus -3.174415175 2.07E-05 Gcnt4 UCSC Mus musculus -3.171442046 4.42E-06 Spats2l UCSC Mus musculus -3.169271377 0.000111998 Tgfb1 UCSC Mus musculus -3.160042252 0.038893899 Fam212b UCSC Mus musculus -3.156367705 1.17E-27 Scnn1g UCSC Mus musculus -3.153426509 6.17E-31 Tacr3 UCSC Mus musculus -3.150619715 0.009385753 1810041L15Rik UCSC Mus musculus -3.148749058 2.21E-17 BC002163 UCSC Mus musculus -3.146370691 0.003547657 Eya2 UCSC Mus musculus -3.143817388 0.014904983 Sstr2 UCSC Mus musculus -3.143001538 0.000331172 Mir3971 UCSC Mus musculus -3.141416319 0.034666263 Sez6l UCSC Mus musculus -3.139882285 2.09E-73 Cdc20 UCSC Mus musculus -3.137986638 5.46E-13 Tspan8 UCSC Mus musculus -3.135634382 5.83E-31 Rasl11b UCSC Mus musculus -3.132217686 9.48E-06 Sod3 UCSC Mus musculus -3.131084901 0.007831734 Iyd UCSC Mus musculus -3.13055709 0.00761567 Rab3b UCSC Mus musculus -3.129987385 2.76E-58 Ifit3 UCSC Mus musculus -3.127976745 0.007155176 Ceacam1 UCSC Mus musculus -3.125030607 3.86E-21 Thrsp UCSC Mus musculus -3.124079287 0.007265525 Adcy8 UCSC Mus musculus -3.11969614 0.047805901 Col4a2 UCSC Mus musculus -3.117269271 0.003626276 Kcnk13 UCSC Mus musculus -3.110387896 3.41E-06 Sgk1 UCSC Mus musculus -3.109601102 1.61E-07 Mgp UCSC Mus musculus -3.108135202 0.003799898 Atp10a UCSC Mus musculus -3.098115343 0.006351763 Lpar1 UCSC Mus musculus -3.097487922 9.75E-06 Rad51 UCSC Mus musculus -3.088776344 2.22E-07 D730005E14Rik UCSC Mus musculus -3.084862325 0.002146717 Ncf1 UCSC Mus musculus -3.068256763 0.004928537 Gm10637 UCSC Mus musculus -3.065387249 0.003425428 Lhfpl2 UCSC Mus musculus -3.065142725 0.006232093 Lrp8 UCSC Mus musculus -3.064095799 9.92E-42 Baiap3 UCSC Mus musculus -3.059159831 5.35E-11 Diabetes Page 72 of 125

Dok7 UCSC Mus musculus -3.054950392 0.001693607 Mcam UCSC Mus musculus -3.053997531 0.000526618 Hdc UCSC Mus musculus -3.050627582 5.16E-08 Metrnl UCSC Mus musculus -3.050496742 2.45E-06 Ppp1r3c UCSC Mus musculus -3.046238896 2.68E-10 Sucnr1 UCSC Mus musculus -3.044417785 0.009561902 1700024P16Rik UCSC Mus musculus -3.042644811 0.001928775 Arhgef39 UCSC Mus musculus -3.034272647 6.86E-05 Rph3al UCSC Mus musculus -3.029886759 1.16E-66 Mrln UCSC Mus musculus -3.024735268 1.06E-26 Nek2 UCSC Mus musculus -3.020757932 7.11E-12 Mecom UCSC Mus musculus -3.016938244 0.033227375 Rhobtb1 UCSC Mus musculus -3.011155382 2.08E-60 Rassf2 UCSC Mus musculus -3.008691296 3.66E-05 Arhgap27 UCSC Mus musculus -3.003512267 0.022778681 Chga UCSC Mus musculus -3.000362499 1.72E-83 Grhl1 UCSC Mus musculus -2.995263827 4.95E-19 Nckap5 UCSC Mus musculus -2.994494639 7.18E-12 Cabp7 UCSC Mus musculus -2.993366336 3.73E-62 Tmem106a UCSC Mus musculus -2.992456009 2.59E-25 Mlxipl UCSC Mus musculus -2.989694562 6.62E-47 Cd9 UCSC Mus musculus -2.986805609 2.83E-05 Ccdc42b UCSC Mus musculus -2.98620064 0.002951268 BC049715 UCSC Mus musculus -2.978703426 7.55E-05 Sgol2a UCSC Mus musculus -2.976846322 1.95E-05 Mslnl UCSC Mus musculus -2.971000212 0.000380851 Gm6377 UCSC Mus musculus -2.969793284 0.022289089 Barhl1 UCSC Mus musculus -2.966695516 0.005388438 Apobec4 UCSC Mus musculus -2.96417233 0.009295479 BC030867 UCSC Mus musculus -2.963091407 0.003645947 Xaf1 UCSC Mus musculus -2.96282885 1.10E-07 Ins2 UCSC Mus musculus -2.959269665 3.83E-55 Anpep UCSC Mus musculus -2.958035378 2.07E-50 Cyr61 UCSC Mus musculus -2.956931294 9.15E-06 Myof UCSC Mus musculus -2.953972887 0.000873423 Rdh12 UCSC Mus musculus -2.950174454 0.002398537 Gsdmd UCSC Mus musculus -2.945295272 2.97E-08 St3gal1 UCSC Mus musculus -2.941002891 7.38E-44 Gm5294 UCSC Mus musculus -2.934542106 2.20E-07 Col4a1 UCSC Mus musculus -2.932755272 8.23E-57 Nr1h4 UCSC Mus musculus -2.931699929 1.22E-33 Gstm1 UCSC Mus musculus -2.929636899 2.76E-57 Csmd2 UCSC Mus musculus -2.929501162 3.12E-15 Egln3 UCSC Mus musculus -2.928903431 0.018273221 Il6ra UCSC Mus musculus -2.927280068 7.93E-64 Arhgap28 UCSC Mus musculus -2.927217245 7.16E-10 Knstrn UCSC Mus musculus -2.924663319 4.73E-14 Vnn1 UCSC Mus musculus -2.916737773 0.040443514 Tmprss6 UCSC Mus musculus -2.914988095 0.000323939 Gm4814 UCSC Mus musculus -2.911801207 2.45E-05 Nbl1 UCSC Mus musculus -2.910663911 1.50E-16 Lars2 UCSC Mus musculus -2.910166139 2.39E-39 Kif22 UCSC Mus musculus -2.910146737 9.79E-09 Page 73 of 125 Diabetes

Cgnl1 UCSC Mus musculus -2.908818949 0.000292383 Abca9 UCSC Mus musculus -2.90851524 0.046162032 Gpr26 UCSC Mus musculus -2.908362107 1.12E-07 Vil1 UCSC Mus musculus -2.906577402 9.92E-116 Spns2 UCSC Mus musculus -2.902627869 0.000101745 Krtap16-1 UCSC Mus musculus -2.902527692 6.49E-06 Myo5c UCSC Mus musculus -2.900442822 0.005938745 Smim5 UCSC Mus musculus -2.900256681 0.007239921 Nr5a2 UCSC Mus musculus -2.895148221 0.015406248 Kif14 UCSC Mus musculus -2.893370057 0.001155605 Nrp1 UCSC Mus musculus -2.893236913 0.015660428 2900060B14Rik UCSC Mus musculus -2.888479285 0.040356317 Spp1 UCSC Mus musculus -2.888217242 0.003427753 Chst8 UCSC Mus musculus -2.887446233 0.009996879 1810019D21Rik UCSC Mus musculus -2.88683158 5.39E-22 B3gnt9 UCSC Mus musculus -2.883490778 3.30E-34 Vdr UCSC Mus musculus -2.872418242 6.86E-76 Gm16576 UCSC Mus musculus -2.864410546 0.008646446 Atp4a UCSC Mus musculus -2.862958632 6.53E-23 Ankle1 UCSC Mus musculus -2.861943154 0.000249137 Rasal3 UCSC Mus musculus -2.858276959 3.19E-05 Ddo UCSC Mus musculus -2.857815855 1.32E-29 Cyp2s1 UCSC Mus musculus -2.857371015 0.003987343 Ero1lb UCSC Mus musculus -2.848261791 4.20E-102 Slc18a1 UCSC Mus musculus -2.847380796 4.61E-52 Col27a1 UCSC Mus musculus -2.845801091 1.86E-21 Slc22a18 UCSC Mus musculus -2.840836419 0.00620556 Fam166a UCSC Mus musculus -2.84052451 8.07E-10 Gm15910 UCSC Mus musculus -2.835788569 0.000171526 Timp3 UCSC Mus musculus -2.834474855 0.023434147 Tnfrsf9 UCSC Mus musculus -2.832847503 3.29E-27 Mxd3 UCSC Mus musculus -2.832157887 0.000525465 Tmem71 UCSC Mus musculus -2.829298466 7.05E-23 Gadd45g UCSC Mus musculus -2.824790968 1.16E-89 Tmem150cos UCSC Mus musculus -2.824710083 0.000153668 Abc16 UCSC Mus musculus -2.822751512 6.05E-79 Slc28a2 UCSC Mus musculus -2.819184058 5.26E-06 Apoe UCSC Mus musculus -2.813627809 0.000822433 Emilin1 UCSC Mus musculus -2.813444643 3.00E-40 Fsbp UCSC Mus musculus -2.812596735 0.042097668 Cstad UCSC Mus musculus -2.811882574 0.005350726 Acyp2 UCSC Mus musculus -2.811002515 1.12E-30 Actn3 UCSC Mus musculus -2.808644341 2.43E-06 Ppy UCSC Mus musculus -2.806867715 2.29E-05 Klk1 UCSC Mus musculus -2.805288751 0.040360108 Sytl4 UCSC Mus musculus -2.800184067 2.11E-112 Spry1 UCSC Mus musculus -2.799485696 0.00281337 Micalcl UCSC Mus musculus -2.786547911 1.32E-15 Antxr1 UCSC Mus musculus -2.782845559 1.72E-08 Gm16702 UCSC Mus musculus -2.782387589 0.035784544 Prss53 UCSC Mus musculus -2.777198605 2.97E-148 Cecr6 UCSC Mus musculus -2.7765559 4.32E-12 Gc UCSC Mus musculus -2.767953819 1.32E-07 Diabetes Page 74 of 125

Cdca5 UCSC Mus musculus -2.760366513 0.000748723 Ppp1r17 UCSC Mus musculus -2.759680561 8.93E-05 Kcnj11 UCSC Mus musculus -2.737840291 1.41E-103 Pqlc3 UCSC Mus musculus -2.736805938 0.000171461 Stab1 UCSC Mus musculus -2.734405544 0.008448292 Igsf21 UCSC Mus musculus -2.734343214 6.61E-05 Ctsc UCSC Mus musculus -2.734148248 0.00291116 Trf UCSC Mus musculus -2.733818585 0.000156198 Nrros UCSC Mus musculus -2.732072502 0.002046228 Spink10 UCSC Mus musculus -2.729138168 0.034291422 Abca4 UCSC Mus musculus -2.727227629 1.80E-05 Hadh UCSC Mus musculus -2.726290333 5.52E-113 Lrtm2 UCSC Mus musculus -2.725321543 9.58E-05 Emp2 UCSC Mus musculus -2.719421043 0.000106587 St8sia5 UCSC Mus musculus -2.714255512 4.93E-22 2700099C18Rik UCSC Mus musculus -2.711370385 0.00173156 Gabrr2 UCSC Mus musculus -2.709317644 0.005473338 Reep6 UCSC Mus musculus -2.70816483 2.71E-64 Plxnd1 UCSC Mus musculus -2.707806325 0.044667705 Tns1 UCSC Mus musculus -2.706903945 0.001292242 Eva1b UCSC Mus musculus -2.703739317 1.46E-68 Hepacam2 UCSC Mus musculus -2.698644155 6.22E-52 Cdk1 UCSC Mus musculus -2.696056102 1.13E-06 Renbp UCSC Mus musculus -2.695196244 0.000812061 Egr3 UCSC Mus musculus -2.693551666 3.03E-12 4933427G17Rik UCSC Mus musculus -2.691091189 0.012448482 Rbp1 UCSC Mus musculus -2.687215422 0.001870003 Mxra7 UCSC Mus musculus -2.679529245 4.19E-15 Alpk1 UCSC Mus musculus -2.678699341 2.31E-05 Zc3h3 UCSC Mus musculus -2.676888616 8.20E-39 Ace2 UCSC Mus musculus -2.676072473 5.35E-19 Aox1 UCSC Mus musculus -2.675977086 1.33E-21 Lgi2 UCSC Mus musculus -2.674796145 6.82E-11 Plet1os UCSC Mus musculus -2.674231215 0.001832092 Edn3 UCSC Mus musculus -2.670294155 0.000736696 Gm11549 UCSC Mus musculus -2.669053065 0.001081204 Nipal1 UCSC Mus musculus -2.667844553 3.41E-30 Mtss1l UCSC Mus musculus -2.66565795 2.70E-32 Alpk3 UCSC Mus musculus -2.664841095 0.004026289 Sepp1 UCSC Mus musculus -2.66226443 5.31E-82 Hsbp1l1 UCSC Mus musculus -2.661435754 2.32E-15 Pycard UCSC Mus musculus -2.66011583 1.74E-14 Nostrin UCSC Mus musculus -2.659096337 2.10E-22 Colgalt2 UCSC Mus musculus -2.653414903 0.011632928 Neurl1b UCSC Mus musculus -2.653379359 2.97E-08 Tmem63a UCSC Mus musculus -2.652069823 1.70E-117 Tgfbr2 UCSC Mus musculus -2.651981155 0.023795393 Fam20a UCSC Mus musculus -2.650048424 1.58E-69 Dnph1 UCSC Mus musculus -2.64586604 3.34E-06 Slc28a3 UCSC Mus musculus -2.641865019 0.027333907 Cacna2d4 UCSC Mus musculus -2.638883598 0.006577066 Ccm2l UCSC Mus musculus -2.638463364 0.005355921 Apod UCSC Mus musculus -2.638223708 1.99E-05 Page 75 of 125 Diabetes

Troap UCSC Mus musculus -2.638193632 2.07E-05 Rgcc UCSC Mus musculus -2.634738908 4.97E-05 Plet1 UCSC Mus musculus -2.633434234 2.80E-09 Fanci UCSC Mus musculus -2.628391321 0.003471876 4930539E08Rik UCSC Mus musculus -2.627870827 2.01E-14 Acot12 UCSC Mus musculus -2.625938009 0.001223206 Fam83d UCSC Mus musculus -2.624359249 1.86E-06 Tmem215 UCSC Mus musculus -2.623147811 1.31E-170 Atp2a3 UCSC Mus musculus -2.62156528 2.97E-172 Lax1 UCSC Mus musculus -2.613211559 0.005471693 Neb UCSC Mus musculus -2.612506824 0.000208848 Pcdhgc3 UCSC Mus musculus -2.608123878 1.00E-48 Ambp UCSC Mus musculus -2.604074602 4.01E-26 Gabra4 UCSC Mus musculus -2.603790116 0.000103403 Cpne6 UCSC Mus musculus -2.600262495 0.005787633 Nkx6-2 UCSC Mus musculus -2.598793658 0.009111592 Kcna2 UCSC Mus musculus -2.594219042 3.84E-08 Oacyl UCSC Mus musculus -2.593624568 5.59E-05 Rgs5 UCSC Mus musculus -2.590972116 0.000847833 Cenpe UCSC Mus musculus -2.582222957 1.42E-09 Relt UCSC Mus musculus -2.580858653 7.10E-48 Fbxw24 UCSC Mus musculus -2.580502432 6.45E-10 Muc4 UCSC Mus musculus -2.57817407 2.95E-18 Adora1 UCSC Mus musculus -2.568115286 1.25E-19 Gpsm1 UCSC Mus musculus -2.566125144 2.36E-41 Fbp2 UCSC Mus musculus -2.558946851 0.011188805 Rnf39 UCSC Mus musculus -2.558046284 0.00166677 Slc38a4 UCSC Mus musculus -2.552938572 1.87E-95 Matn2 UCSC Mus musculus -2.552198038 1.41E-48 1700003M02Rik UCSC Mus musculus -2.551185126 0.028488394 Pdgfb UCSC Mus musculus -2.547171485 0.000274423 Tesc UCSC Mus musculus -2.544506637 1.65E-05 Lpl UCSC Mus musculus -2.540344551 7.50E-06 Trim12a UCSC Mus musculus -2.539303367 0.015201588 Fermt1 UCSC Mus musculus -2.537790309 4.71E-05 Tgm5 UCSC Mus musculus -2.535744292 3.77E-06 Cdhr2 UCSC Mus musculus -2.534044663 1.32E-06 Ttyh2 UCSC Mus musculus -2.53254725 3.33E-75 Papss2 UCSC Mus musculus -2.52992098 4.94E-170 Cybrd1 UCSC Mus musculus -2.52322319 0.033415598 Spc24 UCSC Mus musculus -2.522630858 3.79E-07 Cenpf UCSC Mus musculus -2.521007754 3.27E-09 4930523C07Rik UCSC Mus musculus -2.520771603 6.43E-05 Rad54b UCSC Mus musculus -2.517341253 0.00983508 Slc41a3 UCSC Mus musculus -2.511940364 3.87E-33 Pyy UCSC Mus musculus -2.511822873 1.89E-07 Nkain1 UCSC Mus musculus -2.50810501 9.28E-05 Rpph1 UCSC Mus musculus -2.506337628 0.000295455 Baz1a UCSC Mus musculus -2.504615691 2.47E-12 Rmi2 UCSC Mus musculus -2.503835421 0.001567916 Eppk1 UCSC Mus musculus -2.500592985 1.13E-05 Psrc1 UCSC Mus musculus -2.49442283 7.68E-06 Pappa2 UCSC Mus musculus -2.491009021 1.63E-10 Diabetes Page 76 of 125

Syndig1l UCSC Mus musculus -2.490662161 5.37E-113 Srbd1 UCSC Mus musculus -2.486113856 7.37E-37 C1qtnf1 UCSC Mus musculus -2.479796897 0.001567916 Lad1 UCSC Mus musculus -2.478081989 4.17E-10 Loxl2 UCSC Mus musculus -2.476949691 1.58E-18 Wfikkn2 UCSC Mus musculus -2.470692791 8.54E-05 Ier3 UCSC Mus musculus -2.467019492 1.44E-13 Fam110c UCSC Mus musculus -2.460763558 0.00908095 Gm19705 UCSC Mus musculus -2.45618374 0.024740186 Pld1 UCSC Mus musculus -2.453498101 2.76E-05 Jag1 UCSC Mus musculus -2.451638828 0.000472508 Hs3st6 UCSC Mus musculus -2.444872878 1.95E-26 Gp5 UCSC Mus musculus -2.444720259 3.05E-07 Sytl3 UCSC Mus musculus -2.436503084 0.003465996 Neat1 UCSC Mus musculus -2.432306718 5.61E-07 Sftpd UCSC Mus musculus -2.4311644 9.98E-06 Glul UCSC Mus musculus -2.430276193 1.26E-103 Tmsb4x UCSC Mus musculus -2.428545081 1.05E-60 Kcnmb2 UCSC Mus musculus -2.426384814 4.06E-56 Pld6 UCSC Mus musculus -2.422767452 1.25E-05 Slc16a6 UCSC Mus musculus -2.422361576 2.25E-36 Syt13 UCSC Mus musculus -2.421207356 2.87E-40 Spata13 UCSC Mus musculus -2.42067809 2.05E-18 Scara3 UCSC Mus musculus -2.416933841 0.015038851 Csf1r UCSC Mus musculus -2.412931513 0.015278423 Igf2 UCSC Mus musculus -2.41168903 1.66E-05 Btbd19 UCSC Mus musculus -2.411053662 1.26E-09 Cfap43 UCSC Mus musculus -2.40844322 0.005694038 Pde6c UCSC Mus musculus -2.408137185 0.017885132 Aurka UCSC Mus musculus -2.405905775 2.27E-06 Gpm6a UCSC Mus musculus -2.405244193 5.68E-10 Cblc UCSC Mus musculus -2.402722818 4.80E-17 Fzd1 UCSC Mus musculus -2.401666972 0.003393981 Ccdc13 UCSC Mus musculus -2.399958489 0.040356317 Phlda1 UCSC Mus musculus -2.394541151 1.87E-17 Ncapg UCSC Mus musculus -2.39337881 0.000279788 Medag UCSC Mus musculus -2.390820051 2.32E-11 Mfsd2a UCSC Mus musculus -2.388994413 0.016405368 Srpk3 UCSC Mus musculus -2.384459263 0.004400314 Esrp2 UCSC Mus musculus -2.382771377 1.95E-16 Msra UCSC Mus musculus -2.378397999 3.22E-24 Sorcs2 UCSC Mus musculus -2.377834508 1.59E-12 Gnmt UCSC Mus musculus -2.377315169 2.52E-08 Neurog3 UCSC Mus musculus -2.373843293 0.002781523 Npr1 UCSC Mus musculus -2.372825883 1.24E-15 Gria3 UCSC Mus musculus -2.371838851 9.60E-17 Ttc28 UCSC Mus musculus -2.362264848 3.84E-35 4930502A04Rik UCSC Mus musculus -2.36166598 1.24E-05 Shc4 UCSC Mus musculus -2.352404408 8.36E-09 Ndrg1 UCSC Mus musculus -2.347114527 4.76E-39 Rab20 UCSC Mus musculus -2.343305127 6.52E-16 Hunk UCSC Mus musculus -2.3428429 5.61E-05 Tenm4 UCSC Mus musculus -2.342114983 1.90E-05 Page 77 of 125 Diabetes

Mmp14 UCSC Mus musculus -2.341750138 0.011835158 Dhrs4 UCSC Mus musculus -2.341076778 1.20E-29 Wnt5b UCSC Mus musculus -2.339905234 6.56E-06 Col1a2 UCSC Mus musculus -2.339385198 0.043820373 Mctp2 UCSC Mus musculus -2.337304502 0.004271996 Rn45s UCSC Mus musculus -2.336386772 2.23E-18 Dlc1 UCSC Mus musculus -2.335514349 4.11E-09 2310022B05Rik UCSC Mus musculus -2.331580196 1.53E-36 Sgk2 UCSC Mus musculus -2.331524474 2.41E-11 Pcp4 UCSC Mus musculus -2.330853096 2.33E-06 Cdca3 UCSC Mus musculus -2.330405278 5.79E-05 Arx UCSC Mus musculus -2.326247881 0.00418474 Podn UCSC Mus musculus -2.326192921 0.036142068 Mb21d1 UCSC Mus musculus -2.325173369 0.008251001 Vegfa UCSC Mus musculus -2.321034157 2.29E-119 6030419C18Rik UCSC Mus musculus -2.319126476 1.62E-05 Ddit4 UCSC Mus musculus -2.318410503 1.94E-70 Strc UCSC Mus musculus -2.317590287 0.011829776 Slco1a5 UCSC Mus musculus -2.316164808 0.012300628 Degs1 UCSC Mus musculus -2.309301037 1.02E-41 Akr1b8 UCSC Mus musculus -2.305140463 0.008828294 Fam46c UCSC Mus musculus -2.304828647 2.29E-68 Mboat1 UCSC Mus musculus -2.302391792 0.005088818 Kif11 UCSC Mus musculus -2.302011365 7.11E-06 Cdc6 UCSC Mus musculus -2.301751141 0.00092351 Gpr182 UCSC Mus musculus -2.298262405 4.24E-08 Zfp750 UCSC Mus musculus -2.294193592 0.006493197 Scd1 UCSC Mus musculus -2.286665971 0.006974657 Enho UCSC Mus musculus -2.285340383 5.65E-29 Oas1g UCSC Mus musculus -2.285286368 0.000965057 Cyth4 UCSC Mus musculus -2.278941322 0.016738788 2810410L24Rik UCSC Mus musculus -2.276590691 1.47E-24 Ky UCSC Mus musculus -2.274128744 3.32E-68 Rhbdl2 UCSC Mus musculus -2.272313647 3.14E-17 H2-T10 UCSC Mus musculus -2.266348055 0.001773291 Kcnip2 UCSC Mus musculus -2.266006498 8.23E-09 Kcnn4 UCSC Mus musculus -2.262077162 0.00112005 Prdm1 UCSC Mus musculus -2.257568171 6.05E-06 Bmp6 UCSC Mus musculus -2.257371389 0.046873772 Car5b UCSC Mus musculus -2.257254716 1.73E-12 H2-Q5 UCSC Mus musculus -2.255658942 0.039056342 Aloxe3 UCSC Mus musculus -2.255516792 1.90E-05 Sorbs3 UCSC Mus musculus -2.252931914 7.72E-05 Kcnk3 UCSC Mus musculus -2.252652394 9.14E-05 Frem2 UCSC Mus musculus -2.251971076 0.000114441 Serinc5 UCSC Mus musculus -2.251925196 7.79E-63 Gm609 UCSC Mus musculus -2.244595272 2.82E-06 Lbh UCSC Mus musculus -2.243900132 1.45E-24 Mgarp UCSC Mus musculus -2.242535914 0.004686233 Chst11 UCSC Mus musculus -2.241414574 1.93E-35 Ifitm2 UCSC Mus musculus -2.239370503 1.15E-10 Gpr179 UCSC Mus musculus -2.238615527 1.09E-05 Pgf UCSC Mus musculus -2.238274179 4.27E-06 Diabetes Page 78 of 125

