Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared Amongst Δγ T, Innate Lymphoid, and Th Cells

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Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst δγ T, Innate Lymphoid, and Th Cells

This information is current as You Jeong Lee, Gabriel J. Starrett, Seungeun Thera Lee, of October 2, 2021. Rendong Yang, Christine M. Henzler, Stephen C. Jameson and Kristin A. Hogquist J Immunol 2016; 197:1460-1470; Prepublished online 6 July 2016; doi: 10.4049/jimmunol.1600643 http://www.jimmunol.org/content/197/4/1460 Downloaded from

Supplementary http://www.jimmunol.org/content/suppl/2016/07/06/jimmunol.160064

Material 3.DCSupplemental http://www.jimmunol.org/ References This article cites 41 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/197/4/1460.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology

Lineage-Speciﬁc Effector Signatures of Invariant NKT Cells Are Shared amongst gd T, Innate Lymphoid, and Th Cells

You Jeong Lee,* Gabriel J. Starrett,† Seungeun Thera Lee,* Rendong Yang,‡ Christine M. Henzler,‡ Stephen C. Jameson,* and Kristin A. Hogquist*

Invariant NKT cells differentiate into three predominant effector lineages in the steady state. To understand these lineages, we sorted undifferentiated invariant NK T progenitor cells and each effector population and analyzed their transcriptional profiles by RNAseq. Bioinformatic comparisons were made to effector subsets among other lymphocytes, specifically Th cells, innate lymphoid cells (ILC), and gd T cells. Myc-associated signature genes were enriched in NKT progenitors, like in other hematopoietic progenitors. Only NKT1 cells, but not NKT2 and NKT17 cells, had transcriptome similarity to NK cells and were also similar to other IFN-g–producing lineages such as Th1, ILC1, and intraepithelial gd T cells. NKT2 and NKT17 cells were similar to their analogous subsets of gd Tcellsand ILCs, but surprisingly, not to Th2 and Th17 cells. We identified a set of genes common to each effector lineage regardless of Ag receptor Downloaded from specificity, suggesting the use of conserved regulatory cores for effector function. The Journal of Immunology, 2016, 197: 1460–1470.

nvariant NKT (iNKT) cells are canonical T cells recognizing It is increasingly appreciated that these iNKT subsets are analogous lipid Ags in the context of CD1d molecules (1). They are toconventionalThcellsubsets(4).NotonlyiNKTcells,butalso positively selected in the thymic cortex at the CD24hi stage 0 (2) innate lymphoid cells (ILCs) and gd T cells, have subsets with I low and differentiate into mature CD24 effector subsets that produce distinct effector programs similar to Th cells (7–9). A previous report IFN-g, IL-4, or IL-17 in the thymic medulla (3, 4). These subsets concluded that iNKT cells share an extensive transcriptional program http://www.jimmunol.org/ were designated as NKT1, NKT2, and NKT17 cells, respectively, and with NK cells and that this program also operates constitutively in their lineage properties are determined by key transcriptional factors intraepithelial gd T cells, activated CD8 T cells, and developing including PLZF, TBET, GATA3, and retinoic acid–related orphan thymocytes (8). However, these analyses were based on an outdated receptor gt(RORgt) (3, 4). Our previous data suggest that a CD24lo, staging model of iNKT cell development and thereby analyzed cells but uncommitted, NKT progenitor (NKTp) can give rise to each that predominantly contained NKT1 cells because of the background differentiatedsubset,andsuchprogenitors were defined as cells mouse strain used. Furthermore, it has not been addressed how the negative for IL-17RB and human CD2 (huCD2) among total PLZFhi transcriptional nature of innate lymphoid and innate-like T cells and NKT2 cells in KN2 IL-4 reporter mice (3, 5). In adoptive transfer conventional Th cells are correlated with each other. by guest on October 2, 2021 assays, a fraction of IL-17RB2huCD22 NKT2 cells differentiated To address these issues, we performed RNAseq analysis of iNKT into NKT1 cells, whereas IL-17RB+huCD2+ NKT2 cells did not. In subsets, including NKTp, NKT1, NKT2, and NKT17 cells. Impor- localization analysis, IL-4–producing huCD2+ NKT2 cells were tantly, we found only NKT1 cells, but not NKT2 and NKT17 cells, mostly in the thymic medulla, whereas huCD22 NKTp cells were shared a transcriptional program with NK (8), activated CD8 T, and relatively enriched in the cortex, consistent with their developing intraepithelial gd T cells. We also identified that NKTp signature ontogeny (6). These results indicated there are four different iNKT genes were shared among differentiating or proliferating hemato- subsets including a progenitor and three differentiated subsets. poietic cells including developing thymocytes, which were associated with an upstream regulator Myc protein. Using previously published data sets, we measured the transcriptional similarity of *Department of Laboratory Medicine and Pathology, Center for Immunology, Uni- versity of Minnesota, Minneapolis, MN 55455; †Department of Biochemistry, Mo- iNKT subsets to those of analogous gd T cells, ILC, and Th cells (7, lecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455; 9, 10). Signature genes of NKT1 cells were defined and found to be and ‡Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, MN 55455 highly shared with ILC1 and Th1 cells, indicating profound similarity between the transcriptional programs of all IFN-g–producing ORCIDs: 0000-0001-5871-5306 (G.J.S.); 0000-0003-4566-2211 (C.M.H.). cells. NKT2 cells were most similar to thymic CD24lowVd6+ gd Received for publication April 12, 2016. Accepted for publication June 14, 2016. T cells, both of which expressed high levels of PLZF, followed by This work was supported by National Institutes of Health Grants R37-AI39560 (to low + K.A.H.), RO1-AI075168 (to S.C.J.), and K99-AI114884 (to Y.J.L). ILC2. NKT17 cells were similar to thymic CD24 Vg2 gd T cells and ILC3 cells. Although Th2 and Th17 cells shared a small core of The raw data presented in this article have been submitted to the National Center for Biotechnology Information database under accession number PRJNA318017. effector signature genes with the analogous subsets of ILC, gd T, and Address correspondence and reprint requests to Dr. You Jeong Lee and Dr. Kristin A. iNKT cells, their overall transcriptional profiles were more distinct. Hogquist, Department of Laboratory Medicine and Pathology, Center for Immunol- These findings indicate that the transcriptional nature of ILC or th ogy, University of Minnesota, 2101 6 Street SE, Minneapolis, MN 55455. E-mail innate-like T cells is distinguished from conventional Th cells. addresses: [email protected] (Y.J.L.) and [email protected] (K.A.H.) The online version of this article contains supplemental material. Abbreviations used in this article: ETP, early thymic precursor; FDR, false discovery rate; huCD2, human CD2; ILC, innate lymphoid cell; iNKT, invariant NKT cell; IPA, Materials and Methods Ingenuity Pathway Analysis; MAIT, mucosal-associated invariant T; NES, normal- Mice ized enrichment score; NKTp, NKT progenitor; RORgt, retinoic acid–related orphan receptor gt. C57BL/6NCr and BALB/c mice were purchased from the National Cancer Institute and The Jackson Laboratory, respectively. BALB/c Tbx21gfp 2 Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 KN2+/ were described previously (3). All of the mouse experiments were www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600643 The Journal of Immunology 1461 performed under protocols approved by the Institutional Animal Care and (BD Biosciences). An RNeasy mini kit (Qiagen, Redwood City, CA) was Use Committee of the University of Minnesota. used to isolate RNA obtained from each sample.

Flow cytometry RNA sequencing Biotinylated PBS-57 loaded or unloaded CD1d monomers were obtained RNA sequencing was done at the University of Minnesota Genomics Center. from the tetramer facility of the National Institutes of Health. For intra- Total RNA was quantified using a fluorimetric RiboGreen assay, and RNA cellular staining, single-cell suspensions were surface stained, fixed, and quality was assessed using capillary electrophoresis and the Agilent RNA permeabilized with the eBioscience Foxp3 staining buffer set. All Abs were Integrity Number (Agilent Technologies). All samples that were submitted from eBioscience, BD Biosciences, or BioLegend, unless indicated. Cells for library creation had an RNA Integrity Number of eight or greater. were analyzed on an LSR II (BD Biosciences), and data were processed with Library creation was performed using Illumina’s Truseq RNA Sample FlowJo software (Tree Star). Preparation Kit (catalog number RS-122-2001; Illumina). Final library size Cell isolation and RNA preparation distribution was validated using capillary electrophoresis and quantified using fluorimetry (PicoGreen) and via quantitative PCR. Indexed libraries Thymocytes were isolated from two to three mice per sample from BALB/c are then normalized, pooled, and size selected to 320 bp 6 5% using Tbx21gfp KN2+/2 mice, and iNKT cells were enriched by CD1d tetramer Caliper’s XT instrument (Caliper Life Sciences). Truseq libraries were pulldown. Briefly, cells stained with PE-conjugated CD1d tetramer were hybridized to a paired end flow cell, amplified on the Illumina cBot, and enriched using anti-PE microbeads (Miltenyi Biotec) according to the subsequently run on the HiSEquation 2000 (Illumina). Raw data are manufacturer’s instruction. TCRb+CD1d tetramer+CD82CD242 thymic available at the National Center for Biotechnology Information under ac- iNKT cells were separated into four subsets and sorted with an FACSAria cession number PRJNA318017. Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021

FIGURE 1. iNKT subsets have unique transcriptional proﬁles. (A) Sorting strategy of iNKT subsets using surface markers. Total thymocytes from BALB/c Tbx21gfp KN2+/2 mice were stained with CD1d tetramer and indicated surface markers and analyzed by their transcription factor proﬁles. Each subset was designated as NKT1, PLZFhi NKT, and NKT17 cells. (B) PLZFhi NKT cells were further separated by expression levels of IL-17RB and human CD2 (huCD2) and designated as NKTp and NKT2 cells. (C) Postsort purities of each subset are shown. (D) Four different subsets of thymic iNKT cells were sorted as triplicates from cells pooled from two to three mice each and analyzed for their RNA transcripts. Heat map was generated using mean fragments per kb of transcript per million values of triplicates to show their differential expression patterns of PLZF (encoded by Zbtb16), TBET (encoded by Tbx21), IL-17RB (encoded by Il17rb), and RORgt (encoded by Rorc). (E) Hierarchical clustering of iNKT subsets is shown using the 1000 genes that are most differentially expressed. (F) Principal component analysis of gene expression is shown for each iNKT subset. Numbers along axes indicate relative scaling of the principal variables. 1462 SHARED LYMPHOID EFFECTOR SIGNATURE GENES

Data analysis from Gene Expression Omnibus with access code GSE37448 for ILC and other cell types including gd T cells with access code GSE15907. We obtained an average of 20 million reads per replicate for triplicates of four different cell types with technical duplicates (total 24 reads). RNAseq reads were aligned to the mouse reference genome (mm10) and most Results recent transcript annotations using TopHat (v2.0.13) (11). Expression iNKT subsets have unique genetic profiles with characteristic levels of all transcripts were quantified using Cuffquant (12), and differentially expressed genes were determined by Cuffdiff (12). Hierar- transcripts chical clustering and principal component analysis were performed We sorted thymic iNKT subsets from BALB/c Tbet/IL-4 reporter based on the raw read counts from the top 1000 genes ranked by 2 2 mice (Tbx21gfp KN2+/ ) mice, in which NKT1 cells are CD4+/ GFP+, the variance of their expression values across samples. Volcano plots 2 2 hi hi were generated using Multiplot Studio (Gene Pattern), and heat maps NKT17 cells are CD4 GFP CD44 , and PLZF NKT2/p cells are 2 were generated with Gene-E (Broad Institute). For heat map generation, CD4+GFP , among total CD1d tetramer-positive cells (Fig. 1A, left if not otherwise indicated, data were log2-transformed and visualized by panel). These marker combinations had ∼97% overlap with subsets relative expression per row with the row mean subtracted and divided by directly defined by transcription factor staining (Fig. 1A, right three row SD. Rows were grouped by the Pearson correlation coefficient via hi hierarchical clustering. Gene set enrichment analysis was performed to panels). PLZF NKT cells were further divided into NKT2 and calculate normalized enrichment score (NES) (13). Prism (GraphPad NKTp cells (Fig. 1B), as we previously showed that IL-17RB and Software) was used for data plotting, and Venny (http://bioinfogp.cnb. huCD2-expressing cells represent terminally differentiated IL-4– csic.es/tools/venny) was used to visualize Venn diagrams. Cytoscape was secreting NKT2 cells, and IL-17RB and huCD2-negative cells used to generate network analysis (14). Upstream regulators and canonical pathway analysis were identified using Qiagen’s Ingenuity contained progenitors that can give rise to differentiated subsets (3). Pathway Analysis (IPA; Qiagen). We used RNAseq of Th cells from For efficient cell sorting, we performed CD1d tetramer enrichment

Array Express with the access code E-MTAB-2582 and microarray data and sorted populations that had .99% purity (Fig. 1C). We isolated Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021

FIGURE 2. Characteristic transcripts of each iNKT subset. (A) Volcano plots were generated after pairwise comparisons between two subsets, and numbers in parentheses indicate numbers of genes upregulated at least 2-fold in each subset with p values ,0.05. Each symbol represents a single gene. Heat maps show cytokines (B), receptors (C), and transcription factors (D) uniquely expressed in one subset at least 2-fold higher than the other three subsets with significant p values (,0.05). Color coding indicates genes highly expressed in NKT1 (green), NKT2 (red), NKT17 (blue), and NKTp (black) cells. *These two genes had insignificant p values (.0.05) in at least one of three comparisons. The Journal of Immunology 1463 four different subsets in triplicate, prepared RNA, and performed factors (Fig. 2D). Tbx21 and Ifng were highly upregulated in NKT1 RNAseq analysis. A heat map generated after RNAseq analysis cells, and Il4 and Rorc were specific to NKT2 and NKT17 cells, showed each subset was positive for the expected transcription respectively. Il13 and Il17a transcripts were highest in NKT2 and factors (Fig. 1D). Hierarchical clustering analysis, using the 1000 NKT17 cells, respectively, although p values were .0.05 in at least most variable genes among the four subsets, showed that NKTp cells one comparison. GATA3 was not detected as a unique gene of are indeed a unique population that had the least similarity with the NKT2 cells, as NKT17 cells also expressed it at a similar level (3). other three subsets (Fig. 1E). Principal component analysis con- NKTp cells had few signature cytokine or receptor transcripts but firmed these subsets have distinct transcriptional profiles (Fig. 1F). uniquely upregulated several transcription factors, including tran- Next, we analyzed genes differentially expressed between subsets scriptional regulators (Hes1, Taf9, Smarcb1, Zfp644,andAes)and of iNKT cells. Pairwise comparison of NKT1, NKT2, and NKT17 ribonuclear proteins (Hnrnpab and Snrpc), suggesting they have cells generated three volcano plots showing 563–915 genes at least distinctive nuclear protein activity (Fig. 2D). 2-fold upregulated in each subset with p values ,0.05 (Fig. 2A, top panels). NKTp cells showed 3.2- to 5.6-fold fewer significantly iNKT subsets have unique signature genes upregulated genes compared with the three differentiated subsets, To further elucidate the transcriptional nature of each iNKT subset, indicating they are transcriptionally less active (Fig. 2A, bottom we generated a list of signature genes that were uniquely expressed panels). Using these data, we generated heat maps showing a se- in each subset, with q values ,0.05 compared with the other three lected list of genes that are uniquely upregulated in one subset subsets as depicted in Fig. 3A and shown in Supplemental Table I. compared with the other three subsets in three different categories, We first looked at how these genes were expressed at different including cytokines (Fig. 2B), receptors (Fig. 2C), and transcription stages of thymic NKT cells, as defined by data from the ImmGen Downloaded from http://www.jimmunol.org/