Galnt4 UCSC Mus musculus -2.23712398 3.25E-18 Degs2 UCSC Mus musculus -2.235815181 5.67E-07 Ppara UCSC Mus musculus -2.234970516 0.004402243 Dnajc22 UCSC Mus musculus -2.234238028 0.044800821 C8b UCSC Mus musculus -2.233346453 9.09E-11 Gbp5 UCSC Mus musculus -2.228589831 0.041850233 AI839979 UCSC Mus musculus -2.22637373 1.07E-07 Rad51ap1 UCSC Mus musculus -2.223913913 0.001333893 Phgdh UCSC Mus musculus -2.223895991 2.52E-12 Pole UCSC Mus musculus -2.221670046 3.01E-05 Ppp1r3b UCSC Mus musculus -2.221543887 0.010790769 Rnase4 UCSC Mus musculus -2.218024213 0.000283992 Egflam UCSC Mus musculus -2.217588452 0.041031829 Slfn9 UCSC Mus musculus -2.216209676 0.001413117 Ovol2 UCSC Mus musculus -2.215487879 9.44E-25 Relb UCSC Mus musculus -2.212134495 0.019547801 Pkdcc UCSC Mus musculus -2.209207811 4.33E-39 Efcab5 UCSC Mus musculus -2.206163639 0.005299545 Sparc UCSC Mus musculus -2.20470289 0.035010521 Hbegf UCSC Mus musculus -2.203892628 1.05E-12 Ier5 UCSC Mus musculus -2.20084982 1.42E-25 Crhr2 UCSC Mus musculus -2.196435143 0.005291148 Vstm2l UCSC Mus musculus -2.193719732 1.07E-57 Kcnc2 UCSC Mus musculus -2.192338872 0.00059125 Sntg2 UCSC Mus musculus -2.176482791 0.000431118 Prr15l UCSC Mus musculus -2.172539014 2.61E-19 Kynu UCSC Mus musculus -2.17178246 0.020030638 Mroh7 UCSC Mus musculus -2.170500175 6.73E-11 Esyt1 UCSC Mus musculus -2.168930704 8.54E-61 Gm10941 UCSC Mus musculus -2.161329545 2.29E-15 Usp18 UCSC Mus musculus -2.157948271 7.78E-43 Il17d UCSC Mus musculus -2.154023542 7.67E-10 Tcp11 UCSC Mus musculus -2.149133954 1.08E-11 Sec16b UCSC Mus musculus -2.147816862 2.55E-14 Cpa2 UCSC Mus musculus -2.147633254 5.90E-05 Smo UCSC Mus musculus -2.143145294 0.000323939 Guca1b UCSC Mus musculus -2.142447671 1.40E-05 Fosl1 UCSC Mus musculus -2.141475972 0.00336597 Gfra1 UCSC Mus musculus -2.141038713 0.000443502 Ceacam10 UCSC Mus musculus -2.140448343 1.38E-05 Tmem206 UCSC Mus musculus -2.139034755 1.08E-47 Sspn UCSC Mus musculus -2.138405754 7.66E-18 Acot4 UCSC Mus musculus -2.137748278 0.01258224 Boc UCSC Mus musculus -2.133128111 4.23E-05 Pde5a UCSC Mus musculus -2.131196925 6.34E-25 Ankrd33b UCSC Mus musculus -2.125111554 1.99E-19 Dlg2 UCSC Mus musculus -2.119218731 0.000394876 Esr1 UCSC Mus musculus -2.117850799 5.57E-15 Msrb3 UCSC Mus musculus -2.11740658 0.005683042 Slc25a29 UCSC Mus musculus -2.114849401 6.54E-29 Pcsk4 UCSC Mus musculus -2.112231234 2.56E-25 Tnfaip8l3 UCSC Mus musculus -2.111722575 0.018988035 Fgl2 UCSC Mus musculus -2.110876259 5.73E-40 Page 79 of 125 Diabetes

2610528J11Rik UCSC Mus musculus -2.101998363 2.00E-06 Trim34a UCSC Mus musculus -2.101816757 1.81E-06 Lrrc8c UCSC Mus musculus -2.099495873 4.21E-05 Adgrg1 UCSC Mus musculus -2.096471192 8.93E-83 Ucp2 UCSC Mus musculus -2.091189446 2.77E-98 Sapcd1 UCSC Mus musculus -2.087798714 0.007861947 Tmem27 UCSC Mus musculus -2.08217695 1.21E-23 Syt7 UCSC Mus musculus -2.081496061 5.41E-85 Slc38a5 UCSC Mus musculus -2.079316419 4.84E-06 Krt8 UCSC Mus musculus -2.079275833 9.75E-39 Ripply3 UCSC Mus musculus -2.076115345 2.43E-26 AI467606 UCSC Mus musculus -2.075618553 1.68E-17 Ust UCSC Mus musculus -2.072562143 2.44E-07 AI182371 UCSC Mus musculus -2.070193173 0.000107055 Gmnn UCSC Mus musculus -2.065866462 5.69E-10 Errfi1 UCSC Mus musculus -2.065256448 2.65E-26 Syt2 UCSC Mus musculus -2.064613535 1.31E-17 Fam135b UCSC Mus musculus -2.057546998 1.81E-12 Fam81a UCSC Mus musculus -2.054721917 0.004657188 Cdh22 UCSC Mus musculus -2.054335966 4.25E-12 Gm13003 UCSC Mus musculus -2.054303187 8.81E-06 Psat1 UCSC Mus musculus -2.053512815 6.74E-09 Myo18b UCSC Mus musculus -2.047692408 0.026670842 Stard8 UCSC Mus musculus -2.046397883 7.30E-06 Dact2 UCSC Mus musculus -2.042593751 7.60E-33 Baiap2l2 UCSC Mus musculus -2.041183856 0.004877812 Tgif1 UCSC Mus musculus -2.036906354 0.0364895 Chd5 UCSC Mus musculus -2.035271105 4.08E-07 Apcdd1 UCSC Mus musculus -2.034525343 0.00255395 Abca14 UCSC Mus musculus -2.034033544 5.29E-07 Adgrg3 UCSC Mus musculus -2.032663918 6.60E-05 Hpgds UCSC Mus musculus -2.032172245 8.82E-17 Trp53inp2 UCSC Mus musculus -2.032022951 1.46E-95 Cyp4v3 UCSC Mus musculus -2.030886493 4.46E-27 Galr1 UCSC Mus musculus -2.028732151 7.92E-18 Slc7a11 UCSC Mus musculus -2.023374084 0.036286971 Cacna1g UCSC Mus musculus -2.02112853 0.002916423 Alox5ap UCSC Mus musculus -2.018834087 6.68E-08 Atp2a2 UCSC Mus musculus -2.017425264 1.55E-53 Nr1i2 UCSC Mus musculus -2.016976503 0.003769816 Oprm1 UCSC Mus musculus -2.016896284 0.000658188 5930403L14Rik UCSC Mus musculus -2.015974761 0.002026406 Ttyh1 UCSC Mus musculus -2.015652543 6.46E-09 Gdf3 UCSC Mus musculus -2.015245314 0.003574741 Racgap1 UCSC Mus musculus -2.01388514 4.58E-40 D430019H16Rik UCSC Mus musculus -2.012800242 0.038655017 Tspan15 UCSC Mus musculus -2.010549603 1.74E-53 Pdk4 UCSC Mus musculus -2.007273011 0.001000992 5330413P13Rik UCSC Mus musculus -2.001343231 1.36E-06 Apoa2 UCSC Mus musculus -2.000773352 0.000542578 Mcm10 UCSC Mus musculus -2.000370493 0.005205338 Pxylp1 UCSC Mus musculus -1.997110815 1.60E-07 Rcbtb2 UCSC Mus musculus -1.996012228 5.66E-48 Diabetes Page 80 of 125

Cryl1 UCSC Mus musculus -1.995410212 1.58E-18 Gfra3 UCSC Mus musculus -1.988483492 2.34E-17 Rec8 UCSC Mus musculus -1.985278224 0.000556607 Pycr2 UCSC Mus musculus -1.982246458 2.47E-35 Prlr UCSC Mus musculus -1.975958758 1.96E-36 Pdzrn3 UCSC Mus musculus -1.969394384 8.16E-06 Rassf10 UCSC Mus musculus -1.965562263 8.30E-18 Kif20a UCSC Mus musculus -1.964123394 4.43E-07 Zdhhc23 UCSC Mus musculus -1.963120144 1.57E-10 Rbms3 UCSC Mus musculus -1.962723372 0.006258054 Cdx4 UCSC Mus musculus -1.960670623 0.001588638 Klb UCSC Mus musculus -1.95973976 2.23E-06 Slc37a4 UCSC Mus musculus -1.957102459 9.17E-56 Scgn UCSC Mus musculus -1.956450802 1.62E-29 Vangl1 UCSC Mus musculus -1.956185684 5.72E-09 Svil UCSC Mus musculus -1.9553033 9.95E-20 Aacs UCSC Mus musculus -1.953160108 1.84E-27 F5 UCSC Mus musculus -1.952412324 0.001081204 Capn8 UCSC Mus musculus -1.949647247 0.033075609 Tspan12 UCSC Mus musculus -1.949149977 0.015122736 Kntc1 UCSC Mus musculus -1.948725652 1.93E-08 Galr3 UCSC Mus musculus -1.945081435 5.04E-21 Spock1 UCSC Mus musculus -1.944737992 1.66E-18 Eldr UCSC Mus musculus -1.942304388 7.99E-05 Grtp1 UCSC Mus musculus -1.941660005 4.05E-20 Galnt9 UCSC Mus musculus -1.939850303 1.26E-07 Ociad2 UCSC Mus musculus -1.937730343 2.56E-52 Kif15 UCSC Mus musculus -1.930664069 0.008573916 Mtfr2 UCSC Mus musculus -1.928712121 0.011214933 Lrrc10b UCSC Mus musculus -1.927639844 4.00E-26 Calhm2 UCSC Mus musculus -1.92560168 0.001589134 Prr15 UCSC Mus musculus -1.9255714 0.002432357 Atp2b4 UCSC Mus musculus -1.923436057 4.02E-14 Dact1 UCSC Mus musculus -1.921479085 3.57E-28 Maob UCSC Mus musculus -1.919515548 2.13E-112 1700110K17Rik UCSC Mus musculus -1.918960546 2.86E-07 4930404N11Rik UCSC Mus musculus -1.918264083 0.041881582 Vav3 UCSC Mus musculus -1.916827563 0.01437754 Gdap2 UCSC Mus musculus -1.916755298 1.03E-26 Fam129a UCSC Mus musculus -1.916754631 6.30E-10 Dpp4 UCSC Mus musculus -1.913514318 6.94E-08 Wipi1 UCSC Mus musculus -1.91286425 3.84E-26 Gtse1 UCSC Mus musculus -1.911769312 0.00039636 Itga6 UCSC Mus musculus -1.908705834 5.43E-16 Ccdc69 UCSC Mus musculus -1.907268993 0.03596263 Pkhd1 UCSC Mus musculus -1.903530713 4.33E-10 Gprc5a UCSC Mus musculus -1.900105247 0.034913252 Pde8b UCSC Mus musculus -1.898412129 3.84E-05 C2 UCSC Mus musculus -1.896212769 0.0112645 Uhrf1 UCSC Mus musculus -1.894570362 0.000511054 4930513N10Rik UCSC Mus musculus -1.890969337 0.034699734 Atf5 UCSC Mus musculus -1.88847287 5.94E-55 Eepd1 UCSC Mus musculus -1.887581613 4.29E-12 Page 81 of 125 Diabetes

Ly6h UCSC Mus musculus -1.878770184 0.004292387 Kcnh5 UCSC Mus musculus -1.875421075 0.016429431 Synpr UCSC Mus musculus -1.869272987 6.57E-28 Ltbr UCSC Mus musculus -1.869135987 1.71E-23 Tyro3 UCSC Mus musculus -1.86188119 0.011293443 Rad51ap2 UCSC Mus musculus -1.861817786 6.63E-08 Mpp3 UCSC Mus musculus -1.859121916 1.90E-16 Sez6 UCSC Mus musculus -1.854766677 0.010618264 Gpx3 UCSC Mus musculus -1.852541327 1.95E-13 Osgin1 UCSC Mus musculus -1.850201315 6.23E-15 Rbfox3 UCSC Mus musculus -1.849638023 0.009693776 Ache UCSC Mus musculus -1.848879589 0.000370718 Gpa33 UCSC Mus musculus -1.846902549 2.10E-08 Lrrc38 UCSC Mus musculus -1.84658788 0.032096141 Fam117a UCSC Mus musculus -1.846193826 3.70E-55 Gm8615 UCSC Mus musculus -1.845759075 0.001226224 4933432I09Rik UCSC Mus musculus -1.845166417 0.028010132 A230072E10Rik UCSC Mus musculus -1.844521913 0.000264654 Arid5a UCSC Mus musculus -1.844068859 4.86E-14 Fcgbp UCSC Mus musculus -1.843992651 0.028954994 Bco2 UCSC Mus musculus -1.841223677 0.000357655 Hhat UCSC Mus musculus -1.840355356 2.06E-13 Pyroxd2 UCSC Mus musculus -1.839064975 1.29E-08 Egf UCSC Mus musculus -1.837223876 2.96E-32 Fancd2 UCSC Mus musculus -1.836041721 0.024425913 Srgap1 UCSC Mus musculus -1.835626851 1.61E-11 Omp UCSC Mus musculus -1.834050557 0.008573916 Galnt18 UCSC Mus musculus -1.833812974 2.39E-11 Irak3 UCSC Mus musculus -1.833205879 0.010278661 Kif20b UCSC Mus musculus -1.831430653 2.76E-05 Cdkn1a UCSC Mus musculus -1.829222583 2.89E-14 Smim24 UCSC Mus musculus -1.822385905 3.60E-05 Glb1l2 UCSC Mus musculus -1.820467265 5.54E-26 Slc12a7 UCSC Mus musculus -1.818418874 1.18E-40 Slc16a12 UCSC Mus musculus -1.816021466 1.61E-55 Arpc1b UCSC Mus musculus -1.811701471 2.73E-14 Hpse UCSC Mus musculus -1.809254004 0.004947252 Npnt UCSC Mus musculus -1.809224689 1.85E-15 Erich6 UCSC Mus musculus -1.807912886 7.49E-06 Cyb5r3 UCSC Mus musculus -1.806845536 6.79E-69 AW822252 UCSC Mus musculus -1.805642101 9.73E-05 Cyb5b UCSC Mus musculus -1.80492877 6.57E-49 Agxt2 UCSC Mus musculus -1.803347374 4.03E-05 Fgfr1 UCSC Mus musculus -1.799269354 1.34E-11 Slc16a9 UCSC Mus musculus -1.796708868 1.07E-16 4930426D05Rik UCSC Mus musculus -1.794811075 0.026945609 Il17rc UCSC Mus musculus -1.794537373 1.98E-27 Lonrf3 UCSC Mus musculus -1.794078436 3.40E-09 Lmcd1 UCSC Mus musculus -1.792747745 0.012083729 Gng12 UCSC Mus musculus -1.788119883 1.71E-47 Tmem179 UCSC Mus musculus -1.787358944 0.041825502 Suox UCSC Mus musculus -1.786681855 9.28E-40 Acly UCSC Mus musculus -1.782816302 8.43E-89 Diabetes Page 82 of 125

Spsb1 UCSC Mus musculus -1.780157775 5.27E-08 Cytip UCSC Mus musculus -1.777565038 0.010467344 Fa2h UCSC Mus musculus -1.776473856 0.01446542 Rtp4 UCSC Mus musculus -1.772894699 3.49E-05 Tspan14 UCSC Mus musculus -1.772572076 3.02E-15 Lrrc18 UCSC Mus musculus -1.772121863 7.50E-07 Calb1 UCSC Mus musculus -1.769693113 1.62E-10 Rap1gap2 UCSC Mus musculus -1.768176459 4.07E-76 Lbp UCSC Mus musculus -1.767713617 0.030056641 Pid1 UCSC Mus musculus -1.766647215 1.78E-26 Adgrd1 UCSC Mus musculus -1.764919487 1.52E-05 Mfsd6l UCSC Mus musculus -1.764181838 4.93E-17 Clcf1 UCSC Mus musculus -1.762049528 0.04027964 Cx3cl1 UCSC Mus musculus -1.760954307 8.49E-06 Arg1 UCSC Mus musculus -1.759870151 8.29E-10 Slc22a23 UCSC Mus musculus -1.755845027 5.58E-29 Hcn4 UCSC Mus musculus -1.754928195 1.71E-09 AI463170 UCSC Mus musculus -1.753691615 0.000531022 C77080 UCSC Mus musculus -1.752559249 2.39E-40 Tnfrsf14 UCSC Mus musculus -1.750217527 0.002944594 3-Mar UCSC Mus musculus -1.747886907 2.16E-13 Tfrc UCSC Mus musculus -1.747458533 2.13E-46 B4galnt3 UCSC Mus musculus -1.746432548 0.023905751 Tmem229b UCSC Mus musculus -1.742883527 1.44E-43 Cntfr UCSC Mus musculus -1.740817674 1.98E-08 C920025E04Rik UCSC Mus musculus -1.740089261 0.040381858 Slc9a3r1 UCSC Mus musculus -1.737974638 5.20E-16 Gnai2 UCSC Mus musculus -1.732975016 2.44E-52 Spsb4 UCSC Mus musculus -1.732296764 0.009373281 Kazn UCSC Mus musculus -1.729755271 1.75E-15 Ehhadh UCSC Mus musculus -1.727941226 4.69E-20 Fam20c UCSC Mus musculus -1.725851021 4.75E-63 Mapkapk3 UCSC Mus musculus -1.724083466 9.07E-06 Sst UCSC Mus musculus -1.722822248 0.000122888 Mif4gd UCSC Mus musculus -1.721476489 2.70E-24 Map3k15 UCSC Mus musculus -1.720674525 4.50E-14 Pcx UCSC Mus musculus -1.718864661 5.68E-44 Kif19a UCSC Mus musculus -1.718183282 1.48E-36 Rrm2 UCSC Mus musculus -1.715697373 3.37E-07 Gale UCSC Mus musculus -1.711971105 8.12E-16 Kctd12 UCSC Mus musculus -1.706356078 7.15E-17 Itpkb UCSC Mus musculus -1.701950104 2.09E-26 9330182O14Rik UCSC Mus musculus -1.69838037 0.041647143 Abhd2 UCSC Mus musculus -1.687573463 4.17E-49 Ivd UCSC Mus musculus -1.687077636 4.93E-17 Tubb3 UCSC Mus musculus -1.687031466 4.35E-13 L1cam UCSC Mus musculus -1.686724468 3.60E-05 Fam43a UCSC Mus musculus -1.680495245 1.42E-08 Def6 UCSC Mus musculus -1.677093491 0.000134012 Ckap2 UCSC Mus musculus -1.675441692 0.000932232 Hpn UCSC Mus musculus -1.675088954 0.043317762 Tmod1 UCSC Mus musculus -1.673743528 1.49E-14 Txnip UCSC Mus musculus -1.671764696 3.98E-15 Page 83 of 125 Diabetes

Upb1 UCSC Mus musculus -1.671509981 6.59E-18 LOC100049077 UCSC Mus musculus -1.667966109 0.000866987 Sv2b UCSC Mus musculus -1.66455105 6.34E-06 Lix1 UCSC Mus musculus -1.656856941 0.036735303 Desi1 UCSC Mus musculus -1.655418974 1.31E-34 Nxph1 UCSC Mus musculus -1.653621122 0.018394675 Dach2 UCSC Mus musculus -1.651486375 0.006111083 Hpcal1 UCSC Mus musculus -1.651341638 2.89E-18 Tnfrsf22 UCSC Mus musculus -1.647411278 1.18E-07 Ggact UCSC Mus musculus -1.646941984 3.39E-48 Scnn1a UCSC Mus musculus -1.645180008 0.000342858 Ybx2 UCSC Mus musculus -1.636758191 0.008042128 Wdr6 UCSC Mus musculus -1.636109378 8.02E-27 Eef1a2 UCSC Mus musculus -1.632952867 0.000135928 Itgb8 UCSC Mus musculus -1.630697667 0.000398013 Il20rb UCSC Mus musculus -1.630328324 0.003470942 Bst2 UCSC Mus musculus -1.626878771 0.009445105 9130023H24Rik UCSC Mus musculus -1.62298345 1.63E-17 Rcan2 UCSC Mus musculus -1.622615655 1.00E-30 Col19a1 UCSC Mus musculus -1.620320106 0.04277647 Grin2d UCSC Mus musculus -1.619970724 0.001907362 Fam129b UCSC Mus musculus -1.616829885 5.28E-42 Dnah8 UCSC Mus musculus -1.615438359 0.010075445 Mir1894 UCSC Mus musculus -1.613910576 0.049653115 Hopx UCSC Mus musculus -1.613316952 1.51E-38 Tnr UCSC Mus musculus -1.612353269 1.17E-08 Gm16712 UCSC Mus musculus -1.609688858 0.006340257 Slc43a2 UCSC Mus musculus -1.607734812 1.14E-40 Serpinh1 UCSC Mus musculus -1.607582257 1.79E-08 Orc6 UCSC Mus musculus -1.605998267 4.30E-16 Bco1 UCSC Mus musculus -1.603780838 1.04E-10 B3gnt3 UCSC Mus musculus -1.602816711 1.91E-22 Slc25a47 UCSC Mus musculus -1.594951536 0.009524089 Sqle UCSC Mus musculus -1.586448841 4.93E-51 Fam210b UCSC Mus musculus -1.585422356 3.20E-09 Pax6os1 UCSC Mus musculus -1.584705512 9.64E-12 Gstt2 UCSC Mus musculus -1.580610051 3.10E-09 Gm10433 UCSC Mus musculus -1.579898484 5.24E-08 Psd4 UCSC Mus musculus -1.578490957 5.42E-27 Cpxm2 UCSC Mus musculus -1.575412382 2.45E-06 Cd24a UCSC Mus musculus -1.57537157 3.01E-05 5330434G04Rik UCSC Mus musculus -1.572148985 7.75E-07 Gpr161 UCSC Mus musculus -1.571918031 2.22E-05 Ndufs2 UCSC Mus musculus -1.56998833 4.78E-13 Tacc2 UCSC Mus musculus -1.568263372 1.25E-10 Syt1 UCSC Mus musculus -1.567048535 0.000314166 Sftpa1 UCSC Mus musculus -1.566501858 0.015399935 Per2 UCSC Mus musculus -1.562955344 6.79E-10 Kifc1 UCSC Mus musculus -1.562442567 0.006578129 Tmem255a UCSC Mus musculus -1.561368498 1.67E-11 Fam83g UCSC Mus musculus -1.560535546 6.00E-15 Crlf1 UCSC Mus musculus -1.560143373 0.003764092 Cpne4 UCSC Mus musculus -1.559758322 0.000195756 Diabetes Page 84 of 125

Dnaic2 UCSC Mus musculus -1.559113005 2.93E-06 Sdc3 UCSC Mus musculus -1.557599951 1.55E-23 Ptpn18 UCSC Mus musculus -1.557193957 0.022229164 Sepsecs UCSC Mus musculus -1.557045981 4.39E-20 Gcgr UCSC Mus musculus -1.554808065 4.18E-12 Mcm5 UCSC Mus musculus -1.554027899 0.001941838 Bcl11a UCSC Mus musculus -1.553356873 0.006389033 Vgf UCSC Mus musculus -1.553335243 0.009261584 Hsbp1 UCSC Mus musculus -1.552877752 3.31E-14 Lrrc36 UCSC Mus musculus -1.55225284 2.53E-06 Dock1 UCSC Mus musculus -1.550920487 0.004962326 Pamr1 UCSC Mus musculus -1.550317256 7.81E-16 Neu2 UCSC Mus musculus -1.549807218 0.024279373 Slc12a4 UCSC Mus musculus -1.549540458 4.17E-10 Ctsh UCSC Mus musculus -1.548336652 0.000332867 Pnmal1 UCSC Mus musculus -1.54785512 1.79E-17 Smpd3 UCSC Mus musculus -1.546988911 3.38E-24 Crim1 UCSC Mus musculus -1.546179773 0.005922816 Chrm3 UCSC Mus musculus -1.542932667 1.05E-32 Adamts17 UCSC Mus musculus -1.542153527 1.41E-11 Lifr UCSC Mus musculus -1.541883853 5.35E-17 Lgals12 UCSC Mus musculus -1.541306289 6.43E-09 Bspry UCSC Mus musculus -1.540519819 2.05E-08 Llgl2 UCSC Mus musculus -1.539898865 2.27E-37 Mical2 UCSC Mus musculus -1.539617498 2.50E-11 Adpgk UCSC Mus musculus -1.539020609 3.37E-14 Pak3 UCSC Mus musculus -1.534656492 1.54E-08 Spock3 UCSC Mus musculus -1.534161927 0.043844469 Gm4925 UCSC Mus musculus -1.533039381 0.000686626 Ptgr1 UCSC Mus musculus -1.529658695 0.008438526 Vav2 UCSC Mus musculus -1.524729194 4.21E-09 1110017D15Rik UCSC Mus musculus -1.524216641 0.006598746 Foxm1 UCSC Mus musculus -1.523393235 3.31E-08 Chd7 UCSC Mus musculus -1.520958833 9.14E-18 Ccnd2 UCSC Mus musculus -1.520340785 1.15E-27 Trp53inp1 UCSC Mus musculus -1.51958175 1.62E-16 Ak5 UCSC Mus musculus -1.519291238 1.20E-07 Prkacb UCSC Mus musculus -1.51880399 2.09E-56 Lingo3 UCSC Mus musculus -1.518506386 0.002543126 Pla2g2f UCSC Mus musculus -1.517569358 1.32E-22 Cks2 UCSC Mus musculus -1.514295178 0.018313952 Zfp36l2 UCSC Mus musculus -1.513369056 4.19E-14 Kcnn3 UCSC Mus musculus -1.513351173 3.76E-09 Tgm2 UCSC Mus musculus -1.51141455 0.02932992 Mthfd1 UCSC Mus musculus -1.507012934 6.98E-60 B630019K06Rik UCSC Mus musculus -1.504943602 2.50E-40 Slc40a1 UCSC Mus musculus -1.504449303 4.93E-17 Nfkbiz UCSC Mus musculus -1.498439213 1.41E-18 Irx2 UCSC Mus musculus -1.498043842 5.55E-05 Shank2 UCSC Mus musculus -1.496713115 0.015182647 Tmem123 UCSC Mus musculus -1.494805548 1.84E-33 Ubash3b UCSC Mus musculus -1.494375612 4.84E-05 Enc1 UCSC Mus musculus -1.490031724 3.75E-10 Page 85 of 125 Diabetes

Ngef UCSC Mus musculus -1.487507257 0.001347598 Elmo1 UCSC Mus musculus -1.484342323 1.02E-10 Ninj1 UCSC Mus musculus -1.482495959 8.54E-20 Igfbp7 UCSC Mus musculus -1.481571897 5.66E-19 Nabp1 UCSC Mus musculus -1.480167548 4.76E-18 Ank UCSC Mus musculus -1.478906102 2.89E-50 Dcdc2a UCSC Mus musculus -1.478163935 1.55E-10 Peg13 UCSC Mus musculus -1.477918789 9.29E-38 Nuak2 UCSC Mus musculus -1.477539374 6.71E-22 Btbd11 UCSC Mus musculus -1.475893246 0.01846033 Agrn UCSC Mus musculus -1.475057791 6.27E-09 Stmn1 UCSC Mus musculus -1.473942906 0.000416044 Elovl5 UCSC Mus musculus -1.47380896 1.03E-39 Scg2 UCSC Mus musculus -1.47303509 4.65E-13 Bcl2l12 UCSC Mus musculus -1.472836775 0.038713526 Tcf19 UCSC Mus musculus -1.471404892 0.003908428 Sec31b UCSC Mus musculus -1.471360748 0.000320208 2010204K13Rik UCSC Mus musculus -1.47117151 0.000136499 Tmem97 UCSC Mus musculus -1.471153147 1.46E-11 Ect2 UCSC Mus musculus -1.4706329 0.00092351 Pitpnm2 UCSC Mus musculus -1.468733391 4.10E-20 Wbscr25 UCSC Mus musculus -1.467744534 0.02293742 Lsmem1 UCSC Mus musculus -1.466832563 0.000927354 Ghsr UCSC Mus musculus -1.466810928 0.040225246 Aoc2 UCSC Mus musculus -1.466678882 1.66E-06 Rnf180 UCSC Mus musculus -1.466514732 5.35E-06 Bace2 UCSC Mus musculus -1.466264956 9.71E-26 Ece1 UCSC Mus musculus -1.465632982 7.88E-55 Sytl1 UCSC Mus musculus -1.465506212 7.27E-28 Mest UCSC Mus musculus -1.462378792 0.000303575 Dock6 UCSC Mus musculus -1.459780798 3.39E-09 Cdca2 UCSC Mus musculus -1.454231388 0.022352092 Tmem8 UCSC Mus musculus -1.451466926 3.33E-24 Lgalsl UCSC Mus musculus -1.450080789 1.58E-33 Tbcd UCSC Mus musculus -1.449425301 6.31E-36 Gm5087 UCSC Mus musculus -1.447375707 0.035922314 Slc17a9 UCSC Mus musculus -1.446564904 4.39E-10 Eda2r UCSC Mus musculus -1.44641849 0.011245916 Fam107b UCSC Mus musculus -1.445864235 0.000132911 Msh5 UCSC Mus musculus -1.444711803 2.94E-05 Krt7 UCSC Mus musculus -1.443842567 1.41E-10 Krt18 UCSC Mus musculus -1.44241268 1.38E-21 Espnl UCSC Mus musculus -1.440031514 8.04E-05 Grem2 UCSC Mus musculus -1.439762704 1.03E-10 Cyp39a1 UCSC Mus musculus -1.439148039 0.000320201 Rpp25 UCSC Mus musculus -1.433952694 0.002759931 Mlph UCSC Mus musculus -1.431670291 1.86E-05 Abtb2 UCSC Mus musculus -1.431526475 1.45E-05 Tlr2 UCSC Mus musculus -1.428227931 4.55E-09 Cacna1h UCSC Mus musculus -1.424685994 0.00220547 Nkiras2 UCSC Mus musculus -1.42240147 1.60E-18 Slc5a1 UCSC Mus musculus -1.421880965 0.049101014 Frmd4b UCSC Mus musculus -1.417484302 1.89E-16 Diabetes Page 86 of 125