FIGURE 3. Only NKT1 cells share a transcriptional program with NK cells. (A) Schematic figure showing a comparison method to generate sig- by guest on October 2, 2021 nature genes based on q values. (B) Expression pattern of signature genes of each iNKT subset was determined in each stage using ImmGen data set. (C) Expression profiles of signature genes of each iNKT subset were analyzed in hematopoietic cells using an Immunological Genome Project data set (accession number GSE15907), which encompassed 214 different hematopoietic lineages. Numbers in parentheses indicate the number of signature genes of each iNKT subset and detailed ImmGen cell type de- scription is shown in Supplemental Fig. 1. BM, bone marrow; DC, dendritic cell; DN, double-negative; DP, double-positive; ETP, early thymic precursor; FRC, fibroblastic reticular cells; Gr, granulocyte; LN, lymph node; Mac, macrophage; Mono, monocyte; SP, single-positive; Spl, spleen; Thy, thymocytes. 1464 SHARED LYMPHOID EFFECTOR SIGNATURE GENES consortium (8) (Fig. 3B). NKT1 signature genes were most highly A second important observation is that only NKT1, but not expressed on stage 3 cells, NKTp and NKT17 signature genes NKTp, NKT2, or NKT17, cells showed transcriptional similarity were mainly on stage 2 cells, and NKT2 signature genes were to NK cells (Fig. 3C). Therefore, the previous conclusion that present in both stage 1 and stage 2 cells. These features are NKT cells have a hybrid nature between T cells and NK cells (8) consistent with previous reconciliation between conventional is not correct, in that it only applies to a subset of NKT cells, stages and functional subsets of iNKT cells in C57BL/6NCr mice albeit one that is particularly prominent in the C57BL/6 strain of (3, 4) and highlight that CD44 and NK1.1 are not accurate mice. With the current ImmGen data set, we could not specify a markers of developmental progression, but include mixed pop- type of lymphoid or myeloid cell overtly sharing transcripts with ulations with developmental progenitor and terminal effector NKT2 and NKT17 cells (Fig. 3C). Overall, these results indicate properties, particularly for stage 2. Next, we analyzed expression that NKTp cells, as well as NKT1, NKT2, and NKT17 cells, are patterns of iNKT signature genes among various hematopoietic unique cells having distinctive transcriptional natures. cells using ImmGen data that encompass 214 different cell types iNKT cells, Th CD4 cells, ILC, and gd T cells share key (Fig. 3C, detailed map in Supplemental Fig. 1). Previously, transcripts NKT cells were suggested to strongly share a transcriptional program with NK cells and that this core effector program was Not only iNKT cells, but also ILCs and gd T cells, have effector also shared with activated OT-1 CD8 T cells, intraepithelial gd subsets producing distinct effector cytokine analogous to con- T cells, and early thymic precursors (ETP) (8). Our NKT1 sig- ventional Th cells (9, 19, 20). However, it has not been addressed nature genes were highly expressed in these cells too, except ETP if these effector subsets share a common transcriptional nature or (Fig. 3C). Instead, NKTp signature genes were enriched in ETP not, and to address this issue, we compared our dataset with and other developing thymocytes and also highly shared among published ones (7, 9, 10). The transcriptional nature of Th cells Downloaded from bone marrow stem cells, pre/pro-B cells, germinal center B cells, was analyzed using RNAseq of in vitro–differentiated naive CD4 thymic dendritic cells, bone marrow macrophages, monocytes, T cells stimulated with anti-CD3/CD28 and cytokines (10), and OT-1 T cells within 48 h of activation, and CD24hi or fetal thymic ILC and gd T cells were analyzed by microarray in previous gd T cells (Supplemental Fig. 1). Thus, the extent to which the ImmGen projects using cells that were sorted immediately ex vivo previous analysis showed iNKT similarity to ETP might have (7, 9). These four different datasets, however, used different reflected the contamination of their population with progenitor analysis platforms, and it was not possible to make direct com- http://www.jimmunol.org/ cells. We reasoned that NKTp cells are often proliferating, and parisons with each other. Thus, to gain insight into potential IPA showed Myc-associated genes were significantly enriched in common effector programs, we first defined a short list of genes NKTp cells (p = 5.12 3 1026), followed by E2F, TP53, and RB1 uniquely expressed in each iNKT subset and analyzed their ex- (Table I). Because Myc regulates gene expression via complex pression patterns in Th cells, ILCs, and gd T cells (Fig. 4A). These means (15), we wanted to determine if the Myc-associated genes genes were enriched in each analogous subset of Th cells and in NKTp were directly regulated by Myc. Thus, we analyzed a ILCs, and NK cells, which were largely indistinguishable from previous Myc-Chip seq dataset of activated mouse CD4 T cells ILC1s (7), were like NKT1 cells. Among various gd T subsets, V (GSE37229) (16). Among the NKTp unique Myc-associated gene usage correlates with distinct effector programs (9, 20). by guest on October 2, 2021 genes (Table I), EIF4A1, SLC2A1, and TFDP1 were within Based on published analysis (9), we identified V5 (intraepithelial 1 kb of a direct Myc binding site, suggesting Myc directly regulate Vg5+), V6 (thymic CD24low Vd6+), and V2 (thymic CD24low these genes. UTX was 12 Mbp away from the nearest Myc binding Vg2+) gd T cells as sharing key effector genes with NKT1, NKT2, site, and the other six genes were from 20 to 500 kb apart. As Myc and NKT17 cells, respectively (Fig. 4A). Interestingly, CD24hi or binds to promoters rather than enhancers (15, 16), these seven fetal-derived gd T subsets shared NKTp signature genes (Fig. 4B), genes are more likely to be regulated indirectly by Myc. iNKT cell suggesting that they may be a functional counterpart of NKTp phenotype in the absence of Myc protein was analyzed previously, cells. Overall, these features show iNKT and gd T cells share and indeed, the frequency of iNKT cells was greatly reduced effector differentiation programs and signature genes with analo- (17, 18). In Myc-deficient mice, the number of CD24hi stage gous ILC and Th cells. 0 NKT cells was normal, but development of iNKT cells was arrested at stage 1 or 2, indicating that positive selection from DP Overlapping signature genes define core transcriptional thymocytes was not affected. Thus, our findings are consistent elements with Myc-dependent cellular proliferation being a critical process Next, we identified signature genes of 13 different cell types from for the development iNKT cells. four different types of lymphoid cells as depicted in Fig. 4C by

Table I. List of upstream regulators of NKTp

Upstream Regulator p Value of Overlap Target Molecules in Dataset MYC 5.12E-06 CCNB1, ECM1, EIF2B1, EIF4A1, LDHB, NDUFS4, SLC2A1, STMN1, TFDP1, UXT E2F4 3.50E-05 GMNN, PTTG1, RPA3, STMN1, UXT E2f 5.68E-05 CCNB1, GMNN, RPA3, UXT E2F1 8.10E-05 CCNB1, GMNN, RPA3, STMN1, TAF9, UXT NDUFA13 2.15E-04 CCNB1, TFDP1 CD 437 3.85E-04 EIF4A1, HMGN2, LSM3, UXT TP53 4.20E-04 CCNB1, EIF2B1, GMNN, HMGN2, PTTG1, SLC2A1, SPC25, STMN1, TFDP1 NRAS 4.31E-04 CCNB1, SLC2A1, SPC25 RBL2 5.92E-04 CCNB1, STMN1, XT AMPK 8.09E-04 CCNB1, LDHB, SLC2A1 MAPT 8.50E-04 ARF5, CCNB1, NDUFS4, STMN1 RB1 9.28E-04 CCNB1, GMNN, TFDP1, UXT Upstream regulators of NKTp cells were generated using IPA, and list shows those with p value ,0.0001. The Journal of Immunology 1465 Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021

FIGURE 4. iNKT cells, Th cells, ILCs, and gd T cells share key transcripts for each subset. (A) Genes highly expressed on NKT1 (green), NKT2 (red), and NKT17 (blue) cells were analyzed for their expression patterns in other analogous lymphoid lineages. (B) NKTp unique genes were analyzed for their expression pattern in various gd T cell subsets. Myc-associated genes among NKTp signatures are highlighted in red. (C) Schematic figures show comparison methods of defining signature genes in each lineage. V1 (Vg1+), V2 (Vg2+), V3 (Vg3+), V5 (Vg5+), and V6 (Vd6+) represent gd T cells. act, activated (CD44hi); E17, embryonic day 17; IEL, intraepithelial lymphocytes, Spl, spleen; Thy; thymus. doing intragroup differential gene expression comparison (Sup- of IL-4–producing NKT2 cells and ILC2s were dependent on plemental Table I). Then, we grouped IFN-g–, IL-4–, and IL-17– IL-25 (21, 22). We identified membrane-bound O-acetyltransferase1 secreting effector subsets cells, referring to them as L1, L2, and L3, (Mboat1 encoded by Mboat1), an enzyme involved in fatty acid respectively, and calculated the number of signature genes over- metabolism (23), as a novel candidate for L2 function. L3 subsets lapping with each other (Fig. 5A). In the L1 group, we found 12 shared RORgt (encoded by Rorc) and its known target molecules signature genes commonly shared among all subsets and 3 and 9 such as IL-1R1 (encoded by Il1r1) and IL-23R (encoded by Il23r) genes in the L2 and L3 groups, respectively. The L1 group was (24). Rev-Erb (encoded by Nr1d1) is a previously identified upstream marked by effector cytokines or chemokines such as RANTES molecule of RORgt, which mediates circadian rhythm (25). (encoded by Ccl5), granzyme B (encoded by Gzmb), and Perforin 1 Syndecan-1 (encoded by Sdc1) is a known regulator of NKT17 cells (encoded by Prf1). IL-4 (encoded by Il4) and the IL-25R (encoded (26), and IL-17RE (encoded by Il17re) is a receptor for IL-17C and by Il17rb) were shared by all L2 subsets, suggesting a central role for important for Th17 cell activation (27). Tmem176b was previously IL-25 signaling. Consistent with this, development and/or expansion detected as a putative RORgt binding partner (24), and we identified 1466 SHARED LYMPHOID EFFECTOR SIGNATURE GENES Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021

FIGURE 5. Overlapping signature genes define core transcriptional elements. (A) Venn diagrams show number of overlapping signature genes between subsets in each group. Genes shared by all subsets in each group are listed below each diagram. (B) Heat map shows frequency of overlapping genes and Pearson correlation of enrichment scores of upstream regulators and canonical pathways between two subsets. Data were log2-transformed and visualized by global expression. (C) Network analysis of signature genes. Each dot represents a single gene connected to subsets expressing them. V2 (Vg2+)andV6(Vd6+) are thymic CD24low gd Tcells,andV5(Vg5+) is intraepithelial gd T cells. Green: IFN-g–producing cells; red: IL-4–producing cells; blue: IL-17–producing cells. two additional candidates common to all L3 subsets; Aquaporin 3 IL-17 at steady state, these two genes were not identified as common (encoded by Aqp3), which is a water channel transporting hydrogen lineage signatures. peroxide and required for T cell migration and IL-23–dependent Next, we sought to visualize the relatedness of the transcriptomes skin inflammation (28, 29), and tudor and KH domain containing of different subsets. After pairwise comparison within groups, we (encoded by Tdrkh), which is essential for spermatogenesis and piwi- generated a heat map showing the frequencies of overlapping interacting RNA biosynthesis (30). Tbx21 and Ifng were not detected signature genes between any two cell types among all 13 different as shared signatures of L1 lineage because some ILC3s are derived subsets. Whereas L1 subsets highly shared their signature genes from ILC1 (31), and these genes remain transcriptionally active in with each other, Th2 in L2 and Th17 in L3 groups had less them (Fig. 4A). As GATA3 was highly expressed in both NKT2 and sharing among signature genes (Fig. 5B, left panel). This feature NKT17 cells, and L3 subsets were not transcriptionally active for was also visualized in network analysis (Fig. 5C), in which each The Journal of Immunology 1467

Table II. NES and FDR of gene set enrichment analysis

NKT1 . NKT2 NKT1 . NKT17 NKT2 . NKT17

Category NES FDR NES FDR NES FDR Correlation iNKT NKT1 7.36 0 6.95 0 0 NA NKT1 NKT2 28.03 0 0 NA 7.19 0 NKT2 NKT17 0 NA 28.2 0 27.5 0 NKT17 CD4 T Th1 4.2 0 3.15 0 1.4 0.1 NKT1 Th2 20.7 0.83 0.79 0.75 21.29 0.15 No correlation Th17 22.89 0 22.4 0 21.5 0.06 NKT17 . NKT2 . NKT1 NK and ILC NK 4.43 0 4.67 0 1.29 0.17 NKT1 ILC1 4.4 0 4.18 0 2.1 0.002 NKT1 . NKT2 . NKT17 ILC2 22.9 0 21.1 0.29 1.5 0.08 NKT2 . NKT17 . NKT1 ILC3 1.5 0.07 23.6 0 24.6 0 NKT17 gd T V5 4.27 0 4.0 0 20.73 .82 NKT1 V6 24.68 0 2.22 0.004 5.05 0 NKT2 . NKT1 . NKT17 V2 2.28 0 24.59 0 25.28 0 NKT17 . NKT1 . NKT2

V1 1.79 0.01 1.58 0.04 21.1 0.33 NKT1 Downloaded from V1 (Vg1+Vd62), V2 (Vg2+), and V6 (Vd6+) are thymic CD24low gd T cells and V5 (Vg5+) is intraepithelial gd T cells. NA, not applicable. dot indicates a single gene with a line connecting to cells express- quantitatively determined how significantly one subset shares a ing them, and the distance between subsets is proportional to the transcriptome with one of the iNKT subsets. For example, NK number of interconnected overlapping genes. In this analysis, L1 signature genes were highly enriched in NKT1 compared with both http://www.jimmunol.org/ subsets were all grouped together, whereas L2 and L3 subsets were NKT2 and NKT17 cells (Supplemental Fig. 2B). Table II shows more separated. V2, NKT17, and ILC3 cells were closely grouped, NES scores and false discovery rate (FDR) of all comparisons and but equidistant between Th1 and Th17 cells, indicating Th17 cells the abbreviated interpretation (correlation column). As a result, do not share more genes in common with other L3 subsets than Th1 signature genes of Th1, ILC1, NK, and V5 were all highly enriched cells share with them (Fig. 5C). NKT2 and V6 were close, but they in NKT1 cells compared with NKT2 and NKT17 cells, indicating were grouped closer to Th17 than Th2 cells. L1 lymphoid cells are transcriptionally similar. Unexpectedly, Th2 The tighter clustering of L1 subsets compared with L2 or L3 signature genes had no skewing toward any of the iNKT subsets, subsets was also reflected in upstream regulators and canonical whereas ILC2 and V6 signature genes were enriched in NKT2 cells by guest on October 2, 2021 pathway enrichment analysis (Supplemental Table II). We gener- (Supplemental Fig. 2). Similarly, Th17 signature genes were not ated heat maps showing Pearson correlation of enrichment score strongly enriched in NKT17 cells, unlike ILC3 and V2 cells. Again, of each upstream regulator and canonical pathway, in which the to visualize these trends, we plotted NES scores as x, y, and z co- L1 group shared more common components than L2 and L3 ordinates, respectively (Table II), plotted them into three different groups (Fig. 5B, middle and right panels). Among canonical two-dimensional coordinates, and grouped together cells having pathways, L1 shared 22, including the strongly enriched NK cell NKT1 (green), NKT2 (red), or NKT17 (blue) nature (Fig. 6A). We signaling pathway. L2 and L3 did not share a single common one, used the NES value of each iNKT subset signatures as a positive though we listed the pathways shared among three out of four control and finally measured distance from the positive control to subsets of L2 and L3 groups (Supplemental Table II). Of interest, each cell type to measure relative distance (Fig. 6B). All L1 sub- the pathways cAMP and protein kinase A signaling were shared groups were closer to NKT1 cells than NKT2 and NKT17 cells, but among L2 cell types, perhaps suggesting an important role for NKT2 and NKT17 cells were more likely to be analogous to gd or adenosine. Other pathways such as airway inflammation in asthma ILC subsets than Th subsets. Th2 signature genes had similar dis- were shared among L2 cell types except Th2, and type 1 diabetes tance from all three subsets of iNKT cells, and Th17 signature mellitus signaling was shared among L3 cell types except V2. genes marginally separated NKT17 cells from NKT2 cells. These Collectively, these features indicate each lymphoid lineage (L1, L2, features quantitatively show that the transcriptional profiles of iNKT and L3) shares key cytokines, transcriptional elements, canonical subsets are most closely related to gd T cells and ILCs, whereas pathways, and upstream regulators, but the overall signature genes CD4 Th cells had the least similarities. of innate lymphoid or innate-like T cells are less shared with the analogous Th cells, especially Th2 and Th17 cells. Discussion In this report, we describe the transcriptional nature of iNKT subsets iNKT subsets are more closely related to innate lymphocytes using RNA sequencing. Our analysis revealed that NKTp cells have a than to conventional Th cells dramatically distinct transcriptional program compared with all other The analysis of overlapping signature genes (Fig. 5B, 5C) indicated iNKT effector subsets, even NKT2 cells (which are largely phe- that there is substantial heterogeneity among subsets within each notypically indistinguishable from NKTp). This progenitor program lymphoid lineage. To quantify the transcriptional similarities of was enriched in Myc-regulated genes, consistent with rapid prolif- iNKT subsets with other lymphoid lineages, we performed multiple eration, which is known to characterize NKT development, and rounds of gene set enrichment analysis (Supplemental Fig. 2). In does not occur with conventional T cells at the analogous stage of this analysis, the differentially expressed genes of each subset of Th development (17, 18). These data should allow for the identification cells, ILCs, and gd T cells were aligned on lists of genes differ- of better markers to experimentally distinguish NKTp from mature entially expressed between iNKT subsets. By measuring NES, we NKT effector cells, a matter that we are currently investigating. 1468 SHARED LYMPHOID EFFECTOR SIGNATURE GENES Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021

FIGURE 6. iNKT subsets are more closely related to innate lymphocytes than to conventional Th cells. (A) NES values (Table I) were regarded as x, y, and z coordinates and plotted in three different axis combinations. Each dot represents labeled population, and green, red, and blue dots without label represent NES of NKT1, NKT2, and NKT17 signature genes, respectively. (B) Relative distance was deﬁned as an arbitrary length between two populations from (A). V2 (Vg2+) and V6 (Vd6+) are thymic CD24low gd T cells, and V5 (Vg5+) is intraepithelial gd T cells.