Klhl7 UCSC Mus musculus -1.415714772 3.29E-22 Dab1 UCSC Mus musculus -1.415166772 0.025398256 Klf5 UCSC Mus musculus -1.415100061 1.30E-13 Sh3d19 UCSC Mus musculus -1.41190424 2.87E-12 Rsad2 UCSC Mus musculus -1.41163422 1.55E-05 Palmd UCSC Mus musculus -1.411096052 0.006776052 Ndst4 UCSC Mus musculus -1.410644311 0.002469567 Akr1c13 UCSC Mus musculus -1.409167451 2.13E-23 1810034E14Rik UCSC Mus musculus -1.408939844 8.69E-06 Otof UCSC Mus musculus -1.408100785 0.041226238 Gm15706 UCSC Mus musculus -1.405226661 1.29E-12 Gatm UCSC Mus musculus -1.402875298 1.26E-15 Hist1h4j UCSC Mus musculus -1.402589117 0.000108991 Rab3d UCSC Mus musculus -1.401229916 4.69E-18 Nell1 UCSC Mus musculus -1.399594685 4.54E-16 Ttc22 UCSC Mus musculus -1.398294459 2.66E-10 Pag1 UCSC Mus musculus -1.394902699 5.54E-10 Shb UCSC Mus musculus -1.394361877 3.52E-15 Slc35f5 UCSC Mus musculus -1.39182908 2.62E-31 Dnaja4 UCSC Mus musculus -1.390973896 2.58E-26 Mctp1 UCSC Mus musculus -1.390069045 0.000464361 Echdc2 UCSC Mus musculus -1.38988614 4.70E-23 Tubb2a UCSC Mus musculus -1.389848933 9.18E-14 Cib1 UCSC Mus musculus -1.389828366 4.13E-10 Hells UCSC Mus musculus -1.389749209 0.012291858 Ezr UCSC Mus musculus -1.385298441 1.13E-13 Flrt1 UCSC Mus musculus -1.385035039 5.63E-06 Sh3pxd2a UCSC Mus musculus -1.384282455 1.80E-10 Kcnq4 UCSC Mus musculus -1.382895319 9.95E-07 Rhbdf1 UCSC Mus musculus -1.378972744 0.001477364 Trp53i11 UCSC Mus musculus -1.377825213 0.000107875 Tmem50b UCSC Mus musculus -1.37599926 9.70E-29 Wars UCSC Mus musculus -1.375712659 1.08E-12 B4galt5 UCSC Mus musculus -1.375652039 3.55E-22 Galnt14 UCSC Mus musculus -1.374768517 1.28E-29 Nav2 UCSC Mus musculus -1.374725476 2.36E-09 Dynlt1b UCSC Mus musculus -1.37119147 0.001212315 Fkbp5 UCSC Mus musculus -1.37100744 1.39E-09 Dapp1 UCSC Mus musculus -1.370561965 1.92E-05 Dusp5 UCSC Mus musculus -1.370407875 1.15E-12 Pole2 UCSC Mus musculus -1.368761899 0.035469811 Nfix UCSC Mus musculus -1.367232459 1.53E-06 Gch1 UCSC Mus musculus -1.367213833 1.51E-16 Zfp185 UCSC Mus musculus -1.366867357 0.036574336 Best3 UCSC Mus musculus -1.366480094 4.03E-05 Lamc2 UCSC Mus musculus -1.36500076 0.000109778 Slc6a15 UCSC Mus musculus -1.362352373 0.048991782 Coro2a UCSC Mus musculus -1.361141429 1.01E-07 Grin2c UCSC Mus musculus -1.358409893 5.69E-10 Gm12359 UCSC Mus musculus -1.357597694 0.02095347 Dok3 UCSC Mus musculus -1.353325066 0.010747729 Ptprk UCSC Mus musculus -1.348834157 0.005106838 Slc31a1 UCSC Mus musculus -1.347343819 1.84E-10 Page 87 of 125 Diabetes

Serpine2 UCSC Mus musculus -1.346906215 0.035679324 Dcbld1 UCSC Mus musculus -1.344285522 0.000592466 Jam2 UCSC Mus musculus -1.343374898 0.003334846 Abat UCSC Mus musculus -1.3430306 9.08E-37 Pfkfb3 UCSC Mus musculus -1.337161032 0.002920448 Trnp1 UCSC Mus musculus -1.335978886 6.91E-07 Zfp189 UCSC Mus musculus -1.335026266 0.000114736 Carhsp1 UCSC Mus musculus -1.334452113 2.26E-17 Map3k14 UCSC Mus musculus -1.333684896 2.64E-10 Tm6sf2 UCSC Mus musculus -1.333586538 0.007461399 D630023F18Rik UCSC Mus musculus -1.333411903 0.047646009 Pard6g UCSC Mus musculus -1.330957257 4.92E-07 Smim22 UCSC Mus musculus -1.329539065 1.03E-08 Paqr4 UCSC Mus musculus -1.327519112 0.023929197 Dgkg UCSC Mus musculus -1.32649258 2.48E-09 Fam183b UCSC Mus musculus -1.325076746 1.89E-11 Comt UCSC Mus musculus -1.324410704 4.03E-13 Nefh UCSC Mus musculus -1.321341019 7.23E-06 Ogdhl UCSC Mus musculus -1.320809349 4.77E-31 Fzd8 UCSC Mus musculus -1.318467852 2.99E-06 Cpm UCSC Mus musculus -1.318228903 1.57E-05 Slc30a7 UCSC Mus musculus -1.312500635 1.01E-12 Mkx UCSC Mus musculus -1.311905121 0.04144559 Nqo1 UCSC Mus musculus -1.310582577 0.000588881 Pbld2 UCSC Mus musculus -1.30916461 8.62E-08 Oxtr UCSC Mus musculus -1.308483504 0.002866595 Ntrk1 UCSC Mus musculus -1.308290214 0.002046194 Vasn UCSC Mus musculus -1.307942355 1.40E-09 Kcnab3 UCSC Mus musculus -1.307805905 7.08E-13 Sdcbp2 UCSC Mus musculus -1.30650631 1.06E-05 Myl7 UCSC Mus musculus -1.305781719 0.04240537 Phtf1os UCSC Mus musculus -1.302415348 0.03068014 Serinc2 UCSC Mus musculus -1.296778682 0.008896769 Edaradd UCSC Mus musculus -1.296404671 0.000500227 Sdk2 UCSC Mus musculus -1.292474362 2.72E-10 Ly96 UCSC Mus musculus -1.290840213 4.82E-05 Sulf2 UCSC Mus musculus -1.288772907 0.003201156 Opn3 UCSC Mus musculus -1.288760967 0.005595136 Hhex UCSC Mus musculus -1.288651362 0.002397997 Prdx3 UCSC Mus musculus -1.287336862 1.32E-30 Foxa3 UCSC Mus musculus -1.285294672 3.42E-08 Slc6a8 UCSC Mus musculus -1.285061752 4.40E-23 Ifngr2 UCSC Mus musculus -1.284730039 6.42E-05 Itpka UCSC Mus musculus -1.284335609 0.022417199 Tuft1 UCSC Mus musculus -1.279943597 1.27E-12 Coa3 UCSC Mus musculus -1.279887105 1.16E-24 Ntn3 UCSC Mus musculus -1.278207636 0.008741589 Pdia2 UCSC Mus musculus -1.276326546 0.033979552 Ager UCSC Mus musculus -1.275846327 0.005907249 Cdc14a UCSC Mus musculus -1.275769652 0.000358384 4833439L19Rik UCSC Mus musculus -1.273529867 5.79E-15 Glrx5 UCSC Mus musculus -1.272270798 1.85E-16 Dnajc24 UCSC Mus musculus -1.271144221 3.64E-14 Diabetes Page 88 of 125

Gstt1 UCSC Mus musculus -1.270665338 1.21E-08 Gad1 UCSC Mus musculus -1.264924596 6.34E-27 Ppap2b UCSC Mus musculus -1.263890706 2.42E-06 Shank3 UCSC Mus musculus -1.263545461 0.000386823 Gm20257 UCSC Mus musculus -1.263073648 4.05E-06 Garnl3 UCSC Mus musculus -1.260991596 0.001001347 Myrf UCSC Mus musculus -1.260978232 6.02E-06 Psmb8 UCSC Mus musculus -1.259063936 0.0003081 Myc UCSC Mus musculus -1.257921471 1.44E-11 Kcnj12 UCSC Mus musculus -1.257453314 0.000332605 Irs2 UCSC Mus musculus -1.25595411 1.77E-08 Cdo1 UCSC Mus musculus -1.255450721 0.00079437 Rras2 UCSC Mus musculus -1.255089458 5.14E-08 Armc5 UCSC Mus musculus -1.254186263 8.06E-21 Elovl2 UCSC Mus musculus -1.253205469 1.71E-08 Stard5 UCSC Mus musculus -1.252383537 6.95E-11 Tmem163 UCSC Mus musculus -1.250370251 4.20E-25 Dusp1 UCSC Mus musculus -1.247483535 1.22E-30 Rims3 UCSC Mus musculus -1.246838458 2.10E-11 Plk3 UCSC Mus musculus -1.244396432 4.78E-24 Hs6st1 UCSC Mus musculus -1.24059029 2.27E-22 Lppos UCSC Mus musculus -1.240219188 9.10E-10 Mthfd1l UCSC Mus musculus -1.237772365 1.37E-18 Slc25a44 UCSC Mus musculus -1.235843018 1.31E-34 Bzw1 UCSC Mus musculus -1.234131982 1.72E-25 Bcar1 UCSC Mus musculus -1.234110904 5.21E-34 Gstz1 UCSC Mus musculus -1.23064839 4.76E-18 Hnf4a UCSC Mus musculus -1.230615928 2.79E-12 Slc6a6 UCSC Mus musculus -1.229231198 9.08E-37 Dtx2 UCSC Mus musculus -1.228858876 4.06E-12 Gpd1 UCSC Mus musculus -1.225797233 3.96E-14 Gipc2 UCSC Mus musculus -1.225121967 0.027412664 Arhgap26 UCSC Mus musculus -1.224248796 2.67E-09 Sel1l3 UCSC Mus musculus -1.222576566 1.35E-06 Irf1 UCSC Mus musculus -1.221591755 9.97E-05 Tnfrsf1a UCSC Mus musculus -1.218979882 6.61E-12 Mapk3 UCSC Mus musculus -1.213187809 1.89E-28 Tha1 UCSC Mus musculus -1.21117597 9.07E-10 Cnn3 UCSC Mus musculus -1.210741354 7.25E-22 Il17re UCSC Mus musculus -1.209869144 9.00E-12 Eps8 UCSC Mus musculus -1.209224453 7.53E-14 Misp UCSC Mus musculus -1.20918944 0.003501895 Lhx1os UCSC Mus musculus -1.20716233 0.007067742 Igsf11 UCSC Mus musculus -1.206524082 0.00095209 Lhx1 UCSC Mus musculus -1.204319464 2.32E-07 Limd1 UCSC Mus musculus -1.203038413 5.94E-30 Gm4013 UCSC Mus musculus -1.202389272 0.000195927 Rab6a UCSC Mus musculus -1.202106481 1.61E-27 Gjd2 UCSC Mus musculus -1.201556663 2.71E-27 Fam19a1 UCSC Mus musculus -1.201412442 0.000478606 Klf15 UCSC Mus musculus -1.200166746 0.00084555 Sphkap UCSC Mus musculus -1.197405886 2.73E-14 Evpl UCSC Mus musculus -1.19534078 0.000124018 Page 89 of 125 Diabetes

Tex30 UCSC Mus musculus -1.194903675 2.19E-08 Slc26a11 UCSC Mus musculus -1.193881709 0.028049409 B3galnt1 UCSC Mus musculus -1.193575818 2.17E-23 Zfp809 UCSC Mus musculus -1.192914632 7.46E-12 Rhpn2 UCSC Mus musculus -1.189224801 3.48E-31 Gyltl1b UCSC Mus musculus -1.189165309 7.08E-14 Gata6 UCSC Mus musculus -1.18856073 5.38E-10 Nod1 UCSC Mus musculus -1.188559066 4.06E-24 Tubb4b UCSC Mus musculus -1.188364039 5.39E-09 Ccrn4l UCSC Mus musculus -1.188342458 1.90E-09 Cchcr1 UCSC Mus musculus -1.186848867 1.54E-07 Pcdh15 UCSC Mus musculus -1.186613343 0.002913788 Nedd9 UCSC Mus musculus -1.186068016 0.000331083 Actn2 UCSC Mus musculus -1.185266106 0.003113557 Lingo1 UCSC Mus musculus -1.18521653 5.33E-05 Btbd17 UCSC Mus musculus -1.1848108 8.39E-09 Dlk1 UCSC Mus musculus -1.184804425 0.048493526 Pitpnm3 UCSC Mus musculus -1.184090455 1.90E-12 Tcf24 UCSC Mus musculus -1.182338061 3.42E-05 Kcng3 UCSC Mus musculus -1.181765745 0.009820019 Birc3 UCSC Mus musculus -1.181660209 0.008455327 Tmem164 UCSC Mus musculus -1.18113552 1.08E-18 Zfp568 UCSC Mus musculus -1.179190358 2.03E-07 Rapgef3 UCSC Mus musculus -1.178623159 0.033357768 Lpcat3 UCSC Mus musculus -1.177404094 1.42E-18 1700018L02Rik UCSC Mus musculus -1.1743687 0.013669498 Tmem125 UCSC Mus musculus -1.174043487 0.016956758 D5Ertd579e UCSC Mus musculus -1.172329816 2.09E-09 Itpr3 UCSC Mus musculus -1.17208449 2.14E-07 Mettl7a1 UCSC Mus musculus -1.171564524 4.27E-05 Rab19 UCSC Mus musculus -1.171413724 0.000321834 Oasl2 UCSC Mus musculus -1.169324903 0.000531002 Ica1l UCSC Mus musculus -1.167070601 1.30E-06 Lefty1 UCSC Mus musculus -1.165188067 0.000606207 Arhgap11a UCSC Mus musculus -1.164390603 1.49E-06 Sdc4 UCSC Mus musculus -1.160717886 2.81E-08 6430548M08Rik UCSC Mus musculus -1.159867012 3.58E-15 4632428C04Rik UCSC Mus musculus -1.1591348 6.07E-09 Gpr39 UCSC Mus musculus -1.158775929 6.61E-05 Mnx1 UCSC Mus musculus -1.158377642 2.19E-08 Cald1 UCSC Mus musculus -1.157481393 0.000267652 Tor4a UCSC Mus musculus -1.156493145 6.43E-09 9-Sep UCSC Mus musculus -1.156201151 3.63E-13 Hmgn3 UCSC Mus musculus -1.155922442 2.29E-16 Enpp3 UCSC Mus musculus -1.154822288 0.031302897 Six4 UCSC Mus musculus -1.152592704 9.41E-09 Surf4 UCSC Mus musculus -1.15085783 6.04E-12 Mmd UCSC Mus musculus -1.150021909 2.38E-08 Coro2b UCSC Mus musculus -1.147104454 2.17E-31 Npepl1 UCSC Mus musculus -1.142173492 1.85E-14 Sall1 UCSC Mus musculus -1.141407281 0.000397242 Trim35 UCSC Mus musculus -1.140415962 2.18E-24 Prkcb UCSC Mus musculus -1.140324427 4.42E-09 Diabetes Page 90 of 125

Ak1 UCSC Mus musculus -1.139178633 5.81E-12 Tmtc3 UCSC Mus musculus -1.136969116 2.74E-10 Sowahc UCSC Mus musculus -1.136829441 2.02E-24 Mob3b UCSC Mus musculus -1.136069158 0.047740414 Caskin2 UCSC Mus musculus -1.135059168 5.68E-11 Fbxl16 UCSC Mus musculus -1.133748209 1.67E-19 Ddx31 UCSC Mus musculus -1.133454627 6.43E-11 Cmtm7 UCSC Mus musculus -1.133416318 0.044179019 Gins3 UCSC Mus musculus -1.130643505 0.012255258 B330016D10Rik UCSC Mus musculus -1.126631516 3.66E-09 Efnb3 UCSC Mus musculus -1.125986927 0.000154601 Wee1 UCSC Mus musculus -1.125358393 3.32E-05 Idh2 UCSC Mus musculus -1.124315201 1.73E-36 Slco2a1 UCSC Mus musculus -1.121499896 0.012723395 Pxt1 UCSC Mus musculus -1.116712137 0.02982542 Gm2518 UCSC Mus musculus -1.115546253 0.000144166 Serping1 UCSC Mus musculus -1.114644598 0.006625547 Fzd7 UCSC Mus musculus -1.114536027 1.94E-07 Tph2 UCSC Mus musculus -1.113955228 1.97E-12 Shc2 UCSC Mus musculus -1.113028961 2.23E-11 Cdkn2c UCSC Mus musculus -1.110567648 0.001589143 Btg1 UCSC Mus musculus -1.109708771 1.94E-18 Stk17b UCSC Mus musculus -1.109443178 0.034291422 Gck UCSC Mus musculus -1.107061565 3.93E-12 Synpo UCSC Mus musculus -1.105591749 2.75E-06 Slc7a8 UCSC Mus musculus -1.105406994 8.45E-08 Cerk UCSC Mus musculus -1.105108932 8.74E-28 Gm15612 UCSC Mus musculus -1.105063173 0.003595217 Gnai3 UCSC Mus musculus -1.104888285 1.70E-32 Fhdc1 UCSC Mus musculus -1.104152831 5.18E-20 Slc4a7 UCSC Mus musculus -1.103807948 1.40E-08 Catip UCSC Mus musculus -1.103444214 0.028692763 Akt1 UCSC Mus musculus -1.102612191 1.25E-19 Hdac6 UCSC Mus musculus -1.100647492 1.73E-09 Psmb10 UCSC Mus musculus -1.100455894 0.018752235 Hip1r UCSC Mus musculus -1.099718123 3.66E-24 1700029I15Rik UCSC Mus musculus -1.097316804 0.006571202 Thsd4 UCSC Mus musculus -1.096618911 0.000156798 Zbtb7c UCSC Mus musculus -1.095705807 0.001420586 Vps37b UCSC Mus musculus -1.095054895 4.38E-08 Ptprz1 UCSC Mus musculus -1.093797799 0.012014583 Lrrfip2 UCSC Mus musculus -1.093635543 4.71E-24 Ap5b1 UCSC Mus musculus -1.090763014 1.29E-05 Ano7 UCSC Mus musculus -1.090579485 0.002822889 Sar1b UCSC Mus musculus -1.089155996 8.09E-12 Fam110a UCSC Mus musculus -1.088893066 2.01E-11 Tigar UCSC Mus musculus -1.088195821 2.92E-22 Dnmt3b UCSC Mus musculus -1.08774648 2.55E-06 Rbks UCSC Mus musculus -1.087720552 0.00221134 Rtkn UCSC Mus musculus -1.086761157 0.005634817 Impdh1 UCSC Mus musculus -1.085149541 1.23E-23 Kcnq1 UCSC Mus musculus -1.085146607 0.018847445 2010111I01Rik UCSC Mus musculus -1.08494806 3.94E-14 Page 91 of 125 Diabetes

Dpm1 UCSC Mus musculus -1.084729539 0.007386201 Klhl32 UCSC Mus musculus -1.083831323 8.73E-24 Pole4 UCSC Mus musculus -1.083770877 4.19E-05 Gm12409 UCSC Mus musculus -1.083656322 0.020664133 Guca1a UCSC Mus musculus -1.082986205 0.025613707 Zbtb42 UCSC Mus musculus -1.08144411 0.000677248 Cldn6 UCSC Mus musculus -1.080813414 9.75E-05 Fhod3 UCSC Mus musculus -1.07965648 2.96E-10 Capn5 UCSC Mus musculus -1.077931799 3.48E-13 Grk5 UCSC Mus musculus -1.076936303 1.11E-09 Klf6 UCSC Mus musculus -1.075099353 2.56E-16 Hn1l UCSC Mus musculus -1.074669197 2.32E-13 Lacc1 UCSC Mus musculus -1.074194149 2.20E-07 E430025E21Rik UCSC Mus musculus -1.074030732 9.45E-12 Asic1 UCSC Mus musculus -1.073816354 3.44E-13 Ino80c UCSC Mus musculus -1.073409999 1.62E-08 Tmem243 UCSC Mus musculus -1.073078366 6.87E-08 Lmntd2 UCSC Mus musculus -1.072077365 2.45E-05 Dcx UCSC Mus musculus -1.071991717 6.12E-09 Disp2 UCSC Mus musculus -1.071548015 7.41E-15 Cenpn UCSC Mus musculus -1.069433661 0.027259726 Cryba2 UCSC Mus musculus -1.068241146 0.001337665 Tex264 UCSC Mus musculus -1.067795673 1.56E-09 Rangap1 UCSC Mus musculus -1.067000739 3.01E-13 Gas2 UCSC Mus musculus -1.064236299 8.25E-05 Irf7 UCSC Mus musculus -1.063791187 0.001789905 Skap1 UCSC Mus musculus -1.063514547 2.87E-14 Tsc22d1 UCSC Mus musculus -1.061760569 8.70E-18 Dhx32 UCSC Mus musculus -1.061152129 2.01E-20 Cdkn2b UCSC Mus musculus -1.06032354 1.29E-07 Ifi30 UCSC Mus musculus -1.05931625 3.21E-10 Nup93 UCSC Mus musculus -1.058752757 1.29E-14 Srebf1 UCSC Mus musculus -1.058536303 7.03E-14 Dmrtc1a UCSC Mus musculus -1.058307577 0.025154409 Zak UCSC Mus musculus -1.058135445 0.006205045 Col11a2 UCSC Mus musculus -1.055311266 0.000934348 Sptlc1 UCSC Mus musculus -1.054250742 3.09E-14 Kcnh1 UCSC Mus musculus -1.052227113 0.013957481 Ech1 UCSC Mus musculus -1.052013299 2.20E-14 Rpia UCSC Mus musculus -1.051593506 2.90E-11 Crot UCSC Mus musculus -1.050297765 1.36E-10 Crybg3 UCSC Mus musculus -1.050272972 0.000452401 Ppp1r3d UCSC Mus musculus -1.050086352 0.000112965 Rwdd4a UCSC Mus musculus -1.047376757 5.50E-11 Man1c1 UCSC Mus musculus -1.047260406 1.86E-08 Sfxn2 UCSC Mus musculus -1.04553092 7.04E-16 Olfm4 UCSC Mus musculus -1.044121405 0.000323164 Ccdc25 UCSC Mus musculus -1.042983336 1.41E-11 Rassf7 UCSC Mus musculus -1.042435508 2.37E-08 Mpz UCSC Mus musculus -1.041041405 0.000970338 Pcbp3 UCSC Mus musculus -1.040377979 2.03E-12 Ctxn1 UCSC Mus musculus -1.040173841 0.001163294 Atp7a UCSC Mus musculus -1.038934655 1.46E-06 Diabetes Page 92 of 125

Vapb UCSC Mus musculus -1.038878899 6.75E-23 Cenpa UCSC Mus musculus -1.038134751 0.005072424 Ppm1e UCSC Mus musculus -1.037110205 0.000156698 Fam120aos UCSC Mus musculus -1.03616176 3.75E-12 Pex26 UCSC Mus musculus -1.035914016 2.34E-13 Reep3 UCSC Mus musculus -1.034454408 3.67E-08 Cables2 UCSC Mus musculus -1.034367781 6.62E-10 Dcaf13 UCSC Mus musculus -1.034175165 5.00E-15 Tmem30b UCSC Mus musculus -1.033026484 2.86E-07 S100a11 UCSC Mus musculus -1.032994974 8.49E-09 Slco3a1 UCSC Mus musculus -1.030534195 0.000135986 Sirt7 UCSC Mus musculus -1.027452733 1.99E-13 Dennd2d UCSC Mus musculus -1.027179983 2.71E-08 Shisa2 UCSC Mus musculus -1.026788265 0.004157373 Arl8b UCSC Mus musculus -1.026255835 9.84E-21 Prkx UCSC Mus musculus -1.025899917 1.06E-08 Ctnnb1 UCSC Mus musculus -1.024402482 5.97E-24 Reep5 UCSC Mus musculus -1.024369852 1.76E-11 Specc1 UCSC Mus musculus -1.022714905 0.000453848 Zc3h10 UCSC Mus musculus -1.02198916 1.11E-15 Arhgef16 UCSC Mus musculus -1.021544946 1.58E-07 Dock10 UCSC Mus musculus -1.019065574 3.84E-06 Chst14 UCSC Mus musculus -1.018181143 0.006106351 Tnfrsf23 UCSC Mus musculus -1.018069612 3.71E-07 Nt5dc1 UCSC Mus musculus -1.017956372 7.37E-06 Fam105a UCSC Mus musculus -1.017336444 7.20E-09 Clic5 UCSC Mus musculus -1.013565988 0.001802274 Fitm2 UCSC Mus musculus -1.012816449 2.01E-07 Ing2 UCSC Mus musculus -1.012788838 7.68E-11 Wnk4 UCSC Mus musculus -1.012070408 4.02E-07 Smim20 UCSC Mus musculus -1.010280531 1.27E-11 Abhd13 UCSC Mus musculus -1.010251071 1.29E-14 Cmtm6 UCSC Mus musculus -1.01021519 1.84E-10 Jagn1 UCSC Mus musculus -1.007062827 8.03E-08 Creb3l1 UCSC Mus musculus -1.006817529 1.41E-09 Dlgap1 UCSC Mus musculus -1.006680412 0.001588913 Ifngr1 UCSC Mus musculus -1.005521817 2.34E-07 Triobp UCSC Mus musculus -1.005261006 1.91E-08 Tmem181b-ps UCSC Mus musculus -1.003713416 0.000536863 Gm11992 UCSC Mus musculus -1.003539252 0.008284637 Cyb5r4 UCSC Mus musculus -1.001724812 3.93E-08 S100a10 UCSC Mus musculus -1.001208888 3.33E-05 Rassf5 UCSC Mus musculus 1.00057821 0.02192969 Pigs UCSC Mus musculus 1.000956105 2.80E-17 Entpd3 UCSC Mus musculus 1.001293345 2.59E-18 Dennd4b UCSC Mus musculus 1.001623669 5.98E-06 Hist1h3d UCSC Mus musculus 1.001791956 0.009171023 Kifc3 UCSC Mus musculus 1.002179511 6.62E-14 Cdh4 UCSC Mus musculus 1.002375276 6.07E-12 Nedd1 UCSC Mus musculus 1.00280254 3.43E-08 Vangl2 UCSC Mus musculus 1.002963971 0.003717555 Myh10 UCSC Mus musculus 1.003653441 1.61E-07 Smim13 UCSC Mus musculus 1.004457239 2.64E-11 Page 93 of 125 Diabetes