We also compared our data to published data sets including Th generated, whereas other cells were directly isolated from in vivo cells, ILCs, and gd T cells and showed that the transcriptional (10). Furthermore, it is unclear whether the differences between nature of NKT subsets are most like the analogous subsets of gd gene expression profiles of some Th subsets and their innate T cells, followed by ILCs. Th1 CD4 T cells were similar to NKT1 counterparts is a consequence of the fact that conventional T cells cells, but Th2 and Th17 cells did not show high similarity to other are analyzed relatively soon after polarization, whereas the innate L2 and L3 subsets. Overall, this study indicates that innate or immune populations may have been in their functional differenti- innate-like T cells share a common transcriptional nature distinct ation states for longer. Two recently published papers came to a from adaptive Th cells. PLZF is a transcription factor directing similar conclusion as ours, showing directly isolated human ILC innate function of iNKT cells (32, 33), and 50–70% of ILCs were and Th subsets are transcriptionally distinct (36), and mouse in vivo derived from bone marrow stem cells that once expressed PLZF Th2 cells acquired part of, but not all of, ILC2 regulomes upon (34). Previous reports showed that V6 and V2 cells express PLZF, infection (37). In contrast, the striking similarities between Th1 and and we also found V5 cells express more abundant PLZF tran- IFN-g–producing innate immune cells indicate that gene expression scripts than naive splenic CD4 T cells (Fig. 4A). In conventional by in vitro Th1 polarization closely matches that of in vivo–dif- Th cells, however, PLZF expression was stably suppressed and not ferentiated NKT1, NK, V5, and ILC1 populations. induced by TCR signaling or inflammatory milieu (35). Therefore, A previous report showed there are three functionally distinct gd PLZF may be one of key transcriptional elements regulating the T cell subsets that develop in the thymus; V1, V6, and V2 cells (9, common nature of ILC and innate-like T cells. One caveat to the 20). In our analysis, however, V1 cells were not clearly catego- interpretation of these data is that the Th cells were in vitro rized as similar to one or more of the iNKT subsets (Fig. 4A), The Journal of Immunology 1469 although they had a weak NKT1 nature (Fig. 6, Table II). Instead, expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7: 562–578. we showed intraepithelial gd T cells corresponded strongly to 13. Subramanian, A., P. Tamayo, V. K. Mootha, S. Mukherjee, B. L. Ebert, NKT1 cells and used V5 as a representative among four different M. A. Gillette, A. Paulovich, S. L. Pomeroy, T. R. Golub, E. S. Lander, and subsets (Fig. 4A). As a result, we found V5, V6, and V2 cells were J. P. Mesirov. 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U S A analogous to NKT1, NKT2, and NKT17 cells, respectively. 102: 15545–15550. Abundance of PLZF transcripts in gd T cell subsets was also 14. Shannon, P., A. Markiel, O. Ozier, N. S. Baliga, J. T. Wang, D. Ramage, analogous to iNKT subsets—high in V6, intermediate in V2 and N. Amin, B. Schwikowski, and T. Ideker. 2003. Cytoscape: a software envi- + ronment for integrated models of biomolecular interaction networks. Genome low in V5 (Fig. 4A). In the absence of PLZF, V6 and Vg4 gd Res. 13: 2498–2504. T cells, which are similar to V2 cells, failed to produce cytokines 15. Levens, D. 2013. Cellular MYCro economics: Balancing MYC function with upon stimulation (38, 39), suggesting PLZF is required for func- MYC expression. [Published erratum appears in 2013 Cold Spring Harb. Per- spect. Med. 3: a022483.] Cold Spring Harb. Perspect. Med. 3: 3. tional maturation of these cells. Further study is required to clarify 16. Nie, Z., G. Hu, G. Wei, K. Cui, A. Yamane, W. Resch, R. Wang, D. R. Green, how Ag receptor specificity and transcription factors direct func- L. Tessarollo, R. Casellas, et al. 2012. c-Myc is a universal amplifier of gd expressed genes in lymphocytes and embryonic stem cells. Cell 151: 68–79. tional heterogeneity of T cells. 17. Dose, M., B. P. Sleckman, J. Han, A. L. Bredemeyer, A. Bendelac, and Mucosal-associated invariant T (MAIT) cells are a specialized F. Gounari. 2009. Intrathymic proliferation wave essential for Valpha14+ natural type of T cells recognizing riboflavin (vitamin B2) metabolites killer T cell development depends on c-Myc. Proc. Natl. Acad. Sci. U S A 106: 8641–8646. in the context of MR1 (40). They have limited T cell diversity in 18. Mycko, M. P., I. Ferrero, A. Wilson, W. Jiang, T. Bianchi, A. Trumpp, and both mice and humans, and a recent report using MR1 tetra- H. R. MacDonald. 2009. Selective requirement for c-Myc at an early stage of mers showed that they all express PLZF and are dependent on it V(alpha)14i NKT cell development. J. Immunol. 182: 4641–4648. 19. De Obaldia, M. E., and A. Bhandoola. 2015. Transcriptional regulation of innate for development (41). In addition, MAITs had subsets expressing and adaptive lymphocyte lineages. Annu. Rev. Immunol. 33: 607–642. Downloaded from TBET and RORgt among the MR1 tetramer-positive cells (41), 20. Kang, J., and N. Malhotra. 2015. Transcription factor networks directing the suggesting the possibility that effector differentiation profiles of development, function, and evolution of innate lymphoid effectors. Annu. Rev. Immunol. 33: 505–538. MAITs might also be analogous to iNKT cells. Future studies will 21. Watarai, H., E. Sekine-Kondo, T. Shigeura, Y. Motomura, T. Yasuda, R. Satoh, be required to analyze their genetic nature in a subset-dependent H. Yoshida, M. Kubo, H. Kawamoto, H. Koseki, and M. Taniguchi. 2012. De- manner. velopment and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines. PLoS Biol. 10: e1001255. In summary, we showed that the four different subsets of 22. von Moltke, J., M. Ji, H. E. Liang, and R. M. Locksley. 2016. Tuft-cell-derived iNKT cells are transcriptionally unique and identified NKTp as IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529: http://www.jimmunol.org/ 221–225. a distinct entity regulated by the Myc-dependent signaling. With 23. Hishikawa, D., H. Shindou, S. Kobayashi, H. Nakanishi, R. Taguchi, and comprehensive comparison analyses, we found the developmental T. Shimizu. 2008. Discovery of a lysophospholipid acyltransferase family es- profiles of iNKT subsets were more similar to those of gd T cells or sential for membrane asymmetry and diversity. Proc. Natl. Acad. Sci. U S A 105: 2830–2835. ILCs than to conventional Th cells and identified core genes 24. Ciofani, M., A. Madar, C. Galan, M. Sellars, K. Mace, F. Pauli, A. Agarwal, showing highest association with each lymphoid effector lineage. W. Huang, C. N. Parkurst, M. Muratet, et al. 2012. A validated regulatory network for Th17 cell specification. Cell 151: 289–303. 25. Yu, X., D. Rollins, K. A. Ruhn, J. J. Stubblefield, C. B. Green, M. Kashiwada, Disclosures P. B. Rothman, J. S. Takahashi, and L. V. Hooper. 2013. TH17 cell differentiation is regulated by the circadian clock. Science 342: 727–730.