Fdxr UCSC Mus musculus 1.004713877 4.87E-12 Zfp219 UCSC Mus musculus 1.005252927 1.30E-17 Klf12 UCSC Mus musculus 1.005253088 2.56E-05 Zfp296 UCSC Mus musculus 1.005473115 0.022400809 Npas2 UCSC Mus musculus 1.005872928 9.08E-06 H1fx UCSC Mus musculus 1.006306054 1.24E-07 Ldhd UCSC Mus musculus 1.007191647 2.85E-16 Syn3 UCSC Mus musculus 1.007301145 0.002130667 Fgd4 UCSC Mus musculus 1.00743255 2.37E-07 Pde4d UCSC Mus musculus 1.008844476 4.78E-06 Wdr60 UCSC Mus musculus 1.009248306 5.31E-08 Dner UCSC Mus musculus 1.009370209 5.90E-05 Tpgs2 UCSC Mus musculus 1.009450358 4.04E-10 Neurod1 UCSC Mus musculus 1.009653694 1.29E-14 Serpini1 UCSC Mus musculus 1.010360709 8.87E-08 Lca5 UCSC Mus musculus 1.011041078 1.32E-05 Mypop UCSC Mus musculus 1.011605105 4.49E-21 Ift140 UCSC Mus musculus 1.011984635 4.72E-08 Sesn3 UCSC Mus musculus 1.012062669 6.80E-19 Lamc1 UCSC Mus musculus 1.012804056 1.61E-05 Shisa4 UCSC Mus musculus 1.01307639 0.048991782 Ccdc134 UCSC Mus musculus 1.013393325 6.87E-14 9530077C05Rik UCSC Mus musculus 1.014108742 1.21E-08 Kif17 UCSC Mus musculus 1.014309999 0.006910128 Tmem121 UCSC Mus musculus 1.014558764 1.65E-05 Gpc4 UCSC Mus musculus 1.014573194 1.88E-14 Dmxl2 UCSC Mus musculus 1.01462604 3.21E-08 Wasf3 UCSC Mus musculus 1.016856145 1.91E-06 Sema3e UCSC Mus musculus 1.018160309 0.005756563 Zfp811 UCSC Mus musculus 1.018570331 0.028418234 Atp8b1 UCSC Mus musculus 1.019613101 3.83E-15 Sfxn5 UCSC Mus musculus 1.020803019 7.58E-05 Sdsl UCSC Mus musculus 1.020940329 2.29E-09 Dgka UCSC Mus musculus 1.021233271 4.74E-09 Pds5b UCSC Mus musculus 1.021656641 1.13E-11 Pfkm UCSC Mus musculus 1.021812746 2.68E-23 Nek3 UCSC Mus musculus 1.022011215 3.88E-08 Fkbp14 UCSC Mus musculus 1.022364168 3.06E-06 Zmym1 UCSC Mus musculus 1.023612378 1.23E-10 Rbp4 UCSC Mus musculus 1.023652467 1.13E-19 Ophn1 UCSC Mus musculus 1.024063292 1.24E-09 Fnbp1l UCSC Mus musculus 1.024992465 2.46E-10 Clybl UCSC Mus musculus 1.025771654 0.001105893 Ddx25 UCSC Mus musculus 1.026443724 1.31E-13 Nomo1 UCSC Mus musculus 1.026526696 1.44E-19 Slc27a1 UCSC Mus musculus 1.026959487 1.04E-09 Lrrc8b UCSC Mus musculus 1.027495085 0.002039789 Txndc16 UCSC Mus musculus 1.029045582 1.07E-11 Efcab12 UCSC Mus musculus 1.029446298 0.016018766 Rorc UCSC Mus musculus 1.02960043 5.16E-08 Vkorc1 UCSC Mus musculus 1.029601155 7.15E-15 Aqp4 UCSC Mus musculus 1.029836751 0.000148562 AW551984 UCSC Mus musculus 1.030797195 0.002154406 Diabetes Page 94 of 125

4930451G09Rik UCSC Mus musculus 1.032168985 1.84E-08 Syne1 UCSC Mus musculus 1.032508864 0.000203741 Hdac5 UCSC Mus musculus 1.032828443 2.73E-09 Ube2r2 UCSC Mus musculus 1.033869914 1.45E-26 Fam69b UCSC Mus musculus 1.03472876 6.10E-05 Park2 UCSC Mus musculus 1.035464686 8.02E-06 Zfp964 UCSC Mus musculus 1.035937204 0.028049409 Reck UCSC Mus musculus 1.03641126 0.000767867 Med12l UCSC Mus musculus 1.03865306 2.26E-08 Dusp26 UCSC Mus musculus 1.039831258 1.41E-05 Svop UCSC Mus musculus 1.041255905 6.57E-07 Pcdhb18 UCSC Mus musculus 1.043254875 6.44E-07 Dclk2 UCSC Mus musculus 1.044362627 2.19E-05 Clasp1 UCSC Mus musculus 1.044500279 2.69E-08 Ppm1k UCSC Mus musculus 1.044533095 1.36E-12 Mpp2 UCSC Mus musculus 1.044768986 1.53E-08 Atp1b1 UCSC Mus musculus 1.046449378 1.50E-15 Fam227a UCSC Mus musculus 1.047120351 3.29E-06 Pam UCSC Mus musculus 1.047342015 3.96E-17 Lcp1 UCSC Mus musculus 1.047496267 0.000664116 Tmed4 UCSC Mus musculus 1.047774711 3.12E-20 Prr12 UCSC Mus musculus 1.047801264 1.25E-06 Dlg4 UCSC Mus musculus 1.048822531 1.99E-15 Tctn1 UCSC Mus musculus 1.049270872 7.64E-13 Arhgef19 UCSC Mus musculus 1.050657236 0.015382144 Ralgps1 UCSC Mus musculus 1.051438408 1.07E-05 Ttc34 UCSC Mus musculus 1.052773242 0.009294355 Mfsd6 UCSC Mus musculus 1.054425722 6.33E-16 Lurap1 UCSC Mus musculus 1.055032495 9.14E-05 Nucb1 UCSC Mus musculus 1.05523121 4.47E-14 Igsf8 UCSC Mus musculus 1.055680252 5.81E-06 Pcsk1n UCSC Mus musculus 1.055857061 3.58E-07 Tusc3 UCSC Mus musculus 1.056478739 4.54E-17 Hexa UCSC Mus musculus 1.057191459 3.61E-10 Tspan6 UCSC Mus musculus 1.057291291 0.00500616 B230217O12Rik UCSC Mus musculus 1.057815582 0.004474863 Setd1b UCSC Mus musculus 1.058577665 6.21E-07 Syngr3 UCSC Mus musculus 1.058832856 0.006721305 Mast1 UCSC Mus musculus 1.059849107 0.001539157 Cep128 UCSC Mus musculus 1.060888151 0.004078763 Nlk UCSC Mus musculus 1.061402732 4.29E-18 Actl6b UCSC Mus musculus 1.062148072 7.75E-16 Dennd5b UCSC Mus musculus 1.062161821 1.23E-11 Nin UCSC Mus musculus 1.062956637 6.15E-09 Pcdhgb2 UCSC Mus musculus 1.064566103 0.004013702 Sp4 UCSC Mus musculus 1.065097251 2.97E-14 Usp27x UCSC Mus musculus 1.065533166 3.10E-05 2500002B13Rik UCSC Mus musculus 1.065925201 0.008810503 Lrrn1 UCSC Mus musculus 1.067487441 8.78E-10 Zbtb12 UCSC Mus musculus 1.068097979 2.84E-09 Arntl2 UCSC Mus musculus 1.068238581 0.027247529 Dusp14 UCSC Mus musculus 1.068524629 0.000380499 Fam221b UCSC Mus musculus 1.07014897 0.020842372 Page 95 of 125 Diabetes

Suv39h2 UCSC Mus musculus 1.07073085 0.000674409 Zfp703 UCSC Mus musculus 1.071803481 0.01083017 Fgd6 UCSC Mus musculus 1.072049432 7.53E-12 Emb UCSC Mus musculus 1.072071536 2.91E-06 Pcdhgb7 UCSC Mus musculus 1.072162435 0.009706697 Ncam1 UCSC Mus musculus 1.074153885 1.64E-09 Paqr9 UCSC Mus musculus 1.074392778 0.00010277 Gm16938 UCSC Mus musculus 1.074764352 0.000272687 Triqk UCSC Mus musculus 1.074984133 5.87E-12 Map3k12 UCSC Mus musculus 1.076188144 8.45E-23 Zbtb8b UCSC Mus musculus 1.076734179 0.026729677 Gprasp2 UCSC Mus musculus 1.076890298 5.40E-21 Grb14 UCSC Mus musculus 1.077150722 1.85E-09 Creld1 UCSC Mus musculus 1.077875978 7.79E-20 Ccdc103 UCSC Mus musculus 1.078012946 0.014720128 C030037D09Rik UCSC Mus musculus 1.079623793 0.000352164 Ulk4 UCSC Mus musculus 1.080218782 0.000608814 Lrrc24 UCSC Mus musculus 1.08118319 3.64E-06 Pcdhga3 UCSC Mus musculus 1.081572838 0.00298264 Mutyh UCSC Mus musculus 1.081654537 0.004159125 Fn3krp UCSC Mus musculus 1.082172515 2.39E-13 Ralgps2 UCSC Mus musculus 1.082730079 2.50E-11 Arid1a UCSC Mus musculus 1.084583995 3.73E-07 Snta1 UCSC Mus musculus 1.084641119 0.00022551 Fbxo31 UCSC Mus musculus 1.085192619 9.60E-12 Gpr157 UCSC Mus musculus 1.085839153 5.27E-07 Angptl6 UCSC Mus musculus 1.086346875 5.65E-06 Klhl5 UCSC Mus musculus 1.087402731 0.024698636 Sall2 UCSC Mus musculus 1.088616826 2.73E-07 Socs5 UCSC Mus musculus 1.089383298 4.22E-14 Fggy UCSC Mus musculus 1.090257392 5.68E-11 Gab3 UCSC Mus musculus 1.090362477 0.016122039 Nqo2 UCSC Mus musculus 1.091221789 2.43E-10 Tmem158 UCSC Mus musculus 1.091250645 0.000433017 Vmn2r29 UCSC Mus musculus 1.091579614 0.005187419 Tctn2 UCSC Mus musculus 1.09167129 5.16E-18 Prkaa2 UCSC Mus musculus 1.092248005 0.000106444 Gm10069 UCSC Mus musculus 1.093532361 5.79E-06 C920006O11Rik UCSC Mus musculus 1.09411926 3.21E-10 Gnptg UCSC Mus musculus 1.094276554 3.00E-23 Zfp239 UCSC Mus musculus 1.094278616 0.000527651 Plagl1 UCSC Mus musculus 1.094725947 4.21E-07 Gpc6 UCSC Mus musculus 1.095593824 0.001671617 Mir3960 UCSC Mus musculus 1.09595543 0.024590308 AA474331 UCSC Mus musculus 1.096288995 3.17E-06 Fam110b UCSC Mus musculus 1.097335215 2.65E-06 Snhg14 UCSC Mus musculus 1.097603653 1.22E-07 Pcdha2 UCSC Mus musculus 1.098409117 0.008419466 6430550D23Rik UCSC Mus musculus 1.098483159 0.027906338 Pcbp4 UCSC Mus musculus 1.099790836 2.24E-07 Ddx26b UCSC Mus musculus 1.099894312 8.66E-13 Wdr89 UCSC Mus musculus 1.100503384 0.001679644 Hnmt UCSC Mus musculus 1.103691501 1.27E-05 Diabetes Page 96 of 125

Sorl1 UCSC Mus musculus 1.105727559 7.31E-08 Ift172 UCSC Mus musculus 1.106041493 5.07E-09 Rnf32 UCSC Mus musculus 1.106150927 2.49E-10 Tmem67 UCSC Mus musculus 1.107400048 1.26E-11 Atp5l UCSC Mus musculus 1.108486777 1.13E-17 Ttll4 UCSC Mus musculus 1.109288166 6.07E-07 Lrriq3 UCSC Mus musculus 1.109839001 0.012204383 Tceal3 UCSC Mus musculus 1.110603383 7.20E-09 Tjp2 UCSC Mus musculus 1.110815618 5.95E-24 Ssc5d UCSC Mus musculus 1.11298264 0.001673961 Fam168a UCSC Mus musculus 1.113295383 1.36E-13 9230114K14Rik UCSC Mus musculus 1.113683363 0.007688184 Syt11 UCSC Mus musculus 1.11382755 3.05E-09 Per1 UCSC Mus musculus 1.114283219 0.019166215 Nbea UCSC Mus musculus 1.114389989 4.13E-10 Zfp947 UCSC Mus musculus 1.115175278 0.000147958 6720483E21Rik UCSC Mus musculus 1.115517427 0.026558207 Radil UCSC Mus musculus 1.115735114 0.004200052 9430065F17Rik UCSC Mus musculus 1.117587588 0.000467308 Lag3 UCSC Mus musculus 1.11774335 0.023325013 Erlec1 UCSC Mus musculus 1.118028179 6.80E-18 Srsf12 UCSC Mus musculus 1.118421774 0.00646342 Lins UCSC Mus musculus 1.118698248 5.40E-15 Tmem151b UCSC Mus musculus 1.119804894 0.015760034 Flna UCSC Mus musculus 1.121183289 5.81E-09 Klhl23 UCSC Mus musculus 1.124330061 0.000133324 Lhfpl5 UCSC Mus musculus 1.126258001 1.62E-08 Plekhb1 UCSC Mus musculus 1.12827935 1.37E-06 Cage1 UCSC Mus musculus 1.12977955 0.005623575 Zmat1 UCSC Mus musculus 1.131189142 2.05E-08 Csrnp1 UCSC Mus musculus 1.131550069 0.037907194 Crlf3 UCSC Mus musculus 1.132234036 2.50E-08 Cnp UCSC Mus musculus 1.132564492 2.46E-05 Pbx4 UCSC Mus musculus 1.132726871 0.004783577 Sh2d3c UCSC Mus musculus 1.133842129 1.41E-06 Xkr4 UCSC Mus musculus 1.13548128 1.61E-06 Itfg1 UCSC Mus musculus 1.135893373 3.19E-19 Smap2 UCSC Mus musculus 1.136417647 2.87E-34 Rnf208 UCSC Mus musculus 1.136590116 1.06E-05 Letm2 UCSC Mus musculus 1.136722616 3.84E-06 Fra10ac1 UCSC Mus musculus 1.13757974 4.69E-20 Tvp23a UCSC Mus musculus 1.138375245 6.74E-07 Prkcsh UCSC Mus musculus 1.139355748 2.07E-10 Atp10d UCSC Mus musculus 1.13993129 0.015719733 Tmem28 UCSC Mus musculus 1.141114009 1.96E-06 Plp2 UCSC Mus musculus 1.141282298 8.37E-11 Sipa1l2 UCSC Mus musculus 1.141565041 3.84E-05 Zyx UCSC Mus musculus 1.141811493 5.57E-06 Akap17b UCSC Mus musculus 1.142289902 5.86E-10 Cby1 UCSC Mus musculus 1.144492569 1.40E-10 Cntln UCSC Mus musculus 1.144699296 3.58E-07 Arhgef9 UCSC Mus musculus 1.144974685 7.13E-06 Zdhhc15 UCSC Mus musculus 1.145805813 0.000541193 Page 97 of 125 Diabetes

Dync2h1 UCSC Mus musculus 1.147155649 4.94E-07 Ddit3 UCSC Mus musculus 1.148124602 7.62E-06 Bcam UCSC Mus musculus 1.148946745 3.11E-08 Gpr85 UCSC Mus musculus 1.14937359 2.35E-11 Syt16 UCSC Mus musculus 1.150234116 0.000176237 Dpp7 UCSC Mus musculus 1.150878089 1.31E-09 Ddost UCSC Mus musculus 1.152403366 4.45E-19 Tmem132b UCSC Mus musculus 1.152520547 4.98E-22 Spa17 UCSC Mus musculus 1.15300563 9.76E-07 Pcyox1l UCSC Mus musculus 1.1555432 4.89E-07 Gys1 UCSC Mus musculus 1.156503394 1.03E-14 1810055G02Rik UCSC Mus musculus 1.160105684 6.90E-09 Skil UCSC Mus musculus 1.16071228 4.50E-11 Gltscr1l UCSC Mus musculus 1.16210041 7.81E-10 Nmb UCSC Mus musculus 1.163737926 0.032112279 Mfhas1 UCSC Mus musculus 1.165131901 7.08E-06 4933431E20Rik UCSC Mus musculus 1.165250422 2.53E-12 Pot1b UCSC Mus musculus 1.165808022 5.84E-05 Fut10 UCSC Mus musculus 1.166323357 2.34E-07 Ciart UCSC Mus musculus 1.166402549 0.008017659 Senp7 UCSC Mus musculus 1.167494056 9.55E-08 Ttc9 UCSC Mus musculus 1.167801568 7.53E-06 Athl1 UCSC Mus musculus 1.168471793 6.69E-12 Lyrm7 UCSC Mus musculus 1.168941554 0.000136238 App UCSC Mus musculus 1.169092496 1.63E-10 Gnpda2 UCSC Mus musculus 1.169848653 1.42E-16 Adam22 UCSC Mus musculus 1.170908133 2.46E-15 Brca2 UCSC Mus musculus 1.171273025 2.71E-05 Mbd4 UCSC Mus musculus 1.172333559 1.17E-05 Dnah2 UCSC Mus musculus 1.174378627 3.43E-05 Ap1s2 UCSC Mus musculus 1.174681632 3.69E-17 Ebpl UCSC Mus musculus 1.174854546 5.71E-06 Cd276 UCSC Mus musculus 1.175701052 3.92E-13 Scg5 UCSC Mus musculus 1.180474992 6.05E-08 Spats2 UCSC Mus musculus 1.181231923 2.73E-05 Spaca6 UCSC Mus musculus 1.181303161 3.52E-06 Ccdc30 UCSC Mus musculus 1.181541565 1.35E-13 Cdyl2 UCSC Mus musculus 1.181817956 1.24E-06 Ctps2 UCSC Mus musculus 1.182185546 1.09E-29 Ncstn UCSC Mus musculus 1.183000538 9.76E-20 6230400D17Rik UCSC Mus musculus 1.183099062 0.041081288 Gtdc1 UCSC Mus musculus 1.184423439 2.94E-06 Fbxo41 UCSC Mus musculus 1.18502297 1.83E-05 Uggt2 UCSC Mus musculus 1.18666866 2.33E-16 A730017C20Rik UCSC Mus musculus 1.186738255 0.001080304 A230057D06Rik UCSC Mus musculus 1.188818778 0.000148404 Usp29 UCSC Mus musculus 1.189244399 3.06E-10 Arhgef40 UCSC Mus musculus 1.189325911 0.003347799 Trim7 UCSC Mus musculus 1.19033429 3.68E-07 Pofut1 UCSC Mus musculus 1.191816227 2.28E-20 Rell2 UCSC Mus musculus 1.192064029 1.89E-14 Scml4 UCSC Mus musculus 1.192602609 3.92E-17 Slc4a8 UCSC Mus musculus 1.195320359 4.66E-10 Diabetes Page 98 of 125

Cers4 UCSC Mus musculus 1.195504504 9.00E-15 Tcn2 UCSC Mus musculus 1.195761749 3.31E-16 Lrrc3 UCSC Mus musculus 1.196517915 0.002516194 Impg2 UCSC Mus musculus 1.196711558 0.036911473 Hist1h4d UCSC Mus musculus 1.198058019 0.003486339 Mok UCSC Mus musculus 1.198253861 1.30E-05 Tmed1 UCSC Mus musculus 1.199974128 7.68E-10 Pla2g16 UCSC Mus musculus 1.2026843 6.98E-12 Cacna1b UCSC Mus musculus 1.20358416 2.33E-06 Hcn1 UCSC Mus musculus 1.203642604 3.66E-20 Cenpq UCSC Mus musculus 1.204793767 0.000133075 Chd9 UCSC Mus musculus 1.205187685 2.12E-07 4933406C10Rik UCSC Mus musculus 1.205203932 0.035655467 Bbs7 UCSC Mus musculus 1.207726885 5.99E-22 Tdrkh UCSC Mus musculus 1.208034895 4.52E-19 Ddr1 UCSC Mus musculus 1.208266053 1.98E-27 Aldh1b1 UCSC Mus musculus 1.209429227 0.000631834 Ggn UCSC Mus musculus 1.209683 9.14E-05 Saxo2 UCSC Mus musculus 1.209883566 0.000884733 Cyp46a1 UCSC Mus musculus 1.21032762 3.22E-07 Ptch1 UCSC Mus musculus 1.211292083 0.00017736 Ccdc173 UCSC Mus musculus 1.211348451 1.32E-08 Fcho1 UCSC Mus musculus 1.213117808 9.37E-12 Atp6ap1 UCSC Mus musculus 1.213589486 3.58E-18 Slc12a5 UCSC Mus musculus 1.213788383 5.78E-11 Zfp781 UCSC Mus musculus 1.214852191 0.000423791 Slc8a2 UCSC Mus musculus 1.215514902 0.004420129 Cfap70 UCSC Mus musculus 1.21580772 0.022782129 Sult2b1 UCSC Mus musculus 1.217906218 0.000347586 Cers6 UCSC Mus musculus 1.219910908 3.51E-17 Nfia UCSC Mus musculus 1.220182174 2.54E-06 Matk UCSC Mus musculus 1.22089823 0.005280209 Eef2k UCSC Mus musculus 1.221322523 3.06E-20 Cep250 UCSC Mus musculus 1.221646596 2.73E-09 Nkapl UCSC Mus musculus 1.223582457 0.000222073 Mirg UCSC Mus musculus 1.225026682 1.34E-06 Col9a2 UCSC Mus musculus 1.225625262 9.85E-05 Wsb1 UCSC Mus musculus 1.226680154 2.64E-14 2810029C07Rik UCSC Mus musculus 1.227202911 5.70E-10 Diras2 UCSC Mus musculus 1.227663666 0.002916037 Erap1 UCSC Mus musculus 1.230737264 8.71E-21 Btbd3 UCSC Mus musculus 1.230872228 5.55E-21 Lin7b UCSC Mus musculus 1.232004402 1.29E-05 Pcdhb17 UCSC Mus musculus 1.232139164 2.83E-09 Fbxo36 UCSC Mus musculus 1.234794134 1.17E-05 Nucb2 UCSC Mus musculus 1.234941418 3.74E-20 Nfkbid UCSC Mus musculus 1.237589668 0.001469526 Rom1 UCSC Mus musculus 1.237864306 7.00E-14 Kctd15 UCSC Mus musculus 1.238739008 1.70E-23 Arsb UCSC Mus musculus 1.238976746 1.75E-19 Zc3h12b UCSC Mus musculus 1.240601338 7.91E-07 Phldb1 UCSC Mus musculus 1.240920088 1.36E-14 St18 UCSC Mus musculus 1.243870043 9.67E-15 Page 99 of 125 Diabetes

Arsa UCSC Mus musculus 1.244684316 3.80E-22 Armcx6 UCSC Mus musculus 1.245329072 1.55E-09 Pcdha3 UCSC Mus musculus 1.245564365 0.03019905 Cst3 UCSC Mus musculus 1.246117524 9.94E-20 1700020D05Rik UCSC Mus musculus 1.248068233 0.003021343 Nap1l2 UCSC Mus musculus 1.248241501 5.17E-13 Hist1h2bn UCSC Mus musculus 1.248945114 0.020302854 Prdm9 UCSC Mus musculus 1.249435349 0.000179255 Lppr4 UCSC Mus musculus 1.249983543 1.31E-18 Pou2f1 UCSC Mus musculus 1.25055626 1.57E-09 Kif9 UCSC Mus musculus 1.251573196 1.38E-15 Snx7 UCSC Mus musculus 1.252622215 6.22E-07 Gm166 UCSC Mus musculus 1.253747955 3.64E-16 Rcn1 UCSC Mus musculus 1.253953596 1.72E-07 Pcdhb11 UCSC Mus musculus 1.254540621 0.00106191 Lsr UCSC Mus musculus 1.258337408 1.15E-27 Gprc6a UCSC Mus musculus 1.260110106 3.50E-08 Zfp503 UCSC Mus musculus 1.260489392 0.030525998 Inppl1 UCSC Mus musculus 1.260918212 3.30E-17 Slc25a14 UCSC Mus musculus 1.261321477 1.27E-25 Pcdhgc4 UCSC Mus musculus 1.261373389 1.18E-09 Pmm1 UCSC Mus musculus 1.262384749 7.47E-11 Lgmn UCSC Mus musculus 1.268578357 1.07E-11 Caskin1 UCSC Mus musculus 1.269718442 1.10E-05 Rragb UCSC Mus musculus 1.270947982 3.54E-24 Lzts2 UCSC Mus musculus 1.271248147 3.06E-12 Ptprs UCSC Mus musculus 1.272452598 1.66E-05 Fmnl3 UCSC Mus musculus 1.274056489 2.72E-06 Rab3c UCSC Mus musculus 1.274448531 0.0008173 1190002N15Rik UCSC Mus musculus 1.275248125 1.78E-10 Acot7 UCSC Mus musculus 1.275977855 0.030996962 Pm20d2 UCSC Mus musculus 1.276996059 6.12E-11 Gstk1 UCSC Mus musculus 1.277870481 3.79E-07 Hexdc UCSC Mus musculus 1.27793153 6.02E-12 Cd99l2 UCSC Mus musculus 1.28097321 2.34E-14 Irf2bpl UCSC Mus musculus 1.281154243 5.87E-16 Maoa UCSC Mus musculus 1.283277381 2.69E-08 Slc1a4 UCSC Mus musculus 1.284043609 8.53E-12 Cdk17 UCSC Mus musculus 1.284951921 1.74E-07 Chac1 UCSC Mus musculus 1.285927112 2.14E-11 Rin2 UCSC Mus musculus 1.286096174 7.01E-15 Hectd2 UCSC Mus musculus 1.286838401 3.41E-06 Mterf2 UCSC Mus musculus 1.288592709 7.29E-07 Pcdhga2 UCSC Mus musculus 1.289937737 0.001721144 Atp11c UCSC Mus musculus 1.291282348 7.83E-11 Plekha5 UCSC Mus musculus 1.291513697 1.91E-24 Zkscan2 UCSC Mus musculus 1.291641287 7.10E-10 Zfp873 UCSC Mus musculus 1.292131289 2.16E-07 Cdon UCSC Mus musculus 1.29305092 6.13E-12 BC051142 UCSC Mus musculus 1.296528854 9.00E-07 Esyt3 UCSC Mus musculus 1.297941013 3.29E-06 Tbc1d30 UCSC Mus musculus 1.29872697 2.08E-13 Gpc1 UCSC Mus musculus 1.300536738 7.68E-11 Diabetes Page 100 of 125

Zpbp UCSC Mus musculus 1.301651263 0.003527867 Golim4 UCSC Mus musculus 1.301950111 3.97E-25 Slc6a9 UCSC Mus musculus 1.302016304 3.05E-09 Gm960 UCSC Mus musculus 1.302242284 0.028940527 Tcf4 UCSC Mus musculus 1.302595251 3.23E-16 Pcdha10 UCSC Mus musculus 1.302866568 0.000158542 Frzb UCSC Mus musculus 1.305017781 1.03E-06 AF357359 UCSC Mus musculus 1.305160921 9.23E-08 Bnip3 UCSC Mus musculus 1.305381131 7.43E-16 BC065397 UCSC Mus musculus 1.305731045 2.75E-08 Etv1 UCSC Mus musculus 1.30626807 3.95E-05 St8sia3 UCSC Mus musculus 1.309864629 4.01E-09 5930430L01Rik UCSC Mus musculus 1.309925258 2.24E-12 Rian UCSC Mus musculus 1.310270233 2.88E-14 Rapgef6 UCSC Mus musculus 1.312782691 4.16E-11 5330417C22Rik UCSC Mus musculus 1.313789015 2.15E-46 1110046J04Rik UCSC Mus musculus 1.314002611 0.013012985 Cep41 UCSC Mus musculus 1.315022321 2.47E-09 Zfp808 UCSC Mus musculus 1.315708737 3.34E-06 St3gal6 UCSC Mus musculus 1.316256077 1.85E-11 Mov10 UCSC Mus musculus 1.316555949 1.74E-09 Gsap UCSC Mus musculus 1.316569087 7.80E-14 Kcnq2 UCSC Mus musculus 1.317740813 0.003493652 D430020J02Rik UCSC Mus musculus 1.319995192 0.001254468 Dync1i1 UCSC Mus musculus 1.322426041 3.34E-06 Slc9a5 UCSC Mus musculus 1.323138188 0.001493644 Etnk2 UCSC Mus musculus 1.323933619 0.001056047 Zfp827 UCSC Mus musculus 1.324625979 5.78E-11 Ccdc176 UCSC Mus musculus 1.325474431 3.53E-06 Zfp52 UCSC Mus musculus 1.325500251 6.14E-15 Trerf1 UCSC Mus musculus 1.325880666 1.73E-10 Fhl4 UCSC Mus musculus 1.327749239 0.004438422 4930480K23Rik UCSC Mus musculus 1.327873508 2.23E-06 Gpr75 UCSC Mus musculus 1.330147717 2.82E-05 Zc4h2 UCSC Mus musculus 1.331490949 2.04E-09 Pafah1b3 UCSC Mus musculus 1.339779129 3.55E-11 Dhfr UCSC Mus musculus 1.34011151 2.21E-05 Cpt1c UCSC Mus musculus 1.342134866 1.03E-10 Sfxn3 UCSC Mus musculus 1.34567446 4.23E-14 Cnpy4 UCSC Mus musculus 1.346170289 2.99E-13 Tmem194 UCSC Mus musculus 1.346385797 2.56E-06 Camk2b UCSC Mus musculus 1.346668509 2.75E-48 Zc3h12c UCSC Mus musculus 1.348317689 3.74E-38 Ccdc15 UCSC Mus musculus 1.349486726 5.35E-06 Cacna1f UCSC Mus musculus 1.349963107 0.004517046 Rasgrf1 UCSC Mus musculus 1.35285069 5.60E-09 Nckap5l UCSC Mus musculus 1.353375611 8.47E-05 Pak1 UCSC Mus musculus 1.354002788 7.36E-14 Rad1 UCSC Mus musculus 1.356563014 2.68E-12 Prx UCSC Mus musculus 1.356574348 0.035858792 Pcsk2os1 UCSC Mus musculus 1.356743943 1.32E-37 Stmn3 UCSC Mus musculus 1.357407158 1.32E-06 Efna5 UCSC Mus musculus 1.358005521 9.69E-18 Page 101 of 125 Diabetes

Plp1 UCSC Mus musculus 1.358466831 3.37E-07 N4bp2 UCSC Mus musculus 1.358592189 1.02E-07 Samd12 UCSC Mus musculus 1.362134313 0.006351763 Myo7a UCSC Mus musculus 1.362483521 1.73E-08 Poli UCSC Mus musculus 1.364478786 1.44E-17 Kmt2a UCSC Mus musculus 1.365435894 1.87E-06 Nek11 UCSC Mus musculus 1.366214352 0.001133227 Haus8 UCSC Mus musculus 1.36670965 8.56E-11 Srxn1 UCSC Mus musculus 1.366897021 4.92E-14 Sox12 UCSC Mus musculus 1.368422166 2.38E-10 Srgap3 UCSC Mus musculus 1.368424682 5.48E-05 Rac3 UCSC Mus musculus 1.368856418 5.68E-07 Casc1 UCSC Mus musculus 1.372911597 0.002308995 Myt1l UCSC Mus musculus 1.373723223 2.52E-12 Tmcc3 UCSC Mus musculus 1.375775961 4.29E-40 2700081O15Rik UCSC Mus musculus 1.379193394 6.07E-14 Sema4c UCSC Mus musculus 1.379365464 2.49E-08 Ccdc184 UCSC Mus musculus 1.379553145 7.08E-12 Lrpprc UCSC Mus musculus 1.380467234 8.62E-32 Ergic3 UCSC Mus musculus 1.380527062 3.71E-25 Tox UCSC Mus musculus 1.380918126 1.02E-06 Usp51 UCSC Mus musculus 1.381109356 2.07E-21 Rnd2 UCSC Mus musculus 1.381597443 0.000531009 Dnaic1 UCSC Mus musculus 1.382194257 5.36E-13 Lonrf2 UCSC Mus musculus 1.383283169 6.87E-19 Bsg UCSC Mus musculus 1.383773836 1.13E-21 Eda UCSC Mus musculus 1.384264142 6.35E-06 F2r UCSC Mus musculus 1.386818431 0.00317258 Map3k13 UCSC Mus musculus 1.392207185 5.36E-07 Pwwp2b UCSC Mus musculus 1.39355691 6.94E-08 Pcdhb13 UCSC Mus musculus 1.394388259 0.007901547 Panct2 UCSC Mus musculus 1.395191325 0.000263742 2610020H08Rik UCSC Mus musculus 1.395305862 2.14E-06 Rnf112 UCSC Mus musculus 1.396160483 5.53E-09 Sh3bp1 UCSC Mus musculus 1.396161087 0.040804567 F3 UCSC Mus musculus 1.397188243 6.45E-10 Mzf1 UCSC Mus musculus 1.39796845 6.85E-12 Wdr93 UCSC Mus musculus 1.398113659 8.67E-05 Tagln3 UCSC Mus musculus 1.400472401 0.01215831 Mir212 UCSC Mus musculus 1.401394445 0.017729477 Vsig8 UCSC Mus musculus 1.402410275 0.008014443 Dmd UCSC Mus musculus 1.402738947 0.004468696 Rcor2 UCSC Mus musculus 1.403996063 0.000137253 Slc4a10 UCSC Mus musculus 1.406783074 2.52E-05 Tmem132a UCSC Mus musculus 1.407277812 4.37E-09 Scel UCSC Mus musculus 1.410201275 1.43E-10 Pygl UCSC Mus musculus 1.41134968 8.40E-05 Frrs1l UCSC Mus musculus 1.411373714 0.02369178 Mycbpap UCSC Mus musculus 1.412432674 1.45E-11 Iqch UCSC Mus musculus 1.412752006 0.011777744 Tubb4a UCSC Mus musculus 1.413278211 8.64E-07 Lrpap1 UCSC Mus musculus 1.413597379 7.10E-19 Pde10a UCSC Mus musculus 1.41410564 3.27E-06 Diabetes Page 102 of 125

Bcorl1 UCSC Mus musculus 1.414116818 3.57E-15 Akap5 UCSC Mus musculus 1.414552858 0.003495701 Trim67 UCSC Mus musculus 1.416305944 2.27E-05 Mttp UCSC Mus musculus 1.418921992 1.41E-10 Zmym3 UCSC Mus musculus 1.421791959 1.15E-16 Lpcat4 UCSC Mus musculus 1.422259062 1.18E-07 Maats1 UCSC Mus musculus 1.423919083 3.70E-08 Hdac9 UCSC Mus musculus 1.42476121 2.34E-15 Sdc2 UCSC Mus musculus 1.426793768 1.42E-11 Wdr90 UCSC Mus musculus 1.429398819 4.36E-13 Ttll13 UCSC Mus musculus 1.430249383 9.15E-10 Gls2 UCSC Mus musculus 1.430556896 1.61E-05 Aicda UCSC Mus musculus 1.430954447 0.046122768 Per3 UCSC Mus musculus 1.434561672 4.32E-05 Grb10 UCSC Mus musculus 1.43718465 3.78E-20 Nova1 UCSC Mus musculus 1.437554616 3.13E-12 Gpr137c UCSC Mus musculus 1.439412902 0.011708306 Epb4.1l1 UCSC Mus musculus 1.439455452 1.44E-27 Nme5 UCSC Mus musculus 1.43952723 4.84E-07 Pkd2l2 UCSC Mus musculus 1.44273487 0.014712081 Frk UCSC Mus musculus 1.443009018 8.54E-20 Cd320 UCSC Mus musculus 1.443582903 1.60E-18 Sfxn4 UCSC Mus musculus 1.443878532 3.21E-10 Ssc4d UCSC Mus musculus 1.444610614 6.75E-12 4430402I18Rik UCSC Mus musculus 1.444649033 0.000169768 Spin2c UCSC Mus musculus 1.444927734 2.17E-07 Nova2 UCSC Mus musculus 1.445057677 3.77E-06 Plekhg6 UCSC Mus musculus 1.445394051 0.020611878 Mex3b UCSC Mus musculus 1.445463798 5.64E-06 Kcnn2 UCSC Mus musculus 1.445609076 0.00034857 Sall4 UCSC Mus musculus 1.445872307 2.97E-12 P4ha1 UCSC Mus musculus 1.447077972 1.94E-28 Chd3 UCSC Mus musculus 1.449285407 4.23E-15 Efna1 UCSC Mus musculus 1.450131126 7.05E-06 Chst10 UCSC Mus musculus 1.45180151 2.37E-11 Steap1 UCSC Mus musculus 1.455667835 0.000357192 Acy1 UCSC Mus musculus 1.455717873 9.41E-12 Stom UCSC Mus musculus 1.456144872 0.00099202 9530082P21Rik UCSC Mus musculus 1.45853696 0.00620556 Gm3704 UCSC Mus musculus 1.458970879 0.025984538 Gm10037 UCSC Mus musculus 1.459557598 0.000493235 Siah1b UCSC Mus musculus 1.459679482 2.56E-13 Rdm1 UCSC Mus musculus 1.460643929 1.40E-06 Myrip UCSC Mus musculus 1.462190869 1.75E-10 Amot UCSC Mus musculus 1.463070142 0.000173369 Rit2 UCSC Mus musculus 1.463497954 1.77E-08 Cr1l UCSC Mus musculus 1.464677429 6.34E-29 Ctsd UCSC Mus musculus 1.464862488 1.32E-24 Slc12a2 UCSC Mus musculus 1.465281411 4.17E-14 Zfp583 UCSC Mus musculus 1.465516137 1.11E-09 Rem2 UCSC Mus musculus 1.469167232 5.47E-14 Jam3 UCSC Mus musculus 1.469593955 3.26E-16 Sez6l2 UCSC Mus musculus 1.469923768 1.25E-39 Page 103 of 125 Diabetes

Zfp951 UCSC Mus musculus 1.471751271 1.60E-09 Fam102b UCSC Mus musculus 1.472827812 1.34E-05 Gm5577 UCSC Mus musculus 1.473535447 3.72E-11 Pabpc5 UCSC Mus musculus 1.477227366 6.94E-05 Rpn2 UCSC Mus musculus 1.478545986 2.15E-42 Palm UCSC Mus musculus 1.482881824 1.13E-05 4833427G06Rik UCSC Mus musculus 1.484009082 0.008290731 Podxl2 UCSC Mus musculus 1.48469525 1.32E-21 Tbl1xr1 UCSC Mus musculus 1.485010627 8.21E-18 Rccd1 UCSC Mus musculus 1.485186036 3.56E-17 Lin28a UCSC Mus musculus 1.486347439 1.79E-08 Amy1 UCSC Mus musculus 1.490946523 0.021559448 Pcdhb12 UCSC Mus musculus 1.491054179 0.004994047 Rapgefl1 UCSC Mus musculus 1.491194533 2.16E-12 Frrs1 UCSC Mus musculus 1.491203979 5.07E-07 Rnf122 UCSC Mus musculus 1.492624046 2.44E-05 A930024E05Rik UCSC Mus musculus 1.492916004 7.13E-05 1700012D14Rik UCSC Mus musculus 1.493190197 0.000650236 Myl6b UCSC Mus musculus 1.493361474 0.000264595 Ubqln2 UCSC Mus musculus 1.493545275 9.26E-38 Eno2 UCSC Mus musculus 1.494019531 4.70E-40 Dos UCSC Mus musculus 1.494925833 1.08E-37 Disp1 UCSC Mus musculus 1.497011536 6.16E-18 Rnf138rt1 UCSC Mus musculus 1.497785903 1.85E-09 Efcab10 UCSC Mus musculus 1.499932244 4.15E-08 Ltbp3 UCSC Mus musculus 1.501122252 6.83E-23 Tanc2 UCSC Mus musculus 1.501970531 9.91E-16 Emc1 UCSC Mus musculus 1.504839919 6.87E-31 Adgrl1 UCSC Mus musculus 1.505219846 1.87E-11 Fam57b UCSC Mus musculus 1.511344286 7.22E-25 Notch2 UCSC Mus musculus 1.514207486 4.52E-05 Ctsf UCSC Mus musculus 1.514412434 1.95E-17 Snap25 UCSC Mus musculus 1.519421435 2.84E-20 Samd14 UCSC Mus musculus 1.520807637 1.29E-07 Gm16894 UCSC Mus musculus 1.524263013 0.002885679 Gm10767 UCSC Mus musculus 1.527472091 0.000389009 Parp8 UCSC Mus musculus 1.528936156 4.16E-43 Cxxc4 UCSC Mus musculus 1.530516244 9.55E-48 Pik3c2b UCSC Mus musculus 1.533813205 1.49E-05 Aim1 UCSC Mus musculus 1.534088885 1.09E-13 Acot9 UCSC Mus musculus 1.534487723 4.74E-13 Hmgb3 UCSC Mus musculus 1.537388787 2.75E-05 9330136K24Rik UCSC Mus musculus 1.538259793 0.002654781 Gaa UCSC Mus musculus 1.538605235 3.06E-31 Gabre UCSC Mus musculus 1.541366569 0.015595794 Gucy2c UCSC Mus musculus 1.542429122 5.53E-10 Pdxp UCSC Mus musculus 1.551646254 2.13E-18 Ift80 UCSC Mus musculus 1.551945319 2.86E-54 Camk1d UCSC Mus musculus 1.559460644 0.000117787 Fmn1 UCSC Mus musculus 1.56162421 0.000681945 Slc37a2 UCSC Mus musculus 1.566140362 0.041046877 Agpat4 UCSC Mus musculus 1.569881412 0.00709792 Pcdhgb4 UCSC Mus musculus 1.571216257 0.007181063 Diabetes Page 104 of 125

Dse UCSC Mus musculus 1.573410683 2.48E-05 Ypel4 UCSC Mus musculus 1.573779278 1.08E-36 Gpx1 UCSC Mus musculus 1.573793994 2.22E-11 Acvr1c UCSC Mus musculus 1.57607745 1.80E-11 Pacrg UCSC Mus musculus 1.576121261 5.66E-11 Ghr UCSC Mus musculus 1.577243225 5.57E-28 Ccdc107 UCSC Mus musculus 1.577437225 9.40E-12 Wwc2 UCSC Mus musculus 1.57801093 0.011653318 Nmrk1 UCSC Mus musculus 1.578947571 4.39E-09 Atp8b5 UCSC Mus musculus 1.580518428 4.88E-08 Sdk1 UCSC Mus musculus 1.581160687 9.77E-14 Cc2d2a UCSC Mus musculus 1.582433874 2.05E-22 Bach2 UCSC Mus musculus 1.584567945 0.011246869 Lhpp UCSC Mus musculus 1.585662381 0.001130199 Peak1 UCSC Mus musculus 1.587886226 7.43E-06 D130043K22Rik UCSC Mus musculus 1.589676784 8.44E-38 Cxadr UCSC Mus musculus 1.58973514 1.15E-20 Plcxd3 UCSC Mus musculus 1.593058146 7.96E-11 Usp11 UCSC Mus musculus 1.594749331 7.48E-15 Slc25a33 UCSC Mus musculus 1.598129192 0.006772106 Akr1c19 UCSC Mus musculus 1.603277439 2.20E-26 Car13 UCSC Mus musculus 1.603732153 0.043607935 Nrm UCSC Mus musculus 1.6037777 0.000317468 Fank1 UCSC Mus musculus 1.604846171 8.38E-06 Spred1 UCSC Mus musculus 1.606172673 0.000779912 Aifm3 UCSC Mus musculus 1.609762722 1.42E-16 Isl1 UCSC Mus musculus 1.612516431 2.08E-42 Dnajc12 UCSC Mus musculus 1.61254238 6.49E-31 Ttll7 UCSC Mus musculus 1.612703542 5.87E-25 Adgb UCSC Mus musculus 1.613266742 2.78E-10 Ksr1 UCSC Mus musculus 1.616594241 0.000462001 Xrcc2 UCSC Mus musculus 1.621173596 6.05E-11 Npr2 UCSC Mus musculus 1.621200514 4.75E-14 Zscan18 UCSC Mus musculus 1.621351181 4.62E-11 Fam212a UCSC Mus musculus 1.622891516 0.027237836 Sdf4 UCSC Mus musculus 1.623118502 5.89E-35 Kif5a UCSC Mus musculus 1.624209092 1.51E-15 Immp2l UCSC Mus musculus 1.625727705 2.32E-05 Lmo1 UCSC Mus musculus 1.627995571 0.000207996 Pcsk6 UCSC Mus musculus 1.628571304 3.00E-34 Cpq UCSC Mus musculus 1.629531838 9.77E-23 Galc UCSC Mus musculus 1.632910361 3.05E-23 Arap2 UCSC Mus musculus 1.633854803 0.003001336 Galm UCSC Mus musculus 1.634599487 0.035356168 B230216N24Rik UCSC Mus musculus 1.635340683 0.010013246 Sema3f UCSC Mus musculus 1.635635188 0.003329 Scd3 UCSC Mus musculus 1.636343181 0.000104265 Rhebl1 UCSC Mus musculus 1.636404997 3.09E-06 Efr3b UCSC Mus musculus 1.638658071 4.91E-24 Trim46 UCSC Mus musculus 1.640783145 5.50E-43 Gpr119 UCSC Mus musculus 1.640989941 2.43E-15 Caprin2 UCSC Mus musculus 1.642908447 1.67E-11 Fam135a UCSC Mus musculus 1.643327752 9.46E-36 Page 105 of 125 Diabetes

Maml2 UCSC Mus musculus 1.646698554 0.003000783 A230103J11Rik UCSC Mus musculus 1.648261796 0.026307046 Usp2 UCSC Mus musculus 1.648566868 4.10E-09 Ccdc39 UCSC Mus musculus 1.64913014 4.44E-08 Gm3696 UCSC Mus musculus 1.656037917 0.03519643 Mapt UCSC Mus musculus 1.656163426 2.33E-24 Nek6 UCSC Mus musculus 1.656280457 5.23E-06 Gm7173 UCSC Mus musculus 1.657495481 0.007555322 Psg16 UCSC Mus musculus 1.659752332 1.66E-15 Npas4 UCSC Mus musculus 1.666735286 1.19E-13 Gm2a UCSC Mus musculus 1.667791249 3.70E-40 Adam5 UCSC Mus musculus 1.670474511 0.007868863 Abcd2 UCSC Mus musculus 1.670726466 4.58E-09 Gucy1a2 UCSC Mus musculus 1.670911754 0.001587917 Pcdhb10 UCSC Mus musculus 1.671074801 0.001935704 Pfn4 UCSC Mus musculus 1.671713725 0.001790947 Hist1h3f UCSC Mus musculus 1.676525063 0.008975526 Rfx6 UCSC Mus musculus 1.676814525 1.25E-39 Ttc39c UCSC Mus musculus 1.679392269 2.81E-10 Adrb2 UCSC Mus musculus 1.679624578 3.89E-09 Gm11837 UCSC Mus musculus 1.680724316 1.14E-05 Aplp1 UCSC Mus musculus 1.683954503 1.82E-33 Fbxo2 UCSC Mus musculus 1.684945686 9.18E-16 Hist1h2bb UCSC Mus musculus 1.686488851 0.003859192 Hexb UCSC Mus musculus 1.687484037 1.89E-27 Vwde UCSC Mus musculus 1.687508243 0.000145408 Zfp940 UCSC Mus musculus 1.688491702 1.49E-09 Tmem74b UCSC Mus musculus 1.688673415 0.008748509 Adam15 UCSC Mus musculus 1.688712515 6.73E-09 Glb1 UCSC Mus musculus 1.689621386 4.19E-26 Cklf UCSC Mus musculus 1.69290087 1.03E-08 Scn3a UCSC Mus musculus 1.695702716 1.62E-18 Ccdc65 UCSC Mus musculus 1.69836218 7.17E-06 St6galnac6 UCSC Mus musculus 1.698952 5.09E-18 Cfap74 UCSC Mus musculus 1.703504975 2.82E-13 Recql4 UCSC Mus musculus 1.705005219 7.08E-10 Armc4 UCSC Mus musculus 1.705374471 8.94E-08 Tmc7 UCSC Mus musculus 1.705553347 4.09E-09 Gsto2 UCSC Mus musculus 1.706297954 4.38E-08 Ppp2r2b UCSC Mus musculus 1.708261558 5.26E-07 Cdc42ep3 UCSC Mus musculus 1.714185596 7.04E-09 Rnf165 UCSC Mus musculus 1.71432133 0.018533545 Foxp2 UCSC Mus musculus 1.718013831 1.84E-07 Epcam UCSC Mus musculus 1.722289598 8.48E-70 Hlf UCSC Mus musculus 1.722938556 5.60E-06 Uchl1 UCSC Mus musculus 1.725881669 8.56E-19 Iqcg UCSC Mus musculus 1.727240428 1.06E-10 Pik3ap1 UCSC Mus musculus 1.733935907 0.000470122 Vcl UCSC Mus musculus 1.734330612 1.30E-40 Pygo1 UCSC Mus musculus 1.735775587 0.000522018 4930570G19Rik UCSC Mus musculus 1.736998902 8.88E-14 4930505A04Rik UCSC Mus musculus 1.745527705 1.64E-05 Stk38l UCSC Mus musculus 1.746854555 2.11E-17 Diabetes Page 106 of 125

Shf UCSC Mus musculus 1.749618217 1.17E-11 Cd22 UCSC Mus musculus 1.752348244 0.002621718 Srl UCSC Mus musculus 1.759693039 8.26E-06 Zfp820 UCSC Mus musculus 1.760697505 6.17E-10 Gstm5 UCSC Mus musculus 1.761371815 3.14E-21 Asphd2 UCSC Mus musculus 1.764553773 0.005192358 9330102E08Rik UCSC Mus musculus 1.765425045 3.00E-10 Srcin1 UCSC Mus musculus 1.768182217 0.02193561 Lrrc48 UCSC Mus musculus 1.768968267 2.03E-11 Ablim2 UCSC Mus musculus 1.769500588 6.64E-14 Mcoln3 UCSC Mus musculus 1.769789771 3.18E-07 Prdx4 UCSC Mus musculus 1.769911639 5.35E-17 Gpc2 UCSC Mus musculus 1.770457868 0.000320654 Shroom1 UCSC Mus musculus 1.772867296 0.000666019 Paqr8 UCSC Mus musculus 1.774232347 2.17E-21 Shank1 UCSC Mus musculus 1.781240613 6.19E-09 Mir134 UCSC Mus musculus 1.783271633 0.00882761 Sertad3 UCSC Mus musculus 1.784767336 5.48E-32 Ptprt UCSC Mus musculus 1.788139617 0.001466328 Adgrb3 UCSC Mus musculus 1.791554886 4.56E-09 Pgbd1 UCSC Mus musculus 1.795774023 2.00E-07 Frat2 UCSC Mus musculus 1.797398083 4.69E-05 1700064M15Rik UCSC Mus musculus 1.801171379 0.046567738 Xylb UCSC Mus musculus 1.802652587 3.34E-16 C530044C16Rik UCSC Mus musculus 1.806946051 0.022838999 Gba UCSC Mus musculus 1.810834063 4.49E-45 A830052D11Rik UCSC Mus musculus 1.812338262 0.000729847 Wdr27 UCSC Mus musculus 1.813610264 0.002490654 Aga UCSC Mus musculus 1.813875527 7.74E-31 Katnal2 UCSC Mus musculus 1.815499916 5.22E-12 St3gal2 UCSC Mus musculus 1.816101717 2.52E-31 Lrrtm4 UCSC Mus musculus 1.816337831 0.001012424 Dock4 UCSC Mus musculus 1.819432098 2.54E-16 Snca UCSC Mus musculus 1.820721582 0.003917536 Nr4a1 UCSC Mus musculus 1.824203493 9.50E-24 Scml2 UCSC Mus musculus 1.827584235 0.004045799 Nap1l3 UCSC Mus musculus 1.827924841 3.55E-20 Sbsn UCSC Mus musculus 1.828029865 3.10E-12 Mirlet7d UCSC Mus musculus 1.830465055 0.023567966 Sema6d UCSC Mus musculus 1.834051315 2.36E-22 Man2b1 UCSC Mus musculus 1.836882312 2.12E-31 Igsf9 UCSC Mus musculus 1.838290894 5.64E-14 Dusp15 UCSC Mus musculus 1.839310975 4.32E-06 Ankrd37 UCSC Mus musculus 1.840696071 1.69E-47 Mical1 UCSC Mus musculus 1.843258927 0.000246254 Nudt17 UCSC Mus musculus 1.844203461 0.000907282 Pcdh8 UCSC Mus musculus 1.846934517 0.003706412 Actrt3 UCSC Mus musculus 1.853578938 2.12E-15 Iqcd UCSC Mus musculus 1.855282309 3.95E-06 Man2b2 UCSC Mus musculus 1.85796091 3.55E-46 Plxdc2 UCSC Mus musculus 1.859199205 9.37E-06 Meig1 UCSC Mus musculus 1.863643519 1.24E-12 Spred3 UCSC Mus musculus 1.863729403 6.50E-24 Page 107 of 125 Diabetes