The authors have no financial conflicts of interest. by guest on October 2, 2021 26. Dai, H., A. Rahman, A. Saxena, A. K. Jaiswal, A. Mohamood, L. Ramirez, S. Noel, H. Rabb, C. Jie, and A. R. Hamad. 2015. Syndecan-1 identifies and controls the frequency of IL-17-producing naı¨ve natural killer T (NKT17) cells References in mice. Eur. J. Immunol. 45: 3045–3051. 1. Bendelac, A., P. B. Savage, and L. Teyton. 2007. The biology of NKT cells. 27. Chang, S. H., J. M. Reynolds, B. P. Pappu, G. Chen, G. J. Martinez, and C. Dong. Annu. Rev. Immunol. 25: 297–336. 2011. Interleukin-17C promotes Th17 cell responses and autoimmune disease 2. Egawa, T., G. Eberl, I. Taniuchi, K. Benlagha, F. Geissmann, L. Hennighausen, via interleukin-17 receptor E. Immunity 35: 611–621. A. Bendelac, and D. R. Littman. 2005. Genetic evidence supporting selection of 28. Hara-Chikuma, M., S. Chikuma, Y. Sugiyama, K. Kabashima, A. S. Verkman, the Valpha14i NKT cell lineage from double-positive thymocyte precursors. S. Inoue, and Y. Miyachi. 2012. Chemokine-dependent T cell migration re- Immunity 22: 705–. quires aquaporin-3-mediated hydrogen peroxide uptake. J. Exp. Med. 209: 3. Lee, Y. J., K. L. Holzapfel, J. Zhu, S. C. Jameson, and K. A. Hogquist. 2013. 1743–1752. Steady-state production of IL-4 modulates immunity in mouse strains and is 29. Hara-Chikuma, M., H. Satooka, S. Watanabe, T. Honda, Y. Miyachi, T. Watanabe, determined by lineage diversity of iNKT cells. Nat. Immunol. 14: 1146–1154. and A. S. Verkman. 2015. Aquaporin-3-mediated hydrogen peroxide transport is 4. Constantinides, M. G., and A. Bendelac. 2013. Transcriptional regulation of the required for NF-kB signalling in keratinocytes and development of psoriasis. Nat. NKT cell lineage. Curr. Opin. Immunol. 25: 161–167. Commun. 6: 7454. 5. Mohrs, K., A. E. Wakil, N. Killeen, R. M. Locksley, and M. Mohrs. 2005. A two- 30. Saxe, J. P., M. Chen, H. Zhao, and H. Lin. 2013. Tdrkh is essential for sper- step process for cytokine production revealed by IL-4 dual-reporter mice. Immunity matogenesis and participates in primary piRNA biogenesis in the germline. 23: 419–429. EMBO J. 32: 1869–1885. 6. Lee, Y. J., H. Wang, G. J. Starrett, V. Phuong, S. C. Jameson, and K. A. Hogquist. 31. Spits, H., D. Artis, M. Colonna, A. Diefenbach, J. P. Di Santo, G. Eberl, 2015. Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Re- S. Koyasu, R. M. Locksley, A. N. McKenzie, R. E. Mebius, et al. 2013. Innate sponse. Immunity 43: 566–578. lymphoid cells–a proposal for uniform nomenclature. Nat. Rev. Immunol. 13: 7. Robinette, M. L., A. Fuchs, V. S. Cortez, J. S. Lee, Y. Wang, S. K. Durum, 145–149. S. Gilfillan, and M. Colonna, Immunological Genome Consortium. 2015. 32. Kovalovsky, D., O. U. Uche, S. Eladad, R. M. Hobbs, W. Yi, E. Alonzo, K. Chua, Transcriptional programs define molecular characteristics of innate lymphoid M. Eidson, H. J. Kim, J. S. Im, et al. 2008. The BTB-zinc finger transcriptional cell classes and subsets. Nat. Immunol. 16: 306–317. regulator PLZF controls the development of invariant natural killer T cell ef- 8. Cohen, N. R., P. J. Brennan, T. Shay, G. F. Watts, M. Brigl, J. Kang, and fector functions. Nat. Immunol. 9: 1055–1064. M. B. Brenner, Immunological Genome Project Consortium. 2013. Shared and 33. Savage, A. K., M. G. Constantinides, J. Han, D. Picard, E. Martin, B. Li, distinct transcriptional programs underlie the hybrid nature of iNKT cells. Nat. O. Lantz, and A. Bendelac. 2008. The transcription factor PLZF directs the Immunol. 14: 90–99. effector program of the NKT cell lineage. Immunity 29: 391–403. 9. Narayan, K., K. E. Sylvia, N. Malhotra, C. C. Yin, G. Martens, T. Vallerskog, 34. Constantinides, M. G., B. D. McDonald, P. A. Verhoef, and A. Bendelac. 2014. H. Kornfeld, N. Xiong, N. R. Cohen, M. B. Brenner, et al; Immunological A committed precursor to innate lymphoid cells. Nature 508: 397–401. Genome Project Consortium. 2012. Intrathymic programming of effector fates in 35. Zhang, S., A. Laouar, L. K. Denzin, and D. B. Sant’Angelo. 2015. Zbtb16 three molecularly distinct gd T cell subtypes. Nat. Immunol. 13: 511–518. (PLZF) is stably suppressed and not inducible in non-innate T cells via T cell 10. Stubbington, M. J., B. Mahata, V. Svensson, A. Deonarine, J. K. Nissen, receptor-mediated signaling. Sci. Rep. 5: 12113. A. G. Betz, and S. A. Teichmann. 2015. An atlas of mouse CD4(+) T cell 36. Koues, O. I., P. L. Collins, M. Cella, M. L. Robinette, S. I. Porter, transcriptomes. Biol. Direct 10: 14. S. C. Pyfrom, J. E. Payton, M. Colonna, and E. M. Oltz. 2016. Distinct Gene 11. Kim, D., G. Pertea, C. Trapnell, H. Pimentel, R. Kelley, and S. L. Salzberg. 2013. Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells. Cell TopHat2: accurate alignment of transcriptomes in the presence of insertions, 165: 1134–1146. deletions and gene fusions. Genome Biol. 14: R36. 37. Shih, H. Y., G. Sciume`, Y. Mikami, L. Guo, H. W. Sun, S. R. Brooks, J. F. Urban, 12. Trapnell, C., A. Roberts, L. Goff, G. Pertea, D. Kim, D. R. Kelley, H. Pimentel, Jr., F. P. Davis, Y. Kanno, and J. J. O’Shea. 2016. Developmental Acquisition of S. L. Salzberg, J. L. Rinn, and L. Pachter. 2012. Differential gene and transcript Regulomes Underlies Innate Lymphoid Cell Functionality. Cell 165: 1120–1133. 1470 SHARED LYMPHOID EFFECTOR SIGNATURE GENES

38. Chien, Y. H., X. Zeng, and I. Prinz. 2013. The natural and the inducible: in- 40. Kjer-Nielsen, L., O. Patel, A. J. Corbett, J. Le Nours, B. Meehan, L. Liu, terleukin (IL)-17-producing gd T cells. Trends Immunol. 34: 151–154. M. Bhati, Z. Chen, L. Kostenko, R. Reantragoon, et al. 2012. MR1 presents 39.Kreslavsky,T.,A.K.Savage,R.Hobbs,F.Gounari,R.Bronson,P.Pereira, microbial vitamin B metabolites to MAIT cells. Nature 491: 717–723. P. P. Pandolﬁ, A. Bendelac, and H. von Boehmer. 2009. TCR-inducible PLZF 41. Rahimpour, A., H. F. Koay, A. Enders, R. Clanchy, S. B. Eckle, B. Meehan, transcription factor required for innate phenotype of a subset of gammadelta Z. Chen, B. Whittle, L. Liu, D. P. Fairlie, et al. 2015. Identiﬁcation of pheno- T cells with restricted TCR diversity. Proc. Natl. Acad. Sci. U S A 106: typically and functionally heterogeneous mouse mucosal-associated invariant 12453–12458. T cells using MR1 tetramers. J. Exp. Med. 212: 1095–1108. Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021 `preT_E TP _Th` `S C_LT34F_B M` ImmGen 214 cells differentiating Supplemental `preT_E TP -2A _Th ` `S C_LTS L_B M` `preT_DN2_Th` `S C_S TS L_B M` `preT_DN2A _Th` `S C_LTS L_FL` `preT_DN2B _Th` `S C_S TS L_FL` `preT_DN2-3_T h` `S C_MP P 34F_B M` `preT_DN3A _Th` different `S C_S T34F_B M`

were `preT_DN3B _Th` `preT_DN3-4_T h` `S C_CMP _B M` `T_DN4_Th` `S C_ME P _B M` `T_IS P _Th` `S C_GMP _B M` `T_DP _Th` `S C_CDP _B M` dataset `T_D P bl _Th` `S C_MDP _B M` `T_DPsm_Th` `MLP _B M` identified `T_DP 69+_Th` `MLP _FL` `T_4+8int_Th` `proB _CLP _B M` `T_4S P 69+_Th` `proB _FrA _B M` `T_4S P 24int_Th`

hematopoietic `proB _FrB C_B M` `T_4S P 24-_Th` hematopoietic `preB _FrC_B M` `T_4int8+_Th` `preB _FrD_B M` Figure `T_8S P 69+_Th` `B _FrE _B M` `T_8S P 24int_Th` and `T_8S P 24-_Th` `proB _CLP _FL` `T_4Nve_Sp` `proB _FrA _FL` `T_4Mem_S p` `proB _FrB C_FL` `T_4Mem44h6 2l_S p ` `preB _FrD_FL` as `T_4Nve_LN` `B_FrE_FL` highlighted `T_4Mem_LN` `B _T1_S p` `T_4Mem44h6 2l_LN ` `B _T2_S p`

shown `T_4Nve_PP` `B _T3_S p`

1 `T_4Nve_MLN` `B _Fo_S p` `T_4_LN_B DC` . `B_GC_Sp` `T_4_P LN_B DC` `B _MZ_S p` `T_4_P a_B DC` `B 1a_S p` `T_4FP 3-_S p`

KTp NK `B _FrF_B M` `T_4FP 3+25+_S p ` cells `B _Fo_MLN`

cells `T_4FP 3+25+_A A ` `T_4FP 3+25+_ LN` `B _Fo_LN` in `T_8Nve_Sp` `B _Fo_P C` `T_8Mem_S p` `B 1b_P C` `T_8Nve_LN` `B 1a_P C` Fig in `T_8Mem_LN` `DC_8-_Th` . `T_8Nve_PP` `DC_8+_Th` sing us `T_8Nve_MLN`

Signature `DC_4+_S p` red unique

. `T_8Nve_Sp_OT1` `DC_8+_S p` `T_8Eff_Sp_OT1_d 5_VSVOv a` `DC_8-4-11b-_S p ` 3 `T_8Eff_Sp_OT1_d 6_VSVOv a` `DC_8-4-11b+_S p ` `T_8Eff_Sp_OT1_d 8_VSVOv a` a `DC_pDC_8-_S p` `T_8Eff_Sp_OT1_d 15 _VSVOva` when `DC_pDC_8+_S p` `T_8Mem_Sp_O T1_ d4 5_VSVOva `

ImmGen and `T_8Mem_S p_O T1_ d1 06_V S V Ov a` `DC_4+_S LN` `T_8Eff_Sp_OT1_1 2h r_ LisOva ` `DC_8+_S LN` `T_8Eff_Sp_OT1_2 4h r_ LisOva ` `DC_8-4-11b-_S LN ` `T_8Eff_Sp_OT1_4 8h r_ LisOva ` `DC_8-4-11b+_S LN ` `DC_pDC_8+_S LN`

transcripts `T_8Eff_Sp_OT1_d 6_ LisOv a`

their `T_8Eff_Sp_OT1_d 8_ LisOv a` `DC_IIhilang-103-11blo_SLN` NKTp `T_8Eff_Sp_OT1_d 10 _LisO va` `DC_IIhilang-103-11b+_SLN` genes `T_8Eff_Sp_OT1_d 15 _LisO va` `DC_IIhilang+103+ 11bl o_SLN ` `T_8Mem_Sp_O T1_ d4 5_Li sOva ` `DC_IIhilang+103- 11b +_S LN` `T_8Mem_Sp_O T1_ d1 00_ LisOv a` `DC_4+_MLN` `NK T_44-NK1_1-_T h` `DC_8+_MLN`

xpe ion s pres ex `NK T_44+NK 1_1-_T h`

dataset `DC_8-4-11b-_M LN` `NK T_44+NK 1_1+_ Th` `DC_8-4-11b+_ MLN `

signature `NK T_4+_S p` `NK T_4-_S p` `DC_pDC_8+_MLN`

of `NKT_4+_Lv` `DC_LC_Sk` `NK T_4-_Lv` `DC_103-11b+_Lv ` `Tgd_Th` `DC_103+11b-_Lv ` `Tgd_vg1+vd6- 24a hi_ Th ` `DC_103+11b-_L uLN ` KT NK `Tgd_vg1+vd6+ 24 ahi_ Th ` `DC_103-11b+_L uLN ` are `Tgd_vg2+24ahi _T h` `DC_103-11b+24 +_ Lu ` . `Tgd_vg2+24ahi _e 17_ T h` `DC_103+11b-_L u` `Tgd_vg3+24ahi _e 17_ T h` Each `DC_103-11b+_PolyIC _L u` `Tgd_vg5+24ahi _T h` `DC_103+11b-_PolyIC _L u` `Tgd_vg1+vd6- 24al o_ Th `

progenitors `DC_103-11b+F 4/8 0lo_K d` patterns `Tgd_vg1+vd6+ 24 alo_ Th ` genes

enriched `DC_103+11b-_S I` `Tgd_vg2+24alo _T h` `DC_103+11b+_S I` `Tgd_vg3+24alo _e 17_ T h` `Tgd_S p` `DC_103+11b-_S al m3_S I ` `Tgd_vg2-_S p` `DC_103+11b+_S al m3 _S I` column `Tgd_vg2-_act_S p` `MF_B M` `Tgd_vg2+_Sp` `MF_RP _S p` `Tgd_vg2+_act_S p` `MF_Lu` `Tgd_vg2-_S p_T CRbk o` `MF_103-11b +24 -_Lu` were `Tgd_vg2+_Sp_ TCRbk o` `MF_II+480lo_P C` `Tgd_vg5-_IE L` `MF_103-11b +_S I` were `Tgd_vg5+_IEL` `MF_11cloSer_SI` `Tgd_vg5-_act_ IEL` `MF_103-11b +_S al m3 _S I` `Tgd_vg5+_act_ IEL` in `MF_11cloSer_Salm 3_SI ` `E p_ME Chi_Th` (NKTp)

was `MF_II-480hi_P C` highly `Fi_MTS 15+_Th ` `Fi_Sk` `MF_Microglia_CNS` `MF_Thio5_II+ 48 0int _P C` analyzed `FRC_MLN`

proliferating `FRC_S LN` `MF_Thio5_II- 480i nt_P C ` `LE C_MLN` `MF_Thio5_II- 480 hi_P C ` `LE C_S LN` `MF_Thio5_II+ 48 0lo_P C ` labeled `B E C_MLN` `Mo_6C+II-_B M` `B E C_S LN` `Mo_6C-II-_B M` expressed `S t_31-38-44-_S LN ` `Mo_6C+II-_B l`

+3 `NK _S p` and `Mo_6C+II+_B l` `NK _49CI-_S p` `Mo_6C-II-_B l` `NK _49CI+_S p` `Mo_6C-II+_Bl` `NK _49H-_S p` `Mo_6C-IIint_Bl` `NK _49H+_S p`

across `Mo_6C+II-_LN` `NK _MCMV 1_S p`

NKT `NK _MCMV 7_S p` `GN_B M` as `NK _H+_MCMV 1_S p` `GN_B l` `NK _H+_MCMV 7_S p` `GN_A rth_B M`

- `NK _b2m-_S p` `GN_Arth_SynF`

3 `NK _DA P 10-_S p` `GN_UrAc_PC` or

in `NK _DA P 12-_S p` `GN_Thio_PC` 1 .