BC046251 UCSC Mus musculus 1.86536352 0.010075445 Gm2694 UCSC Mus musculus 1.865970948 0.006995935 Sntg1 UCSC Mus musculus 1.86770471 2.23E-11 Tnfaip8l1 UCSC Mus musculus 1.867889597 0.000494985 Cpn1 UCSC Mus musculus 1.868022287 5.00E-69 Rab15 UCSC Mus musculus 1.868326933 0.01709361 Clip3 UCSC Mus musculus 1.86940861 2.39E-21 9030624G23Rik UCSC Mus musculus 1.87011622 0.031628058 Trim38 UCSC Mus musculus 1.874626688 0.019130016 Tmem130 UCSC Mus musculus 1.878368694 2.48E-28 Dazl UCSC Mus musculus 1.87906106 0.001337665 Car11 UCSC Mus musculus 1.879530503 2.93E-05 Sema4g UCSC Mus musculus 1.879826849 5.05E-05 Sytl5 UCSC Mus musculus 1.879967538 6.39E-21 Nrxn1 UCSC Mus musculus 1.880198469 3.99E-31 Gpr150 UCSC Mus musculus 1.886559084 0.003398995 Zcwpw1 UCSC Mus musculus 1.888239422 1.06E-09 Nab2 UCSC Mus musculus 1.888792774 2.96E-07 Pgm2l1 UCSC Mus musculus 1.889595939 5.53E-16 Neurl2 UCSC Mus musculus 1.890199106 0.001446502 Slc4a3 UCSC Mus musculus 1.891943731 1.44E-43 Ctnna2 UCSC Mus musculus 1.89225808 2.01E-32 Nrxn2 UCSC Mus musculus 1.892465712 0.011764059 Fam161a UCSC Mus musculus 1.894790183 2.16E-41 Usp13 UCSC Mus musculus 1.899747962 0.001840638 Meg3 UCSC Mus musculus 1.901780646 4.45E-14 Pcdha12 UCSC Mus musculus 1.901906188 0.006866812 Nr4a3 UCSC Mus musculus 1.90299334 0.037041051 Zfp467 UCSC Mus musculus 1.908254985 3.76E-13 Dzank1 UCSC Mus musculus 1.909360166 3.60E-21 P3h4 UCSC Mus musculus 1.914081158 1.67E-29 Slit2 UCSC Mus musculus 1.914805743 0.000333795 4933412E12Rik UCSC Mus musculus 1.91554931 4.66E-06 Zmynd12 UCSC Mus musculus 1.916106652 0.000757315 1700028K03Rik UCSC Mus musculus 1.916300269 0.044800821 A830018L16Rik UCSC Mus musculus 1.922230714 0.000475053 Ldlrad4 UCSC Mus musculus 1.923188528 4.37E-47 Aph1c UCSC Mus musculus 1.924385593 2.79E-07 Nr6a1 UCSC Mus musculus 1.928491529 2.78E-23 Dnah7a UCSC Mus musculus 1.93191655 5.59E-05 Gstp1 UCSC Mus musculus 1.933584684 6.13E-29 Mlf1 UCSC Mus musculus 1.941497577 0.000566628 1700013F07Rik UCSC Mus musculus 1.945785432 8.15E-05 Doc2b UCSC Mus musculus 1.949385674 6.12E-11 Plod3 UCSC Mus musculus 1.953731271 6.95E-52 Adssl1 UCSC Mus musculus 1.956810025 7.32E-08 4930503L19Rik UCSC Mus musculus 1.957961718 4.17E-26 Fam83b UCSC Mus musculus 1.959307571 4.93E-09 Cyp2d22 UCSC Mus musculus 1.959887618 1.54E-14 A230056P14Rik UCSC Mus musculus 1.960889683 1.96E-06 2610020C07Rik UCSC Mus musculus 1.962262495 0.014324147 Arid5b UCSC Mus musculus 1.966397249 4.86E-15 Tpmt UCSC Mus musculus 1.968370902 4.06E-13 Diabetes Page 108 of 125

Tmpo UCSC Mus musculus 1.969768973 2.46E-105 Vegfc UCSC Mus musculus 1.971342307 6.36E-12 Sptb UCSC Mus musculus 1.972613374 1.24E-12 Foxj1 UCSC Mus musculus 1.978844951 0.005230218 Smarca1 UCSC Mus musculus 1.978955437 2.30E-34 4930412C18Rik UCSC Mus musculus 1.981216667 0.030674599 Ypel1 UCSC Mus musculus 1.98569024 8.56E-12 Sema6b UCSC Mus musculus 1.98977393 1.09E-08 Tmem145 UCSC Mus musculus 1.990723487 4.61E-32 Ckmt1 UCSC Mus musculus 1.996383684 2.62E-54 Anxa9 UCSC Mus musculus 2.001435954 2.67E-08 Dock7 UCSC Mus musculus 2.012938844 2.01E-36 Cep112 UCSC Mus musculus 2.013682059 9.33E-18 Pak7 UCSC Mus musculus 2.015282201 2.57E-10 Xrra1 UCSC Mus musculus 2.016487367 7.60E-12 Cecr2 UCSC Mus musculus 2.023196639 0.000112635 Gm7694 UCSC Mus musculus 2.025736118 1.54E-05 Spef2 UCSC Mus musculus 2.026276446 0.030297192 Dnajc21 UCSC Mus musculus 2.029450858 1.77E-57 Ldhb UCSC Mus musculus 2.030624762 1.32E-29 Fam109b UCSC Mus musculus 2.031559742 5.25E-05 A830010M20Rik UCSC Mus musculus 2.033316004 1.02E-41 Gm996 UCSC Mus musculus 2.034208566 1.64E-22 Snai2 UCSC Mus musculus 2.037705466 0.000367606 Acbd7 UCSC Mus musculus 2.044778967 0.001078764 3632451O06Rik UCSC Mus musculus 2.045184459 0.003778826 Dmtn UCSC Mus musculus 2.047140955 0.009600742 5031434O11Rik UCSC Mus musculus 2.058160707 5.99E-10 Lca5l UCSC Mus musculus 2.059961504 7.01E-06 A930006K02Rik UCSC Mus musculus 2.061226095 2.07E-10 Pcdha8 UCSC Mus musculus 2.061921498 0.041253509 Cep85l UCSC Mus musculus 2.066776857 7.13E-09 1700028E10Rik UCSC Mus musculus 2.068316008 0.012049918 Epha7 UCSC Mus musculus 2.070838934 1.01E-11 Nacad UCSC Mus musculus 2.073429944 8.51E-11 Elmod1 UCSC Mus musculus 2.074272854 2.06E-21 Klhl3 UCSC Mus musculus 2.077453375 1.32E-08 Spry2 UCSC Mus musculus 2.081152825 1.86E-38 Iglon5 UCSC Mus musculus 2.08424236 4.21E-07 Bcl6 UCSC Mus musculus 2.085753899 9.39E-12 Kcnh8 UCSC Mus musculus 2.086418233 8.21E-19 Ggh UCSC Mus musculus 2.093870135 8.48E-21 AI450353 UCSC Mus musculus 2.094541827 0.000109376 Gad2 UCSC Mus musculus 2.095472015 3.28E-11 Prr36 UCSC Mus musculus 2.099258663 2.75E-05 Tenm3 UCSC Mus musculus 2.103739787 1.55E-19 Pld3 UCSC Mus musculus 2.104983402 1.63E-55 Itpripl1 UCSC Mus musculus 2.117062221 9.12E-05 Plag1 UCSC Mus musculus 2.11743373 2.62E-20 Stxbp5l UCSC Mus musculus 2.118860088 9.44E-25 Ifit2 UCSC Mus musculus 2.120119327 0.008394966 Fancb UCSC Mus musculus 2.120575802 2.04E-12 Dnm1 UCSC Mus musculus 2.121699537 1.23E-09 Page 109 of 125 Diabetes

Adam23 UCSC Mus musculus 2.121841916 1.93E-10 Btbd8 UCSC Mus musculus 2.124737811 6.54E-07 Rasip1 UCSC Mus musculus 2.127158815 2.44E-07 Sspo UCSC Mus musculus 2.127497553 2.97E-12 Zfp385a UCSC Mus musculus 2.128453666 6.02E-16 Dgkb UCSC Mus musculus 2.132939562 6.13E-05 Cdkn2a UCSC Mus musculus 2.134324887 1.03E-05 Unkl UCSC Mus musculus 2.135273952 2.37E-24 Lincpint UCSC Mus musculus 2.140388317 0.001661007 Sult4a1 UCSC Mus musculus 2.146849065 3.51E-16 Mnd1 UCSC Mus musculus 2.14731623 8.15E-05 Camk4 UCSC Mus musculus 2.148269295 0.000643173 Cobl UCSC Mus musculus 2.15113044 1.71E-16 Pcdhb8 UCSC Mus musculus 2.155238875 0.002187022 Rasgrf2 UCSC Mus musculus 2.156312289 7.93E-09 Gpr137b-ps UCSC Mus musculus 2.157018206 1.22E-23 Cldn34c1 UCSC Mus musculus 2.162639232 0.022352092 Scn3b UCSC Mus musculus 2.163777582 2.16E-31 Klf8 UCSC Mus musculus 2.16664005 9.47E-23 Fmnl1 UCSC Mus musculus 2.171101952 1.98E-08 Zfp473 UCSC Mus musculus 2.171301585 1.20E-08 Cspg5 UCSC Mus musculus 2.173843559 1.69E-31 Gyk UCSC Mus musculus 2.174602822 1.63E-07 4921507P07Rik UCSC Mus musculus 2.178554097 5.21E-21 Nek5 UCSC Mus musculus 2.179905385 7.04E-15 Clasp2 UCSC Mus musculus 2.182650182 1.55E-50 Rab3il1 UCSC Mus musculus 2.183265243 3.21E-08 Prcp UCSC Mus musculus 2.184160722 2.88E-30 Mir339 UCSC Mus musculus 2.188572303 0.018847445 Kcnc1 UCSC Mus musculus 2.20046177 1.99E-09 Erc2 UCSC Mus musculus 2.200812624 4.74E-56 Snap91 UCSC Mus musculus 2.214121506 2.24E-25 Amigo2 UCSC Mus musculus 2.223795446 2.92E-31 Dtx4 UCSC Mus musculus 2.224545227 3.61E-14 Mir132 UCSC Mus musculus 2.224932919 0.00037347 Paqr7 UCSC Mus musculus 2.237175105 7.07E-06 Gla UCSC Mus musculus 2.243551718 5.53E-47 St3gal4 UCSC Mus musculus 2.244361563 4.96E-15 Timp2 UCSC Mus musculus 2.246742102 3.54E-12 Arrb1 UCSC Mus musculus 2.256334848 2.89E-30 Abca8b UCSC Mus musculus 2.258038749 1.27E-42 Tmem151a UCSC Mus musculus 2.265064199 2.41E-29 Trpc4 UCSC Mus musculus 2.265387175 5.76E-08 Erich5 UCSC Mus musculus 2.265504659 8.28E-12 Trpv3 UCSC Mus musculus 2.268219426 0.046775535 Marcksl1-ps4 UCSC Mus musculus 2.274489102 1.68E-10 Krt1 UCSC Mus musculus 2.27801402 1.31E-11 9230110C19Rik UCSC Mus musculus 2.278624272 3.34E-21 Gamt UCSC Mus musculus 2.281716406 0.000866112 Bcl2l14 UCSC Mus musculus 2.282354967 1.67E-05 Pcdhb6 UCSC Mus musculus 2.283216191 0.000760119 Pkd1l3 UCSC Mus musculus 2.287555887 0.046094863 Lrrc46 UCSC Mus musculus 2.291545688 2.37E-10 Diabetes Page 110 of 125

Nav3 UCSC Mus musculus 2.292693126 2.60E-09 Efhc1 UCSC Mus musculus 2.293422037 8.79E-55 Ttc12 UCSC Mus musculus 2.294889565 7.52E-20 Mvb12b UCSC Mus musculus 2.296619083 3.03E-32 Gm8787 UCSC Mus musculus 2.298688553 0.022209977 Hoxb2 UCSC Mus musculus 2.300199804 0.038400231 Ptprg UCSC Mus musculus 2.303502268 1.15E-13 Sil1 UCSC Mus musculus 2.305021625 3.26E-84 Arhgap18 UCSC Mus musculus 2.306555719 1.73E-23 Jph4 UCSC Mus musculus 2.311410347 3.04E-23 Adamts9 UCSC Mus musculus 2.312109493 0.001852285 Wdr54 UCSC Mus musculus 2.312544243 2.17E-08 Cntn1 UCSC Mus musculus 2.316141284 5.52E-32 Snora43 UCSC Mus musculus 2.326489296 0.04823614 Rsph4a UCSC Mus musculus 2.330179026 1.87E-32 6330403K07Rik UCSC Mus musculus 2.335497969 3.04E-10 Rhof UCSC Mus musculus 2.335638488 3.56E-18 Atp7b UCSC Mus musculus 2.341717616 2.00E-11 Slmo1 UCSC Mus musculus 2.351466073 2.23E-13 Cryab UCSC Mus musculus 2.353802748 0.000114897 Ifnar2 UCSC Mus musculus 2.361293185 1.87E-40 Clec2l UCSC Mus musculus 2.363655858 0.027474978 Exd1 UCSC Mus musculus 2.374740885 0.011790286 1500004A13Rik UCSC Mus musculus 2.388268794 3.42E-11 Dact3 UCSC Mus musculus 2.388642747 6.71E-17 Pcdha9 UCSC Mus musculus 2.389932361 0.000141589 Ephb2 UCSC Mus musculus 2.391820543 2.77E-15 Scube1 UCSC Mus musculus 2.400484771 0.024542103 Pnpla3 UCSC Mus musculus 2.403314918 1.02E-09 Csdc2 UCSC Mus musculus 2.405519625 8.84E-24 Cfap44 UCSC Mus musculus 2.408374583 5.16E-08 Kank3 UCSC Mus musculus 2.410600134 1.04E-13 Pdzd7 UCSC Mus musculus 2.411932339 4.32E-09 Dusp4 UCSC Mus musculus 2.41394237 4.26E-19 Sec14l2 UCSC Mus musculus 2.419460008 2.22E-05 Abhd14a UCSC Mus musculus 2.42317245 8.56E-69 1700003E16Rik UCSC Mus musculus 2.425935361 2.43E-06 Ankef1 UCSC Mus musculus 2.433018881 2.40E-17 Fgf12 UCSC Mus musculus 2.439045532 2.08E-44 Icam5 UCSC Mus musculus 2.442243112 0.0161005 Zmat4 UCSC Mus musculus 2.447260073 0.010875043 Tbkbp1 UCSC Mus musculus 2.450390025 2.20E-05 Mt3 UCSC Mus musculus 2.451313175 1.78E-14 Gcnt1 UCSC Mus musculus 2.455859383 1.19E-08 Tekt5 UCSC Mus musculus 2.459946951 1.34E-05 Myo1a UCSC Mus musculus 2.462875209 0.03636648 Calr3 UCSC Mus musculus 2.464469904 6.60E-10 Gpr6 UCSC Mus musculus 2.46804631 6.13E-05 Gm16062 UCSC Mus musculus 2.469096571 0.00085015 Peg10 UCSC Mus musculus 2.47349969 5.56E-17 Fam101a UCSC Mus musculus 2.476970231 2.55E-43 3-Sep UCSC Mus musculus 2.487358235 2.48E-29 Greb1l UCSC Mus musculus 2.495597786 1.87E-12 Page 111 of 125 Diabetes

Wwc1 UCSC Mus musculus 2.505003149 1.17E-26 Nenf UCSC Mus musculus 2.50663848 3.17E-70 Thbs3 UCSC Mus musculus 2.508496912 2.94E-23 Caly UCSC Mus musculus 2.510039826 1.08E-10 Gm1673 UCSC Mus musculus 2.510948953 2.30E-19 Ccnb1ip1 UCSC Mus musculus 2.51677591 0.012237132 Cercam UCSC Mus musculus 2.522061707 4.71E-12 Susd2 UCSC Mus musculus 2.523501805 3.80E-18 Lor UCSC Mus musculus 2.531893753 1.43E-07 Pald1 UCSC Mus musculus 2.542082379 3.51E-06 Tpbg UCSC Mus musculus 2.542083054 0.008994089 Kif27 UCSC Mus musculus 2.543544843 5.66E-10 Ttc21a UCSC Mus musculus 2.54893047 1.90E-08 Mast2 UCSC Mus musculus 2.563071662 2.30E-62 Wasf1 UCSC Mus musculus 2.563776493 3.37E-36 Enkur UCSC Mus musculus 2.566275327 0.000115104 Oat UCSC Mus musculus 2.574010086 9.54E-33 Lrrk2 UCSC Mus musculus 2.577614924 1.34E-13 Prickle2 UCSC Mus musculus 2.586436651 4.13E-17 Tmem14a UCSC Mus musculus 2.603061451 2.26E-40 Chgb UCSC Mus musculus 2.603374951 1.73E-135 Tro UCSC Mus musculus 2.608968282 8.38E-22 Rsg1 UCSC Mus musculus 2.613065651 1.30E-07 Chrd UCSC Mus musculus 2.617596809 2.18E-25 Slc26a8 UCSC Mus musculus 2.619399229 6.41E-18 Clu UCSC Mus musculus 2.620775335 5.48E-22 Qpct UCSC Mus musculus 2.621143897 2.09E-08 Itga4 UCSC Mus musculus 2.623787617 5.73E-16 Chrna7 UCSC Mus musculus 2.627728791 0.019613795 Arhgef4 UCSC Mus musculus 2.628680434 7.13E-35 Awat2 UCSC Mus musculus 2.632886614 9.60E-06 Rtbdn UCSC Mus musculus 2.639990323 5.60E-05 2410004P03Rik UCSC Mus musculus 2.651333555 0.008046402 Stag3 UCSC Mus musculus 2.651562346 2.76E-05 Btg3 UCSC Mus musculus 2.657529401 1.46E-47 Jakmip2 UCSC Mus musculus 2.675624694 0.001125555 Stpg1 UCSC Mus musculus 2.679492844 8.45E-18 Pnp2 UCSC Mus musculus 2.682152873 0.027508239 Capsl UCSC Mus musculus 2.697972137 3.84E-81 C130083M11Rik UCSC Mus musculus 2.711094181 0.026766733 Col25a1 UCSC Mus musculus 2.711794188 0.005094532 Armc2 UCSC Mus musculus 2.712057001 6.23E-12 Ptchd2 UCSC Mus musculus 2.716992889 9.68E-08 Mpv17l UCSC Mus musculus 2.717579692 4.25E-36 C1ra UCSC Mus musculus 2.718570489 2.48E-06 4930432K21Rik UCSC Mus musculus 2.731534265 0.002498109 Ogfod3 UCSC Mus musculus 2.742533607 2.15E-67 Kcnip4 UCSC Mus musculus 2.744117443 3.01E-44 Clstn3 UCSC Mus musculus 2.745159606 3.92E-23 Nos3 UCSC Mus musculus 2.745469497 3.20E-09 Gnai1 UCSC Mus musculus 2.752806431 3.53E-95 Igdcc4 UCSC Mus musculus 2.754936975 4.16E-18 Gpr3 UCSC Mus musculus 2.76145623 2.90E-08 Diabetes Page 112 of 125

Asb4 UCSC Mus musculus 2.7638044 1.93E-10 Col8a1 UCSC Mus musculus 2.773261576 0.000138032 Hmgn5 UCSC Mus musculus 2.774508865 2.31E-46 Opcml UCSC Mus musculus 2.782027399 5.89E-05 Pcdha5 UCSC Mus musculus 2.784101344 0.006059682 Pcdhb15 UCSC Mus musculus 2.788123376 3.93E-08 Nos1ap UCSC Mus musculus 2.804696905 0.01051108 Stk32b UCSC Mus musculus 2.822463289 1.07E-46 Slc29a4 UCSC Mus musculus 2.83002413 7.19E-103 Fbxo15 UCSC Mus musculus 2.831831353 0.042152819 Larp6 UCSC Mus musculus 2.843817435 0.011550783 Dhrs9 UCSC Mus musculus 2.844841466 0.02095347 Lypd6b UCSC Mus musculus 2.848675855 0.040987025 A930012L18Rik UCSC Mus musculus 2.857545577 2.05E-06 Nsun7 UCSC Mus musculus 2.858941629 0.001214619 Nrxn3 UCSC Mus musculus 2.862373048 0.035400549 Gm3636 UCSC Mus musculus 2.865741915 3.40E-14 Scn4a UCSC Mus musculus 2.874092892 0.002515952 Inpp4b UCSC Mus musculus 2.878906762 1.57E-15 Sgip1 UCSC Mus musculus 2.879913216 1.00E-06 Cfap52 UCSC Mus musculus 2.881383129 0.000333795 Ccdc151 UCSC Mus musculus 2.884703215 1.43E-32 Gm21284 UCSC Mus musculus 2.90097049 1.29E-06 Samd5 UCSC Mus musculus 2.901004825 0.02849497 Cited1 UCSC Mus musculus 2.913826386 0.000162805 Dusp6 UCSC Mus musculus 2.91514993 1.60E-21 Asic2 UCSC Mus musculus 2.92483587 7.48E-16 Lrrtm2 UCSC Mus musculus 2.927023777 5.36E-32 Oas3 UCSC Mus musculus 2.933752001 0.019174178 Astn2 UCSC Mus musculus 2.951070073 0.000582736 Fam196a UCSC Mus musculus 2.972601632 2.77E-14 Top1mt UCSC Mus musculus 2.974254593 7.43E-11 Arhgap36 UCSC Mus musculus 2.974312955 6.13E-20 Hcrtr2 UCSC Mus musculus 2.977289738 0.024150561 Icam2 UCSC Mus musculus 2.977765849 0.000205377 Klhl13 UCSC Mus musculus 2.989073434 1.00E-16 Psd2 UCSC Mus musculus 2.994234919 4.41E-11 Rab6b UCSC Mus musculus 2.995547374 0.01187238 Cfap58 UCSC Mus musculus 3.001432391 1.71E-15 4930581F22Rik UCSC Mus musculus 3.019364747 1.97E-25 9430021M05Rik UCSC Mus musculus 3.037094201 6.32E-20 Apc2 UCSC Mus musculus 3.056627487 5.26E-39 Gabrg1 UCSC Mus musculus 3.062367901 5.44E-07 Fam46a UCSC Mus musculus 3.064008309 5.27E-91 Ccdc132 UCSC Mus musculus 3.066023292 4.79E-79 Snora69 UCSC Mus musculus 3.066900521 0.037719514 Rasgrp1 UCSC Mus musculus 3.080309692 3.74E-39 6430531B16Rik UCSC Mus musculus 3.083771893 3.37E-06 Map1a UCSC Mus musculus 3.091877685 0.000132233 Spry4 UCSC Mus musculus 3.092393816 1.43E-31 Scg3 UCSC Mus musculus 3.092466712 5.76E-130 D16Ertd472e UCSC Mus musculus 3.093025849 1.06E-59 Cnih2 UCSC Mus musculus 3.100740174 1.60E-40 Page 113 of 125 Diabetes

Cpne8 UCSC Mus musculus 3.109039262 5.49E-40 Hebp2 UCSC Mus musculus 3.115444171 3.04E-05 Ppfibp2 UCSC Mus musculus 3.11809878 0.004597249 Olfml2b UCSC Mus musculus 3.123205498 3.57E-07 Negr1 UCSC Mus musculus 3.125056673 8.54E-40 Wdr17 UCSC Mus musculus 3.126315163 4.44E-26 Trpv2 UCSC Mus musculus 3.130902142 0.002824184 2810408A11Rik UCSC Mus musculus 3.135132803 8.60E-05 Chst9 UCSC Mus musculus 3.156782761 9.77E-14 Pla2g4e UCSC Mus musculus 3.156806223 0.003815642 Tnfrsf21 UCSC Mus musculus 3.167930047 1.97E-30 Egfl7 UCSC Mus musculus 3.200325254 2.41E-13 Fam13c UCSC Mus musculus 3.209652555 5.06E-15 4930444P10Rik UCSC Mus musculus 3.220146729 5.14E-05 Nr4a2 UCSC Mus musculus 3.235569113 2.00E-108 Hrasls UCSC Mus musculus 3.242093935 0.000674255 Kcnj9 UCSC Mus musculus 3.258987431 6.70E-07 Cadm3 UCSC Mus musculus 3.270290857 0.030440441 Epdr1 UCSC Mus musculus 3.278713961 2.37E-51 Znhit6 UCSC Mus musculus 3.279766755 8.81E-66 C230035I16Rik UCSC Mus musculus 3.299844995 2.81E-20 BB557941 UCSC Mus musculus 3.308728732 4.24E-14 Gpc3 UCSC Mus musculus 3.312018143 0.003654591 3632454L22Rik UCSC Mus musculus 3.321246528 0.006326759 Hs3st1 UCSC Mus musculus 3.328870474 0.000186556 Mei4 UCSC Mus musculus 3.330829904 6.06E-05 Gda UCSC Mus musculus 3.333807767 0.022037865 Smarcd3 UCSC Mus musculus 3.367890804 8.68E-16 Kcnmb4 UCSC Mus musculus 3.399999304 2.17E-05 Asic3 UCSC Mus musculus 3.40092119 0.041542974 Dynlrb2 UCSC Mus musculus 3.417785735 8.80E-12 Cd247 UCSC Mus musculus 3.431529024 3.56E-11 Ccdc150 UCSC Mus musculus 3.437725825 0.008298158 1700016K19Rik UCSC Mus musculus 3.478380959 8.01E-12 BC048546 UCSC Mus musculus 3.479679648 9.76E-63 Khdrbs2 UCSC Mus musculus 3.48176542 0.001458881 Mgat5b UCSC Mus musculus 3.48683079 1.99E-05 Lrrc7 UCSC Mus musculus 3.499256612 0.000723792 Brinp1 UCSC Mus musculus 3.52422015 5.38E-06 Gm10640 UCSC Mus musculus 3.535752497 0.007036542 Slc45a3 UCSC Mus musculus 3.536486427 0.001502603 Rnf152 UCSC Mus musculus 3.540179971 2.39E-25 Myh7b UCSC Mus musculus 3.550981359 6.43E-09 Igsf1 UCSC Mus musculus 3.563000702 3.80E-116 Ribc2 UCSC Mus musculus 3.563378415 0.021629137 Casq1 UCSC Mus musculus 3.567362271 0.018696784 Lrp1 UCSC Mus musculus 3.571706572 9.54E-65 Foxc1 UCSC Mus musculus 3.58027297 0.005642697 Gas1 UCSC Mus musculus 3.58527966 6.69E-05 Mirlet7e UCSC Mus musculus 3.591664922 0.010850254 Gprc5b UCSC Mus musculus 3.606322841 2.17E-26 Ism1 UCSC Mus musculus 3.613061504 1.67E-06 Dcaf12l2 UCSC Mus musculus 3.613330245 2.32E-06 Diabetes Page 114 of 125

Zfp575 UCSC Mus musculus 3.625948643 5.74E-14 Ablim3 UCSC Mus musculus 3.629926866 1.63E-07 Sema4f UCSC Mus musculus 3.640214292 1.91E-12 Adamts6 UCSC Mus musculus 3.680035634 1.47E-65 Prrt4 UCSC Mus musculus 3.687634888 0.018729428 Ppef2 UCSC Mus musculus 3.689875776 0.001207832 Dbx2 UCSC Mus musculus 3.691225238 0.01308219 Sema3g UCSC Mus musculus 3.714457727 2.42E-23 Dnah5 UCSC Mus musculus 3.726447131 0.034770791 Reln UCSC Mus musculus 3.807442645 0.000403511 Dnaaf3 UCSC Mus musculus 3.818280415 2.85E-13 Atcay UCSC Mus musculus 3.834459872 0.016018766 Spag4 UCSC Mus musculus 3.844008637 3.61E-08 Slco4c1 UCSC Mus musculus 3.846677788 0.003835062 Kcnh4 UCSC Mus musculus 3.854012126 1.73E-08 Cd55 UCSC Mus musculus 3.861595731 7.64E-28 Gpr52 UCSC Mus musculus 3.868389427 0.000675276 Mir431 UCSC Mus musculus 3.871940871 0.026104181 Wif1 UCSC Mus musculus 3.89548289 0.019308404 1700001L19Rik UCSC Mus musculus 3.90379753 1.00E-06 Creg1 UCSC Mus musculus 3.909152277 3.14E-161 Mboat4 UCSC Mus musculus 3.925566128 0.029907705 Lrrc34 UCSC Mus musculus 3.943623517 2.26E-09 Ccdc78 UCSC Mus musculus 3.946181187 0.005951477 Pcdha11 UCSC Mus musculus 3.972029906 3.20E-06 Fbn2 UCSC Mus musculus 3.978404999 5.63E-14 Gsta3 UCSC Mus musculus 3.996188343 5.04E-06 Prdm6 UCSC Mus musculus 4.008720664 0.000165254 Ddx4 UCSC Mus musculus 4.02191463 0.001852285 Spag6 UCSC Mus musculus 4.031536936 4.07E-11 Rasl10b UCSC Mus musculus 4.036633795 6.09E-38 Fabp5 UCSC Mus musculus 4.057900009 7.86E-75 Mmp16 UCSC Mus musculus 4.065356674 5.81E-10 LOC100862268 UCSC Mus musculus 4.077633368 9.30E-06 Sstr1 UCSC Mus musculus 4.087757934 5.39E-11 Fkbp9 UCSC Mus musculus 4.08919747 1.40E-82 AA387883 UCSC Mus musculus 4.090564225 5.30E-21 Slc38a11 UCSC Mus musculus 4.119601731 2.88E-09 4930568G15Rik UCSC Mus musculus 4.125434538 0.049916896 Shcbp1l UCSC Mus musculus 4.21493431 1.03E-19 Pdgfd UCSC Mus musculus 4.242969541 1.80E-08 Mdh1b UCSC Mus musculus 4.247856784 7.80E-12 4930483J18Rik UCSC Mus musculus 4.261724313 0.030123201 Gabrd UCSC Mus musculus 4.281076379 6.11E-34 Ncan UCSC Mus musculus 4.282908178 4.23E-05 Fsd1 UCSC Mus musculus 4.307192901 1.36E-16 Mmp17 UCSC Mus musculus 4.347770807 1.00E-14 Smim18 UCSC Mus musculus 4.382143446 2.95E-13 A230056J06Rik UCSC Mus musculus 4.382478655 0.004939774 Tmem74 UCSC Mus musculus 4.394322142 0.024879837 Pde3a UCSC Mus musculus 4.394924289 1.86E-28 Ddah1 UCSC Mus musculus 4.398447799 9.14E-05 Lrriq4 UCSC Mus musculus 4.429514801 0.000597194 Page 115 of 125 Diabetes

Atp2b3 UCSC Mus musculus 4.434614743 0.000191355 Rnd3 UCSC Mus musculus 4.472818125 7.71E-52 Slc2a7 UCSC Mus musculus 4.48946006 4.20E-08 Tram2 UCSC Mus musculus 4.50094031 1.46E-95 Foxr2 UCSC Mus musculus 4.543086747 0.018236958 Gstp2 UCSC Mus musculus 4.570911526 0.019373032 Dydc2 UCSC Mus musculus 4.575336698 4.62E-06 Gm6961 UCSC Mus musculus 4.604758339 0.022671682 Nrg1 UCSC Mus musculus 4.61181827 0.000326022 Adgra1 UCSC Mus musculus 4.637968034 4.71E-06 Gpr37 UCSC Mus musculus 4.665784955 0.015307554 Scn2a1 UCSC Mus musculus 4.673659455 1.10E-15 Gpr162 UCSC Mus musculus 4.67829112 3.84E-168 Gng3 UCSC Mus musculus 4.696819556 4.38E-06 4931440J10Rik UCSC Mus musculus 4.714176889 0.04541163 Gm13483 UCSC Mus musculus 4.737050903 1.76E-13 Adgrb1 UCSC Mus musculus 4.762085565 0.000323247 Chst1 UCSC Mus musculus 4.768892114 0.00177084 Nell2 UCSC Mus musculus 4.820365026 3.46E-16 Zfp804a UCSC Mus musculus 4.840630191 0.037975983 Slc2a12 UCSC Mus musculus 4.855582709 5.35E-45 Tacr2 UCSC Mus musculus 4.865025697 0.032112279 Gal UCSC Mus musculus 4.91717299 0.006680586 Nanos2 UCSC Mus musculus 4.918024411 0.028856056 Ostn UCSC Mus musculus 4.928542659 0.040714131 Nefl UCSC Mus musculus 4.976019322 0.02522647 Rnf207 UCSC Mus musculus 4.978057009 0.023397262 Lrig3 UCSC Mus musculus 4.982460793 0.024648692 Mir874 UCSC Mus musculus 4.983261847 0.023058527 Ipw UCSC Mus musculus 4.990103873 0.004657916 Gm6537 UCSC Mus musculus 5.005479693 8.17E-08 Sct UCSC Mus musculus 5.013395634 0.000337612 Fam26f UCSC Mus musculus 5.041361296 0.003994779 Pdzrn4 UCSC Mus musculus 5.162971726 4.97E-37 A630095E13Rik UCSC Mus musculus 5.174785077 0.018939693 Optc UCSC Mus musculus 5.203577488 0.02630482 Gpr61 UCSC Mus musculus 5.205471628 0.012993805 Inhba UCSC Mus musculus 5.220044166 1.51E-10 Basp1 UCSC Mus musculus 5.25641662 1.61E-264 Tnni3 UCSC Mus musculus 5.279418741 9.61E-09 Cnksr2 UCSC Mus musculus 5.28985786 0.017484837 Fat3 UCSC Mus musculus 5.292174416 1.16E-12 1500009C09Rik UCSC Mus musculus 5.311682604 0.008871374 Cyp1a1 UCSC Mus musculus 5.315173261 0.009501201 Chodl UCSC Mus musculus 5.339480149 0.001822421 Kcnd2 UCSC Mus musculus 5.341047524 1.87E-08 Cbln1 UCSC Mus musculus 5.345916812 0.005976258 Gm5468 UCSC Mus musculus 5.349867155 0.001332047 Pianp UCSC Mus musculus 5.352542555 0.004850074 Slc24a3 UCSC Mus musculus 5.366013507 1.45E-37 Lrrc4c UCSC Mus musculus 5.371432099 0.007127287 Best1 UCSC Mus musculus 5.372953959 0.006530134 Gm5820 UCSC Mus musculus 5.38000071 4.01E-07 Diabetes Page 116 of 125

Gm1661 UCSC Mus musculus 5.380802733 2.17E-14 Dio2 UCSC Mus musculus 5.504070033 0.006648325 4930447M23Rik UCSC Mus musculus 5.550472449 0.003495701 Rasgef1c UCSC Mus musculus 5.578156318 0.004123306 6330415B21Rik UCSC Mus musculus 5.585347566 0.003912628 Layn UCSC Mus musculus 5.597797887 2.17E-12 Pde1a UCSC Mus musculus 5.645809529 2.09E-25 Adcy5 UCSC Mus musculus 5.654073668 1.61E-51 Gucy1b3 UCSC Mus musculus 5.668302239 2.36E-301 A330074K22Rik UCSC Mus musculus 5.677633165 6.37E-11 Nxf2 UCSC Mus musculus 5.764958186 0.000215068 Klhl1 UCSC Mus musculus 5.770452252 5.96E-06 Tmem136 UCSC Mus musculus 5.7714867 0.002570375 Npvf UCSC Mus musculus 5.857514278 0.001081797 Sema3c UCSC Mus musculus 5.937042217 0 Nlrp12 UCSC Mus musculus 6.041697163 5.81E-05 Gucy1a3 UCSC Mus musculus 6.057436158 3.27E-97 Itga8 UCSC Mus musculus 6.120181623 4.31E-05 L3mbtl1 UCSC Mus musculus 6.14879152 4.95E-40 Pcdh9 UCSC Mus musculus 6.165217796 9.40E-15 Fst UCSC Mus musculus 6.173719573 0.002689107 Zfp652os UCSC Mus musculus 6.215517789 0.000218927 Dll3 UCSC Mus musculus 6.242408169 0.000195756 Adra1b UCSC Mus musculus 6.320450733 8.35E-07 Lrrc2 UCSC Mus musculus 6.424653414 7.16E-05 Nrg4 UCSC Mus musculus 6.503634333 9.85E-05 Cntnap3 UCSC Mus musculus 6.531027525 1.92E-05 Csn1s2b UCSC Mus musculus 6.599375749 0.000197801 Kif26b UCSC Mus musculus 7.108428975 1.43E-06 1700020L24Rik UCSC Mus musculus 7.343313097 4.31E-07 Epha5 UCSC Mus musculus 7.462321596 1.49E-13 Neto1 UCSC Mus musculus 7.504948449 5.86E-06 Tctex1d1 UCSC Mus musculus 7.792153451 2.76E-08 Cbln2 UCSC Mus musculus 7.856825071 2.21E-08 Fgf13 UCSC Mus musculus 8.195088498 4.67E-10 Lsamp UCSC Mus musculus 8.198050142 8.85E-10 Abcg5 UCSC Mus musculus 8.199160351 3.10E-10 Zfpm2 UCSC Mus musculus 8.259528359 3.84E-09 Bmper UCSC Mus musculus 8.338017861 3.01E-10 2900011O08Rik UCSC Mus musculus 8.538802579 6.78E-11 Gdpd2 UCSC Mus musculus 9.081332693 1.53E-15 4833423E24Rik UCSC Mus musculus 9.104424268 1.79E-23 Stac UCSC Mus musculus 9.48196429 1.25E-13 Page 117 of 125 Diabetes

GO terms/gene list for differentially expressed βDKO genes

-log(10) p- Term p-value Genes value

Atp1b1, Cd22, Cd24a, Cd36, Cd9, Cd93, Cd96, Cd99l2, Cuzd1, Egfl7, Epha2, Fat3, Frem2, L1cam, Radil, Sspo, Tyro3, Adam15, Adam23, Ache, Adgrg1, Amigo2, App, Aplp1, Bcam, Boc, Bcar1, Cdh22, Cdh4, Celsr1, Cdhr2, Cib1, Clstn3, Comp, Ctnna2, Ctnnb1, Cadm3, Cdon, Cercam, Cx3cl1, Cx3cr1, Cldn11, Col8a1, Col19a1, Col15a1, Col28a1, Csf3r, Ctgf, Cntn1, Cxadr, Cyr61, Dpp4, Emilin1, Emb, Emp2, Fermt1, Flrt1, Fbln5, Fbln7, Fblim1, Gp9, Grhl2, Hpse, Hapln1, cell adhesion 4.00E-17 16.40 Igsf11, Inppl1, Igfbp7, Igfals, Itga2, Itga4, Itga6, Itga8, Itgax, Icam1, Icam2, Icam5, Izumo1, Jam3, Klra2, Kirrel3, Lamc1, Lamc2, Lsamp, Lyve1, Mcam, Msln, Mslnl, Muc4s, Megf10, Myh10, Npnt, Ncam1, Nedd9, Nrxn1, Nrxn3, Ncan, Negr1, Ninj1, Olfm4, Parvb, Podxl2, Podxl, Prkx, Ptprk, Ptprs, Pcdh15, Pcdh8, Pcdha3, Pcdha9, Pcdhb18, Pcdhgb4, Reln, Rom1, Scarf2, Spp1, Sdk1, Sdk2, Sorbs3, Spon1, Spon2, Stab1, Stab2, Sdc3, Tnr, Tenm3, Thbs3, Tgfbi, Tmem8, Troap, Ttyh1, Vcam1, Vcl, Zan, Zyx

Atp5l, Atp2a2, Atp2b4, Atp2a3, Atp7a, Atp7b, Atp6ap1, Atp4a, Atp1b1, Bspry, Fxyd3, Kcnip4, Kcnip2, Nipal1, Racap1, Wnk4, Asic1, Asic2, Asic3, Best1, Best3, Cacna1b, Cacna1h, Cacna1f, Cacna2d4, Calhm2, Cp, Clic5, Chrna4, Chrna7, Chrnb4, Cldn15, Cngb3, Cybb, Fam26f, Gabra4, Gabrd, Gabrg1, Gabrr2), Gria3, Grin2c, Grin2d, Hcn1, Hcn4, Itpr3, Lrrc38, Lrrc55, Lrrc8b, Lrrc8c, Lhfpl5, Mcoln3, Pkd1l3, Pkd2l2, Kcnk13, Kcnk3, Kcnn2, Kcnn3, Kcnn4, Kcnj11, Kcnj12, Kcnj13, (Kcnj3, Kcnj4, Kcnj5, Kcnj9, Kcnmb1, Kcnmb2, Kcnmb4, Kcnc1, Kcnc2, Kcnd2, Kcnab1, Kcnab3, Kcna2, ion transport 1.10E-12 11.96 Kcnf1, Kcng3, Kcnh1, Kcnh5, Kcnh8, Kcnq1, Kcnq2, Kcnq4, P2rx6, Sfxn2, Sfxn3, Sfxn4, Sfxn5, Steap1, Scnn1a, Scnn1b, Scnn1g, Scn3b, Scn4a, Slc12a1, Slc12a2, Slc12a4, Slc12a5, Slc12a7, Slc17a4, Slc22a18, Slc22a23, Slc24a, Slc26a1, Slc26a11, Slc26a8, Slc30a7, Slc30a8, Slc31a1, Slc38a11, Slc38a4, Slc4a3, Slc4a8, Slc4a7, Slc4a10sSlc40a1, Slc5a1, Slc5a10, Slc5a9, Slc6a15, Slc6a8, Slc8a2, Slco1a5, Slco1a6, Slco2a1, Slco2b1, Slco3a1, Slco4c1, Slco5a1, Tcn2, Trf, Trpc4, Trpm1, Trpm5, Trpv2, Trpv3, Trpv6, Tmc7, Tmem37, Tmem63a, Ttyh1, Ttyh2 Atp5l, Atp2a2, Atp2b4, Atp2a3, Atp7a, Atp7b, Atp6ap1, Atp4a, Atp1b1, Bspry, Fxyd3, Kcnip4, Kcnip2, Nipal1, Racap1, Wnk4, Asic1, Asic2, Asic3, Best1, Best3, Cacna1b, Cacna1h, Cacna1f, Cacna2d4, Calhm2, Cp, Clic5, Chrna4, Chrna7, Chrnb4, Cldn15, Cngb3, Cybb, Fam26f, Gabra4, Gabrd, Gabrg1, Gabrr2), Gria3, Grin2c, Grin2d, Hcn1, Hcn4, Itpr3, Lrrc38, Lrrc55, Lrrc8b, Lrrc8c, Lhfpl5, Mcoln3, Pkd1l3, Pkd2l2, Kcnk13, Kcnk3, Kcnn2, Kcnn3, Kcnn4, Kcnj11, Kcnj12, Kcnj13, (Kcnj3, Kcnj4, Kcnj5, Kcnj9, Kcnmb1, Kcnmb2, Kcnmb4, Kcnc1, Kcnc2, Kcnd2, Kcnab1, Kcnab3, Kcna2, ion transport 1.10E-12 11.96 Kcnf1, Kcng3, Kcnh1, Kcnh5, Kcnh8, Kcnq1, Kcnq2, Kcnq4, P2rx6, Sfxn2, Sfxn3, Sfxn4, Sfxn5, Steap1, Scnn1a, Scnn1b, Scnn1g, Scn3b, Scn4a, Slc12a1, Slc12a2, Slc12a4, Slc12a5, Slc12a7, Slc17a4, Slc22a18, Slc22a23,Diabetes Slc24a, Slc26a1, Slc26a11, Page 118 of 125 Slc26a8, Slc30a7, Slc30a8, Slc31a1, Slc38a11, Slc38a4, Slc4a3, Slc4a8, Slc4a7, Slc4a10sSlc40a1, Slc5a1, Slc5a10, Slc5a9, Slc6a15, Slc6a8, Slc8a2, Slco1a5, Slco1a6, Slco2a1, Slco2b1, Slco3a1, Slco4c1, Slco5a1, Tcn2, Trf, Trpc4, Trpm1, Trpm5, Trpv2, Trpv3, Trpv6, Tmc7, Tmem37, Tmem63a, Ttyh1, Ttyh2

Atp4a, Atp1b1, Kcnip4, Kcnip2, Hcn1, Hcn4, Kcnk13, Kcnk16, Kcnk2, Kcnn2, Kcnn3, Kcnn4, Kcnj11, Kcnj12, Kcjn13, Kcnj3, Kcnj4, potassium ion Kcnj5, Kcnj9, Kcnmb1, Kcnmb2, Kcnmb4, 8.80E-09 8.06 transport Kcnc1, Kcnc2, Kcnd2, Kcnab1, Kcnab3, Kcna2, Kcnf1, Kcng3, Kcnh1, Kcnh5, Kcnh8, Kcnq1, Kcnq2, Kcnq4, Scn4a, Slc12a1, Slc12a2, Slc12a4, Slc12a5, Slc12a7, Slc24a3

Axl, Cited1, Ddx25, Ddx4, Edaradd, Egfl7, Eya2, Epha2, Gpsm1, Iqcg, L1cam, Lhx1, Lhx6, Mecom, Micalcl, Mycbpap, Nell1, Nkapl, Nkx6-2, Nme5, Rorc, Rasgrp1, 1110017D15Rik, Racgap1, Arhgap22, Shank1, Sox11, Shcbp1l, Spic, Acvr1c, Adgrg1, Agrn, Anpep, Angptl6, Anks4b, Arx, Bmp6, Bmpr1b, Cdhr2, Cib1, Camk2b, Calr3, Caprin2, Ctnna2, Ctnnb1, Cdx4, Cdc20, Cby1, Cspg5, Chd5, Cchcr1, Col19a1, Ctgf, Cpne5, Cpne6, Dock7, Dazl, Dlk1, Dll3, Dner, Dab1, Dab2, Dcx, Dusp6, Ect2, Eda2r, Eda, Efna5, Efnb3, Ehf, Fgf1, Fgfr3, Foxa3, Foxn1, Frzb, Frk, Ggn, Gadd45b, Gadd45g, Hhex, cell differentiation 1.30E-07 6.89 Hck, Hnf4a, Hils1, Igsf9, Itga8, Lgals3, Lrrk2, Meg3, Mgp, Matk, Meig1, Myrf, Myt1l, Mlf1, Nanos2, Npnt, Ngfr, Neurod1, Neurog3, Ngef, Nrp1, Ntrk1, Ntrk3, Notch1, Notch2, Nr6a1, Ostn, Ptchd2, Peg10, Pld6, Piwil4, Plet1, Pgf, Plk5, Pbxip1, Paqr7, Paqr8, Psmb8, Pkdcc, Prkx, Rfx6, Sfrp5, Sema4f, Sema3c, Sema3e, Sema4a, Sema4c, Sema4g, Sema6b, Sema6d, Serpine2, Srpk3, Slit1, Slit2, Slc26a8, Slco4c1, Shb, Stmn1, Suv39h2, Syt1, Syt2, Sdc2, Tcp11, Tenm3, Tenm4, Tesc, Tcf4, Tgfbr2, Tmtc3, Tmem176b, Ttll7, Tdrkh, Vegfa, Vegfc, Wnt4, Zfp750 Page 119 of 125 Diabetes

Lyn, Arhgef39, Adra2a, Ager, Aif1, Bcar1, Cib1, Ctsh, Ccl3, Cxcl10, Cxcl16, Cxcr4, Cx3cl1, F2r, Csf1r, C3ar1, Cyr61, Dab2, Fam110c, Fgf1, Foxf1, Hbegf, Irs2, Itga6, positive Lamc2, Mmp14, Mcam, Mylk, Ntrk3, Notch1, regulation of cell 3.30E-07 6.48 Pak1, Pld1, Plet1, Plau, Pdgfb, Pdgfd, Podxl, migration Ptprz1, Rhod, Rras2, Sema4f, Sema3c, Sema3e, Sema3f, Sema3g, Sema4a, Sema4c, Sema4g, Sema6b, Snai2, Tgfb1, Vegfa, Vil1, Wnt5b, Zfp703

Bcl6, Btg1, Cebpa, Cd9, Fbxo2, Lyn, Ndrg1, Pds5b, Rerg, 4930503L19Rik, Rian, Rassf5, Tgif1, Wdr6, Atf5, Acvrl1, Adora1, Adgrg1, Agt, Bche, Cib1, Ctnnb1, Chd5, F2r, Csf1r, Cdkn1a, Cdkn2a, Cdkn2b, Cdkn2c, Dlc1, Ddr1, Fgfr2, Fgfr3, Foxa3, Fosl1, Frzb, Gal, negative Gpc3, Hspa1a, Hnf4a, Inhba, Ing2, Inppl1, regulation of cell 3.30E-07 6.48 Inpp5d, Irf1, Ifit3, Il1a, Il1b, Lefty1, Lzts2, Lif, proliferation Kmt2a, Meg3, Ntrk1, Nos3, Notch1, Notch2, Ovol2, Ptch1, Podn, Plk5, Ptprz1, Ptprk, Rgcc, Rxfp2, Ripply3, Runx1, Sfrp5, Serpine2, Slit2, Slc9a3r1, Sstr1, Sstr2, Spry1, Spry2, Tesc, Timp2, Tlr2, Trp53inp1, Tgfb1, Tgfbr2, Trpv2, Trim35, Tnfrsf9, Tnf, Vegfc, Vdr, Zfp503

Oas2, Oas3, Oasl2, Axl, Bcl6, Cd14, Cd300a, Cd55, Cd74, Cd79a, Fcgr1, Gpr183, Itk, Lyn, Mx1, Mb21d1, Nlrc4, Prdm1, Pycard, Slamf7, Tbkbp1, Adgre1, Bst2, Camk4, Csf1r, Cr1l, C1qc, C1qa, C1qb, C1ra, C2, C4bp, C8b, Cfb, Erap1, Exo1, Fcna, Ffar2, Ffar3, Gsdmd, immune system Gbp5, Hck, Hmgb3, H2-Aa, H2-Ab1, H2-Eb1, 1.10E-06 5.96 process Inppl1, Inpp5d, Ifi30, Ifitm2, Irf1, Irf5 Irf7, Ifit2, Ifit3, Jagn1, Lgals3, Lgals9, Lilrb4a, Lbp, Ly86, Ly96, Lax1, Mfsd6, Myo1g, Nrros, Nr1h4, Nod1, Pik3cg, Pag1, Kcnn4, Psmb8, Prkcb, Rsad2, Ssc5d, Sema4a, Serping, Serinc5, Spon2, Skap1, Sftpd, Tlr12, Tlr13, Tlr2, Tmem173, Tnfrsf21

Adpgk, Fggy, B4galt5, Amy1, Chst14, Chst8, Chst9, Chst1, Chst10, Chst11, Chil1, Chil6, Fbp2, Galm, Gale, Gla, Glb1, Glb1l2, Galc, carbohydrate Gck, Gnpda2, Gaa, Gba, Gpd1, Ggta1, metabolic 1.30E-06 5.89 Hhipl1, Hpse, Hk2, Hexdc, Hexa, Hexb, process Hyal1, Ins1, Ins2, Igf2, Klb, Ldha, Ldhb, Pygl, Mdh1b, Mgam, Man2b1, Man2b2, Neu2, Pgm2l1, Pofut1, Ppp1r1a, Ppp1r3b, Ppp1r3c, Pdk4, Pklr, Rbks, Akt1, Xylb Diabetes Page 120 of 125 Genes upregulated in βDKO β cells and bound by Pdx1 (Figure 8A) 1190002N15Rik, 1700012D14Rik, 1700013F07Rik, 1700016K19Rik, 1700028K03Rik, 4430402I18Rik, 4930503L19Rik, 5330417C22Rik, 6430550D23Rik, 9230114K14Rik, 9530077C05Rik, 9530082P21Rik, A230056P14Rik, A230057D06Rik, Abcd2, Abcg5, Acbd7, Acvr1c, Adam22, Adam23, Adamts6, Adamts9, Adgrb3, Agpat4, AI450353, Aim1, Akr1c19, Aldh1b1, Amigo2, Angptl6, Ankef1, Ankrd37, Ap1s2, Apc2, Aph1c, App, Arhgap18, Arhgap36, Arid1a, Arid5b, Arsb, Asb4, Asic2, Astn2, Atp1b1, Atp5l, Atp7b, Atp8b1, Atp8b5, Bach2, BC048546, Bcl6, Bmper, Bnip3, Brca2, Btbd3, Btg3, C230035I16Rik, Calr3, Camk1d, Camk2b, Car11, Casc1, Casq1, Cc2d2a, Ccdc107, Ccdc132, Ccdc150, Ccdc151, Ccdc173, Ccdc30, Ccdc39, Ccdc65, Cd247, Cd276, Cdc42ep3, Cdh4, Cdk17, Cdon, Cecr2, Cep112, Cep128, Cers4, Cers6, Cfap52, Cfap58, Chac1, Chd3, Chd9, Chgb, Chst1, Ciart, Clasp1, Clasp2, Clstn3, Clu, Clybl, Cnih2, Cnksr2, Cntn1, Col25a1, Col8a1, Col9a2, Cpn1, Ctnna2, Cxxc4, Cyp1a1, Dazl, Ddit3, Ddost, Ddr1, Ddx4, Dennd4b, Dgkb, Dhfr, Diras2, Dmxl2, Dnah2, Dnah5, Dnaic1, Dnajc12, Dnajc21, Doc2b, Dock7, Dos, Dusp14, Dusp15, Dusp26, Dusp4, Dusp6, Dusp9, Dync2h1, Dzank1, Eef2k, Efcab10, Efhc1, Efna5, Emb, Enkur, Entpd3, Epha5, Epha7, Erap1, Erc2, Etnk2, Etv1, Exd1, F3, Fabp5, Fam101a, Fam110b, Fam135a, Fam161a, Fam168a, Fam196a, Fam46a, Fam57b, Fancb, Fank1, Fat3, Fbxo15, Fbxo2, Fbxo31, Fdxr, Fgd4, Fgd6, Fgf12, Fggy, Fkbp9, Fmn1, Fmnl3, Fnbp1l, Foxp2, Fra10ac1, Frk, Frrs1l, Frzb, Fut10, Gaa, Gal, Gas1, Ghr, Ghrl, Gm166, Gm1661, Gm2a, Gm996, Golim4, Gpc4, Gpc6, Gpr3, Gpr37, Gpr52, Gpr6, Gpr61, Gpr85, Gprc5b, Grb10, Grb14, Greb1l, Gsap, Gsto2, Gtdc1, Gucy1a2, Gucy1a3, Gucy1b3, Hcn1, Hcrtr2, Hdac5, Hectd2, Hexa, Hexdc, Hlf, Hoxb2, Icam2, Ifnar2, Ift140, Igsf8, Immp2l, Impg2, Inhba, Inpp4b, Inppl1, Iqcd, Irf2bpl, Isl1, Ism1, Itga4, Jam3, Jph4, Katnal2, Kcnc1, Kcnd2, Kcnip4, Kctd15, Kif17, Kif9, Kifc3, Klf12, Klhl1, L3mbtl1, Lag3, Lamc1, Ldhb, Ldhd, Ldlrad4, Letm2, Lhpp, Lin28a, Lmo1, Lrp1, Lrpprc, Lrrc24, Lrrc48, Lrrc7, Lrrc8b, Lrrn1, Lsamp, Lsr, Ltbp3, Lypd6b, Lyrm7, Maml2, Map3k12, Map3k13, Mapt, Med12l, Meg3, Meig1, Mfsd6, Mgat5b, Mir874, Mirlet7d, Mmp16, Mmp17, Mpp2, Mterf2, Mttp, Mvb12b, Myh10, Myh7b, Myl6b, Myt1l, N4bp2, Nav3, Nbea, Ncam1, Negr1, Nek6, Nell2, Nenf, Neurl2, Neurod1, Nfia, Nfkbid, Nlk, Nomo1, Nos1ap, Npas2, Npas4, Npr2, Npvf, Nr4a1, Nr4a3, Nr6a1, Nrm, Nrxn1, Nrxn3, Nucb2, Ogfod3, Olfml2b, Olfr54, Opcml, Optc, P4ha1, Pacrg, Pak7, Palm, Pam, Park2, Parp8, Pcdh8, Pcdh9, Pcdha10, Pcdha11, Pcdha12, Pcdha2, Pcdha3, Pcdha5, Pcdha8, Pcdha9, Pcdhgc4, Pcsk1n, Pcsk6, Pcyox1l, Pde10a, Pde3a, Pde4d, Pds5b, Pdxp, Pdzrn4, Per1, Per3, Pgm2l1, Pik3ap1, Pik3c2b, Pla2g16, Plag1, Plcxd3, Plekha5, Plod3, Podxl2, Pou2f1, Ppef2, Ppm1k, Ppp2r2b, Prdm6, Prickle2, Prkcsh, Psd2, Ptchd2, Ptprg, Ptprs, Ptprt, Pygl, Qpct, Rab6b, Rad1, Radil, Ralgps1, Ralgps2, Rapgef6, Rasgef1c, Rasgrf1, Rasgrf2, Rasgrp1, Rasip1, Rasl10b, Rbp4, Rccd1, Rcn1, Recql4, Rell2, Reln, Rem2, Rfx6, Rhof, Rhox8, Rian, Rin2, Rnd2, Rnf112, Rnf122, Rnf32, Rorc, Rpn2, Rsph4a, Sall4, Samd12, Scel, Scg3, Scg5, Scml4, Scn3a, Scn3b, Scn4a, Sdc2, Sdk1, Sec1, Sema3c, Sema3f, Sema6d, Senp7, Sertad3, Sesn3, Sfxn3, Sfxn5, Sgip1, Sh2d3c, Shf, Shisa4, Sil1, Skil, Slc25a33, Slc26a8, Slc27a1, Slc29a4, Slc2a7, Slc37a2, Slc45a2, Slc4a3, Slc4a8, Slit2, Smap2, Smarcd3, Snap25, Snap91, Snora69, Sntg1, Snx7, Socs5, Sorl1, Spa17, Spats2, Spry4, Srcin1, Srgap3, Srl, Ssc4d, St18, St3gal6, Stk32b, Stpg1, Stxbp5l, Susd2, Syn3, Syne1, Syt16, Sytl5, Tanc2, Tbc1d30, Tbl1xr1, Tcf4, Tctn1, Tctn2, Tdrkh, Tenm3, Tjp2, Tmc7, Tmcc3, Tmed1, Tmem130, Tmem132a, Tmem14a, Tmem158, Tmem194, Tmpo, Tnfrsf21, Tox, Tram2, Trerf1, Trim46, Trim67, Trim7, Ttc34, Ttc9, Ubqln2, Uggt2, Ulk4, Usp2, Usp29, Vkorc1, Vwde, Wasf1, Wasf3, Wdr89, Wdr90, Wsb1, Wwc1, Xrra1, Xylb, Ypel1, Zbtb12, Zc3h12c, Zfp219, Zfp239, Zfp473, Zfp503, Zfp575, Zfp703, Zmat4, Zmynd12, Znhit6

-log(10) Term p-value p-value Genes Fat3, Amigo2, Cdh4, Clstn3, Ptprt, Pcdh8, Pcdh9, homophilic cell adhesion via plasma Pcdha10, Pcdha11, Pcdha12, Pcdha2, Pcdha3, 3.30E-07 6.48 membrane adhesion molecules Pcdha5, Pcdha8, Pcdha9, Pcdhgc4, Sdk1, Tenm3 Atp1b1, Fat3, Radil, Adam23, Amigo2, App, Cdh4, Clstn3, Ctnna2, Cdon, Col8a1, Cntn1, Emb, Inppl1, Itga4, Icam2, Jam3, Lamc1, Lsamp, cell adhesion 5.60E-07 6.25 Myh10, Ncam1, Nrxn1, Nrxn3, Negr1, Podxl2, Ptprs, Pcdh8, Pcdha, Pcdha9, Reln, Sdk1, Tenm3 Page 121 of 125 Diabetes positive regulation of synapse Asic2, Adgrb3, Amigo2, Clstn3, Efna5, Eef2k, 5.40E-06 5.27 assembly Ghrl, Lrrc24, Lrrn1, Nrxn1, Nrxn3 neuromuscular process controlling Gm2a, Ap1s2, App, Camk2b, Gaa, Hexa, Jph4, 8.00E-06 5.10 balance Myh10, Nrxn1, Nr4a3 Epha5, Cdh4, Efna5, Etv1, Gas1, Lamc1, Meg3, axon guidance 5.40E-05 4.27 Myh10, Ncam1, Nr4a3, Reln, Sema3c, Sema3f, Slit2 Gpr52, Gprc5b, Park2, App, Gaa, Hexa, Klhl1, locomotory behavior 2.40E-04 3.62 Negr1, Pak7, Reln, Snap25 Arid1a, Btbd3, Chac1, Epha5, Epha7, Smarcd3, App, Camk1d, Camk2b, Cntn1, Dock7, Efna5, nervous system development 2.60E-04 3.59 Gal, Hdac5, Myt1l, Neurod1, Sema3c, Sema6d, Slit2, Scn3b, Sdc2, Tcf4 Dusp14, Dusp26, Dusp4, Dusp6, Dusp9, protein dephosphorylation 4.40E-04 3.36 Dusp15, Lhpp, Ppm1k, Ptprg, Ptprs, Ptprt, Pdxp Diabetes Page 122 of 125

Genes downregulated in βDKO β cells and bound by Pdx1 (Figure 8A) 1700011H14Rik, 1700018L02Rik, 1700029I15Rik, 1810011O10Rik, 1810041L15Rik, 2010107G12Rik, 2010111I01Rik, 2010204K13Rik, 2310022B05Rik, 2810417H13Rik, 2900060B14Rik, 3930402G23Rik, 4833439L19Rik, 4930470P17Rik, 4930513N10Rik, 4930539E08Rik, 4930550C14Rik, 4931409K22Rik, 5330439B14Rik, 5830416P10Rik, 6430548M08Rik, 6430562O15Rik, 8430408G22Rik, 9130023H24Rik, 9130230L23Rik, 9530036O11Rik, Aacs, Abat, Abca4, Abcc3, Abcc8, Abhd13, Abhd2, Ace2, Acly, Actc1, Actn2, Acvrl1, Adamts17, Adgrd1, Adgrf1, Adgrg1, Adh1, Adh7, Adora1, Adora3, Adpgk, Adra2a, Adtrp, Agt, Agxt2, AI427809, Ak1, Ak5, Akr1c13, Akt1, Alb, Aldh1a1, Aldh1a3, Aldob, Alox5ap, Aloxe3, Alpk3, Angptl2, Angptl7, Ank, Ankrd33b, Anln, Antxr1, Anxa13, Anxa2, Aox1, Apcdd1, Aplnr, Apoa2, Apobec4, Areg, Arg1, Arhgap11a, Arhgap26, Arhgap28, Arhgdib, Arhgef16, Arid5a, Arl8b, Armc5, Artn, Arx, Asic1, Atf3, Atf5, Atp2a2, Atp2a3, Atp2b4, Atp4a, Atp7a, Aurka, Aurkb, Avpr1b, B330016D10Rik, B3galnt1, B3gnt3, B4galnt3, B4galt5, B830017H08Rik, Bace2, Barhl1, Barx2, BC002163, BC089597, Bcar1, Best3, Birc3, Birc5, Bmp6, Bmpr1b, Boc, Btbd17, Btg1, Bzw1, C1qa, C1qb, C1qc, C2cd4b, C8b, Cabp7, Cacna1g, Cacna2d4, Capn5, Capn8, Capn9, Cartpt, Cbs, Ccdc25, Ccnb2, Ccnd2, Ccrn4l, Cd36, Cd72, Cd83, Cd93, Cdc14a, Cdc6, Cdca2, Cdh22, Cdk1, Cdk15, Cdo1, Cebpa, Cecr6, Celsr1, Cep55, Cerk, Ces1d, Ces5a, Cgnl1, Chd5, Chd7, Chga, Chil1, Chrm3, Chrnb4, Chst11, Chst8, Cilp, Cited4, Ckap2, Ckap2l, Cks2, Cldn11, Cmtm6, Cnn3, Cntfr, Coa3, Col15a1, Col19a1, Col1a2, Col27a1, Col28a1, Col4a1, Col4a2, Comp, Comt, Coro2a, Coro2b, Cplx3, Cpm, Cpne4, Cpxm2, Creb3l1, Crhr2, Cryba2, Crybb3, Crybg3, Cstad, Ctnnb1, Cuzd1, Cyb5b, Cyb5r3, Cybrd1, Cym, Cyp4f39, Cyr61, D030025P21Rik, D430019H16Rik, D5Ertd579e, Dab1, Dact1, Dact2, Dapp1, Dcaf13, Dcdc2a, Dct, Dcx, Ddc, Ddit4, Ddit4l, Ddx31, Defb1, Degs1, Degs2, Depdc1b, Dgkg, Dhrs4, Dhx32, Dio1, Disp2, Dlc1, Dlg2, Dlgap1, Dlk1, Dnah8, Dnaic2, Dnaja4, Dnajc24, Dnase2b, Dnmt3b, Dock1, Dock10, Dpp4, Dram1, Dtl, Dusp1, Dusp5, E430025E21Rik, Ece1, Ech1, Ect2, Edaradd, Edn2, Edn3, Eepd1, Efcab5, Ehf, Ehhadh, Eldr, Elmo1, Elovl5, Emid1, Endou, Enho, Eps8, Erich6, Ero1lb, Errfi1, Esco2, Esr1, Esyt1, Eva1b, Evpl, Exo1, Eya2, Ezr, Fa2h, Fam105a, Fam107a, Fam107b, Fam117a, Fam129a, Fam129b, Fam135b, Fam151a, Fam163a, Fam19a1, Fam20a, Fam20c, Fam210b, Fam43a, Fam46c, Fam64a, Fam71a, Fam81a, Fam83d, Fam83g, Fanci, Fblim1, Fbp1, Fbp2, Fbxl16, Ffar1, Ffar2, Fgfr1, Fgfr2, Fhdc1, Fhod3, Fibin, Fitm2, Fkbp1b, Flrt1, Fmo1, Foxq1, Frem2, Frmd4b, Fzd8, G6pc2, Gad1, Gadd45b, Gadd45g, Gale, Galnt14, Galnt18, Galnt4, Galnt9, Galr1, Galr3, Garnl3, Gas2, Gast, GatmGc, Gcg, Gcgr, Gch1, Gck, Gcnt4Gdap2, Gdf15, Gem, Gfra1, Ggact, Ggta1, Ghsr, Gins3, Gipr, Gjd2, Glb1l2, Gldc, Glis1, Glod5, Glp1r, Glrx5, Glul, Gm10941, Gm11992, Gm4925, Gm5087, Gm5105, Gm572, Gm609, Gm7616, Gmnn, Gnai2, Gnai3, Gng12, Gpd1, Gpr142, Gpr161, Gpr179, Gpr183, Gpr26, Gpr39, Gprc5a, Gpsm1, Gpx3, Grhl1, Grin2c, Grip2, Grk5, Grm4, Gstm1, Gstt1, Gstt2, Gstt3, Gstz1, Gtse1, Guca1b, Gyltl1b, Hadh, Hapln1, Hcar1, Hcar2, Hcn4, Hdac6, Hdc, Hepacam2, Hhat, Hhatl, Hhex, Hip1r, Hmgn3, Hn1l, Hpcal1, Hpse, Hrh3, Hs3st6, Hs6st1, Hspb8, Hyal1, Iapp, Ica1l, Idh2, Ier5, Ifngr2, Igfbp7, Igsf11, Igsf21, Il17re, Il1a, Il1b, Il1rn, Il20rb, Il6ra, Impdh1, Ing2, Ins1, Ins2, Insrr, Irak3, Irf1, Irs2, Itk, Itpkb, Ivd, Iyd, Kazn, Kcnab3, Kcnc2, Kcng3, Kcnh1, Kcnh5, Kcnj11, Kcnj12, Kcnj13, Kcnj5, Kcnk13, Kcnmb1, Kcnmb2, Page 123 of 125 Diabetes Kcnn3, Kctd12, Kif20a, Kif2c, Kifc1, Kirrel3, Klb, Klf5, Klhl32, Klhl7, Kntc1, Krt18, Krt19, Krt7, Krt8, Krt80, Ky, Kynu, Lacc1, Laptm5, Lars2, Lbh, Lbp, Lgals12, Lgals3, Lgals9, Lgalsl, Lgi2, Lhfpl2, Lhx1, Lif, Lifr, Limd1, Lingo1, Lix1, Llgl2, Lonrf3, Lpcat3, Lrp8, Lrrc10b, Lrrc18, Lrrc36, Lrrc8c, Lrrfip2, Lrtm2, Ltbp2, Luzp2, Ly6h, Lyve1, Lyz2, Mab21l1, Mafa, Man1c1, Map3k14, Map3k15, Mapkapk3, Matn2, Mctp2, Mecom, Medag, Megf10, Mettl7a1, Mfsd6l, Mgarp, Mgst1, Misp, Mki67, Mlxipl, Mmd, Mnx1, Mob3b, Mpp3, Mroh7, Msh5, Msrb3, Mthfd1l, Mtss1l, Muc4, Mx1, Mxd3, Mxra7, Myc, Mycn, Myl7, Myo18b, Myof, Myrf, Nabp1, Nav2, Ncf1, Nckap5, Ndrg1, Ndst4, Ndufs2, Neat1, Neb, Necab2, Neil3, Nek2, Nell1, Neurl1b, Neurl3, Neurog3, Nfix, Nfkbiz, Ngfr, Ninj1, Nipal1, Nkiras2, Nkx6.2, Nostrin, Notch1, Npepl1, Npnt, Npr1, Nptx2, Npy, Nqo1, Nr1h4, Nr1i2, Nrp1, Ntrk1, Ntrk3, Nuak2, Nuf2, Nup93, Nupr1, Nusap1, Nxph1, Oacyl, Oasl2, Ociad2, Ogdhl, Oit1, Olfm4, Omp, Oprm1, Orc6, Osgin1, Otoa, Ovol2, Oxtr, P2ry12, P2ry14, Pag1, Palmd, Pappa, Pappa2, Papss2, Parvb, Pax6os1, Pbld2, Pcbp3, Pcdh15, Pcdhgc3, Pcp4, Pcsk4, Pcsk9, Pcx, Pde5a, Pde6c, Pde8b, Pdia2, Pdk4, Pdlim4, Pdyn, Pdzrn3, Peg13, Per2, Pex26, Pfkfb3, Phlda1, Phtf1os, Pid1, Pigr, Pitpnm2, Pitpnm3, Pkdcc, Pkhd1, Pla2g2d, Platr26, Plb1, Plcz1, Pld1, Plet1, Plk3, Podxl, Pole4, Ppm1e, Ppp1r17, Ppp1r1a, Ppp1r3b, Ppp1r3c, Ppy, Pqlc3, Prdm14, Prkacb, Prkcb, Prlr, Proc, Prr29, Prr5l, Prss23, Psat1, Psmb10, Psrc1, Ptgr1, Ptprk, Ptprz1, Pxt1, Pxylp1, Pyy, Rab20, Rab37, Rab3b, Rab6a, Rad54b, Rangap1, Rap1gap2, Rasd1, Rasl11a, Rasl11b, Rassf10, Rassf2, Rassf7, Rbms3, Rbp3, Rcan2, Rcbtb2, Reep3, Reep6, Relt, Rerg, Rfx4, Rgs16, Rgs5, Rgs8, Rhbdl2, Rhobtb1, Rhoj, Rhpn2, Ripply3, Rnase4, Rnf180, Rnu12, Rph3a, Rph3al, Rpia, Rpp25, Rras2, Rrm2, Rsad2, Rtp4, Runx1, Rwdd4a, Rxfp2, S100a10, S100a11, S100a3, Sall1, Sar1b, Scara3, Scg2, Scgn, Scnn1b, Scnn1g, Sdc3, Sdcbp2, Sdk2, Sec16b, Sec31b, Sepp1, Sepsecs, Serinc5, Serpina10, Serpine1, Serpine2, Serpinh1, Sez6l, Sfrp5, Sfxn2, Sgk1, Sgk2, Sh3d19, Sh3pxd2a, Shank2, Shb, Shc2, Shc4, Shcbp1, Shisa2, Skap1, Slc12a1, Slc12a4, Slc12a7, Slc14a2, Slc16a12, Slc16a6, Slc16a9, Slc18a1, Slc22a23, Slc25a44, Slc25a47, Slc28a3, Slc2a2, Slc30a7, Slc30a8, Slc31a1, Slc35f5, Slc37a4, Slc38a4, Slc40a1, Slc41a3, Slc43a2, Slc5a10, Slc6a19, Slc6a6, Slc7a8, Slc9a3r1, Slco1a5, Slco1a6, Slco2a1, Slco3a1, Slit1, Smim20, Smim24, Smpd3, Sntg2, Sorbs3, Sorcs2, Sowahc, Spc24, Specc1, Speer2, Sphkap, Spink10, Spock1, Spon1, Spry1, Spsb1, Spsb4, Sptlc1, Srbd1, Srebf1, Srgap1, Sspn, Sst, Sstr3, St3gal1, St6gal1, St8sia5, Stac2, Stard5, Stc1, Stk17b, Strip2, Sulf2, Surf4, Sv2b, Svil, Svopl, Syndig1, Syndig1l, Synpo, Synpr, Syt1, Syt13, Syt2, Syt7, Sytl4, Tacc2, Tat, Tbcd, Tcp11, Tdo2, Tenm4, Tesc, Tgif1, Tgm2, Th, Thbd, Thsd4, Tigar, Tinagl1, Tlr12, Tmem154, Tmem163, Tmem164, Tmem173, Tmem176a, Tmem176b, Tmem181bps, Tmem206, Tmem207, Tmem215, Tmem229b, Tmem243, Tmem40, Tmem50b, Tmem63a, Tmem71, Tmem97, Tmod1, Tmprss4, Tmtc3, Tnfrsf9, Tnfsf10, Tnni3k, Tnr, Tph2, Trh, Triobp, Trnp1, Trp53i11, Trp53inp1, Trp53inp2, Trpm1, Tsc22d1, Tspan14, Tspan15, Tspan8, Ttc22, Ttc28, Ttk, Ttr, Ttyh1, Ttyh2, Tubb2a, Tubb3, Tubb4b, Tubb6, Tuft1, Txnip, Ubash3b, Uckl1os, Ucn3, Ucp2, Uhrf1, Unc13c, Uox, Upb1, Ust, Vapb, Vasn, Vav2, Vav3, Vcam1, Vdr, Vegfa, Vil1, Vipr1, Vps37b, Vstm2l, Vwa5b1, Wars, Wbscr25, Wdr6, Wee1, Wfikkn2, Wipi1, Wnk4, Wnt4, Ybx2, Zbtb42, Zbtb7c, Zc3h10, Zc3h3, Zfp36l2, Zfp568, Zfp750

-log(10) Term p-value p-value Genes Cartpt, Chrm3, Gck, G6pc2, Ins1, Ins2, Il1b, Per2, Kcnj11, regulation of insulin secretion 3.50E-06 5.46 Srebf1, Syt7 positive regulation of insulin Abat, Gpr39, Aacs, Ffar1, Gipr, Glp1r, Gck, Glul, Irs2, 6.70E-06 5.17 secretion Slc30a8, Trh, Ucn3 Cebpa, Cd36, Ero1lb, Gpr39, Mlxipl, Adra2a, Ffar1, Ffar2, glucose homeostasis 1.50E-05 4.82 Gcgr, Gck, G6pc2, Ins2, Ngfr, Nr1h4, Pdk4, Rph3al, Slc30a8, Slc37a4, Akt1 Btg1, Cebpa, Ndrg1, Rerg, Tgif1, Wdr6, Atf5, Acvrl1, Adora1, Adgrg1, Agt, Ctnnb1, Chd5, Dlc1, Fgfr2, Ing2, Irf1, negative regulation of cell 2.30E-05 4.64 Il1a, Il1b, Lif, Ntrk1, Notch1, Ovol2, Ptprz1, Ptprk, Rxfp2, proliferation Ripply3, Runx1, Sfrp5, Serpine2, Slc9a3r1, Spry1, Tesc, Trp53inp1, Tnfrsf9, Vdr Fkbp1b, Mlxipl, Apoa2, Gipr, Glp1r, Glul, Irs2, Slc30a8, response to glucose 2.50E-05 4.60 Slc37a4, Srebf1, Txnip, Trh, Ucn3, Mafa Diabetes Page 124 of 125 Atp2a2, Atp2b4, Atp2a3, Atp7a, Atp4a, Nipal1, Wnk4, Asic1, Best3, Cacna2d4, Chrnb4, Grin2c, Hcn4, Lrrc8c, Kcnk13, Kcnn3, Kcnj11, Kcnj12, Kcnj13, Kcnj5, Kcnm1, Kcnmb2, Kcnn2, Kcnab3, Kcng3, Kcnh1, Kcnh5, Sfxn2, ion transport 2.60E-05 4.59 Scnn1b, Scnn1g, Slc12a1, Slc12a4, Slc12a7, Slc22a23, Slc30a7, Slc30a8, Slc31a1, Slc38a4, Slc40a1, Slc5a10, Slco1a5, Slco1a6, Slco2a1, Slco3a1, Trpm1, Tmem63a, Ttyh1, Ttyh2 Cd36, Cd93, Cuzd1, Frem2, Adgrg1, Boc, Bcar1, Cdh22, Celsr1, Comp, Ctnnb1, Cldn11, Col19a1, Col15a1, Col28a1, Cyr61, Dpp4, Flrt1, Fblim1, Hpse, Hapln1, Igsf11, cell adhesion 2.80E-05 4.55 Igfbp7, Kirrel3, Lyve1, Muc4, Megf10, Npnt, Ninj1, Olfm4, Parvb, Podxl, Ptprk, Pcdh15, Sdk2, Sorbs3, Spon1, Sdc3, Tnr, Tinagl1, Ttyh1, Vcam1 Atp4a, Hcn4, Kcnk13, Kcnn3, Kcnj11, Kcnj12, Kcnj13, potassium ion transport 3.00E-05 4.52 Kcnj5, Kcnmb1, Kcnmb2, Kcnc2, Kcnab3, Kcng3, Kcnh1, Kcnh5, Slc12a1, Slc12a4, Slc12a7 Page 125 of 125 Diabetes

Fold Change, Stage 6 Expression (tpm) Expression (tpm) Gene SC- β cells compated NKX6.1+ progenitors Stage 6 SC- β cells Symbol to NKX6.1+ (from Stage 5, v8) (all weeks, v8) Progenitors SMARCA1 130.301 203.857 1.565 SMARCA2 31.836 557.074 17.498 SMARCA4 207.984 92.492 0.445 SMARCA5 127.577 90.808 0.712 SMARCAD1 101.034 82.666 0.818 SMARCAL1 10.430 8.017 0.769 SMARCB1 125.397 63.107 0.503 SMARCC1 336.806 117.323 0.348 SMARCC2 173.891 189.507 1.090 SMARCD1 190.003 84.943 0.447 SMARCD2 55.888 26.547 0.475 SMARCD3 20.471 8.703 0.425 SMARCE1 177.783 138.192 0.777 ARID1A 376.192 323.520 0.860 ARID1B 186.656 262.347 1.406 BCL11A 47.637 20.214 0.424 BCL11B 23.429 5.896 0.252 BCL7A 51.529 23.178 0.450 BCL7B 62.815 119.912 1.909 BCL7C 43.823 32.255 0.736 DPF1 5.293 18.155 3.430 DPF2 77.838 63.263 0.813 DPF3 3.503 4.430 1.265 PBRM1 116.602 119.881 1.028