NKT1 NKTp NKT1 NKTp A NKT1 > NKT2 NKT1 > NKT17 NKT2 > NKT17 Input

Th1 >Th2 and Th17

Th2 >Th1 and Th17

Th17 >Th1 and Th2

ILC1 >ILC2 and ILC3

ILC2 >ILC1 and ILC3

ILC3 >ILC1 and ILC2

NK >ILC2 and ILC3 C NKT1 > NKT2 NKT1 > NKT17 NKT2 > NKT17

V5 > V2 & V6

V6 >V5 & V2

V2 >V5 &V6

Supplemental Figure 2. Gene set enrichment analysis (GSEA). Signature genes of T helper cells (a), innate lymphoid cells (ILC) (b) and γδ T cells (c) were probed on genes differentially expressed between iNKT subsets. Subset signature genes were listed is Supplementary Table 1. V2 (Vγ2+) and V6 (Vδ6+) are thymic CD24low cells γδ T cells and V5 (Vγ5+) is intraepithelial γδ T cells. Supplementary Table 1. List of subset signature genes. Gene lists were generated as depicted in Fig. 3A and 4C. NKT1 NKT2 NKT17 NKTp NKT1 NKT2 NKT17 ILC1 ILC2 ILC3 NK cells Th1 Th2 Th17 V1 V6 V2 V5 >NKTp, NKT2 & NKT17 >NKTp, NKT1 & NKT17 >NKTp, NKT1 & NKT2 >NKT1, NKT2 & NKT17 >NKT2 &NKT17 >NKT1 & NKT17 >NKT2 & NKT17 >ILC2 & ILC3 >ILC1 & ILC3 >ILC1 & ILC2 >ILC2 & ILC3 >Th2 & Th17 >Th1 & Th17 >Th1 & Th2 >V2 & V6 >V2 & V5 >V5 & V6 >V2 & V6 140 62 81 45 191 197 126 433 318 421 529 1000 1000 1756 23 387 194 408 1700026L06RIK 2610018G03RIK 1300014I06RIK 1190005F20RIK 1700026L06RIK 1700040L02RIK 1300014I06RIK 1110038D17RIK 0610010O12RIK MARCH7 0610007P22RIK SEPT6 MARCH10 SEPT5 C1QL3 ACSL3 ACVR2A ACSF2 1700128F08RIK 3830431G21RIK 2310007L24RIK 2010107E04RIK 1700128F08RIK 2610018G03RIK 2310007L24RIK 1110054O05RIK 1110002B05RIK SEPT5 0610037P05RIK 1110037F02RIK 0610009L18RIK SEPT8 CCL5 ADAMTS3 ADAM12 ADH1 2700097O09RIK 4930555I21RIK ABI3BP ARF5 2700097O09RIK 2810417H13RIK 2410066E13RIK 1700025G04RIK 1700113H08RIK 1700009P17RIK 1110038D17RIK 1110059E24RIK 1110032F04RIK SEPT11 CD8B1 ADAMTS6 ADAM8 ADRB1 4933440M02RIK 6330406I15RIK ACPP ART2A-PS 4933440M02RIK 3830431G21RIK 3230401D17RIK 2210404J11RIK 1810011H11RIK 1700012B07RIK 1110054O05RIK 1700001O22RIK 1110034G24RIK 0610010F05RIK CRTAM ADAMTSL3 ADRB2 AHRR 6330512M04RIK ABHD13 ADD3 CCNB1 6330512M04RIK 4930452B06RIK 6720401G13RIK 2810417H13RIK 2510009E07RIK 2010002N04RIK 1600012F09RIK 1700025G04RIK 1110058L19RIK 1600002H07RIK DAPL1 ADK AHCYL2 ALPI A430084P05RIK ACP5 ADRB2 CDC26 A430084P05RIK 4930555I21RIK 9130401M01RIK 4632428N05RIK 2810055G20RIK 3230401D17RIK 1600012H06RIK 1700040L02RIK 1190005I06RIK 1600014C10RIK EOMES AKAP6 AI504432 ANXA4 ANXA2 ANO7 AGPAT5 CIAO1 AB124611 4930588N13RIK AAGAB 4930486L24RIK 3110043O21RIK 4930503L19RIK 1700020L24RIK 2510009E07RIK 1700056E22RIK 1700008J07RIK GPR15 AKR1C12 AI646023 AOAH APOL9B APBB2 ANKRD6 CNIH4 AHNAK 6330403K07RIK ABI3BP 6030458C11RIK 4930412O13RIK 6720401G13RIK 1700025G04RIK 2610020H08RIK 1810011H11RIK 1700021K19RIK GRIA3 AKR1C18 ANKRD35 APH1B ARL4D ARHGAP20 APP CUL4B AIM1 6330406I15RIK ACPP 6330512M04RIK 4930562F07RIK 8430410A17RIK 1700040L02RIK 2900026A02RIK 2310035C23RIK 1700029J07RIK HMCN1 ALS2 ANKRD6 APLP1 AW112010 ARMCX1 AQP3 DAPP1 AIM1L 9030617O03RIK ADD3 A430078G23RIK 4932438H23RIK 9130011J15RIK 2010012O05RIK 4930486L24RIK 2410015M20RIK 1700048O20RIK IFT80 ALS2CL AQP3 APLP2 BIN1 ATP1A3 ARL5C ECM1 ALAD ABHD13 ADPGK A430084P05RIK 9430020K01RIK A830080D01RIK 2810006K23RIK 4933430I17RIK 2410137M14RIK 1700128F08RIK ITGA4 ANP32E ARHGAP21 APOA1 BTG2 BTLA ARNT2 EIF2B1 ANXA2 ABHD4 ADRB2 A530054K11RIK A4GALT ABCC3 2810417H13RIK 5430417L22RIK 2610008E11RIK 1810022K09RIK KIT APOO ARHGAP26 APOA4 CCDC136 C330018D20RIK BLK EIF4A1 APOL9B ACP5 AGPAT5 A630001G21RIK A930011G23RIK ABHD4 2810422O20RIK 5430427O19RIK 2700046G09RIK 1810055G02RIK KLRI1 APOOL ARHGAP31 APOL10B CCL1 CDCA5 CACNA1A EPB4.9 ARL4D ADH1 ANKRD6 A630089N07RIK ABCC8 ABI3BP 3110001D03RIK 5730508B09RIK 2810408M09RIK 2010015L04RIK MIR365-1 ARHGAP11A ARID5A APOL9A CCL4 CMTM4 CCDC86 FKBP2 AW112010 ADK APP A830007P12RIK ACBD7 ABLIM3 3110003A17RIK 5830411N06RIK 4921507P07RIK 2010204K13RIK MS4A4C ARHGAP24 ARNTL APOL9B CCL5 DEPDC1A CD72 GARS B4GALT1 AGFG1 AQP3 AB124611 ACER2 ACPP 4430402I18RIK 6330403K07RIK 4930453N24RIK 2310014L17RIK PRR5L ARL4D ATF6 APPL2 CCR8 DLEC1 CHAD GMNN BCL2 AHCYL1 ARL5C ABCA1 ACOT6 ACSL1 4831426I19RIK A 4932438H23RIK 2310036O22RIK RRAS2 ASAP1 ATOH8 ARAP3 CD160 DNM3 CORO2B HIST2H2AC BIN1 AMPD1 ARNT2 ACSS1 ACSBG1 ACVR2A 4930486L24RIK A530064D06RIK 5830415F09RIK 2310057M21RIK SELL ASF1B ATP10D ARHGEF5 CD2 DYRK4 CPE HMGN2 BRD2 ANLN ATG7 ACTN1 ADAM19 ADRBK2 6330512M04RIK AA467197 5830416P10RIK 2410089E03RIK THEMIS ASPM ATP2B1 ARID3A CD244 E2F7 CREG1 IFI27L2A BTG2 ANO7 BATF ADAM4 ADCY9 AHRR 9130023H24RIK AAGAB 6430571L13RIK 2700097O09RIK TNFSF8 ATIC B3GNT5 ARRDC3 CD63 F13A1 CRMP1 IFT27 CAR2 ANP32E BLK ADAMTS10 ADM AI848100 A430078G23RIK ABCA3 9430020K01RIK 2810403A07RIK TRIO ATP1B1 BIK ARRDC4 CERCAM FABP7 CRTAM LAGE3 CCDC136 APBB2 CACNA1A ADAMTS14 AKR1C12 ALPK1 A430084P05RIK ABCC3 9930012K11RIK 2900005J15RIK TSGA10 BC021614 BLK ART2B CHSY1 FAM169B D17H6S56E-3 LDHB CCL1 ARHGAP19 CCDC86 ADAMTS6 ALDH3A1 AMICA1 A530054K11RIK ABCD1 A430078G23RIK 2900011O08RIK TUBA3B BC094916 C630004H02RIK AS3MT CLDN12 FAM55B DOCK5 LSM3 CCL4 ARHGAP20 CD37 ADD3 ALOX5 AMZ2 A630001G21RIK ABCG1 A630033H20RIK 3000002C10RIK BRIP1 CAMK2D ASB2 CLIC5 FAM71F2 ELMOD1 MAK16 CCL5 ARMCX1 CD72 AFF3 ALPK3 ANXA5 A630033H20RIK ABCG2 AA987161 3110007F17RIK BTLA CCDC109B ASPH CPNE7 FLRT2 EMB MKL2 CCR8 ASF1B CHAD AI467606 AMPH AP1AR A630089N07RIK ABHD4 ABCB9 3110043O21RIK BUB1 CCR2 ATG4C CRIM1 GATA1 F2R NDUFA13 CD160 ATP1A3 CNR2 AKR1B10 ANKS6 APOBEC1 A830007P12RIK ABHD8 ABCC1 4632434I11RIK BUB1B CCR6 ATP6V0A2 CSDA GM129 FAM189A1 NDUFS4 CD2 AURKA CORO2B ALKBH4 AP1S3 APOL7E A930038C07RIK ACADL ABHD14B 4833439L19RIK BZW2 CD163L1 AUH CTLA2B GM973 FAM83A NUDCD2 CD244 BC021785 CPE ANKMY2 APBB2 AQP3 AB124611 ACSF2 ABHD6 4930452B06RIK C330027C09RIK CD44 B3GALT5 CTSW GPR97 FRMD6 NUP50 CD63 BIRC5 CREG1 ANKRD24 AR ARHGAP6 ABCA1 ACSL4 ABTB2 4930470H14RIK CACNA1D CD55 B3GNT7 CX3CR1 GPRASP2 FSTL4 OXSR1 CD74 BRCA1 CRMP1 ANKRD44 AREG ARHGAP8 ABCD1 ACTN1 ACAP3 4930503L19RIK CAP2 CDC14B B4GALNT2 CXCR3 HC FUT7 PTTG1 CD86 BTF3L4 CRTAM ANXA1 ARG1 ARHGEF5 ABCG2 ACVRL1 ACAT2 4930519F09RIK CASC5 CDH10 B4GALNT4 DAPK2 HECW2 FXYD7 RNFT1 CD97 BTLA D17H6S56E-3 ANXA2 ARHGEF10L ARPC3 ABTB2 ADA ACBD7 5830418K08RIK CASD1 CDON BAIAP3 DENND4A HIST2H2BE GM10791 RPA3 CERCAM C330018D20RIK DHODH APBB1IP ARHGEF11 ARRB1 ACER3 ADORA2A ACCS 6030468B19RIK CBX5 CLIP1 BC005624 DOPEY2 IL17RB GM2A SLC2A1 CHSY1 CASC5 DOCK5 ARHGAP15 ARHGEF12 ARRDC3 ACPL2 ADORA3 ACOT11 6430548M08RIK CCDC125 CLOCK BC013712 ELOVL7 KHDRBS3 GM9961 SPC25 CLDN12 CCDC126 DPY19L3 ARHGAP25 ARL5C ARRDC4 ACSS1 AGFG1 ACOT2 6430550D23RIK CCNA2 CORO2B BC016495 EOMES LIMS1 HS3ST1 SRP68 CLIC5 CCNB1 ELMOD1 ARHGEF18 ART2B ASAH1 ACSS2 AGFG2 ACRBP 6820431F20RIK CCNB1 CPEB2 BCL2 FAM26F LRP11 IL17RE STMN1 CLN3 CCNG2 EMB ARHGEF2 ASS1 ASPHD2 ADAMTS10 AGPAT5 ACSS1 8430427H17RIK CCNB2 CPM BCL2L11 FAM65B NUDT7 IL1R1 TAF9 COMMD8 CCR9 ENTPD7 ARL2BP ATP6V0A1 ATP1A3 ADAMTS14 AGRN ACSS2 9030612E09RIK CCNE2 CRY1 BEND7 FASL OLFML3 IL23R TFDP1 CPNE7 CCS ERO1L ARL4C ATP8A2 ATP6V0D2 ADAP1 AHCY ACTN2 9430008C03RIK CCR10 CRYBG3 BMF FCER1G ORC1 KCNK1 THAP2 CRIM1 CD200 F2R ARL4D B830017H08RIK AVIL ADD3 AHCYL1 ACYP1 9430015G10RIK CCR4 CXCR6 BMP2K FGD5 PCSK1 LAPTM4B TMEM199 CSDA CD28 FAH ARMC7 BACE2 AW549877 AFF3 AHDC1 ADAM8 A430093F15RIK CCR8 CYP2S1 C030046I01RIK FGL2 PDE4C LINGO4 TXN1 CTLA2A CD81 FAM189A1 ARPC5L BAMBI B3GALT2 AGPAT3 AIM1L ADAMTS10 A630001G21RIK CD28 CYSLTR1 C1QTNF6 FGR PECAM1 LTA USMG5 CTLA2B CDC45 FAM83A ARRDC1 BCL11B B3GALT5 AI314976 AIPL1 ADAMTSL4 A630089N07RIK CD4 DERL3 CABLES1 FILIP1L PGAM2 LY6G5B UXT CTSW CDC6 FCHSD2 ARSB BEX4 B4GALNT2 AI467606 AKT2 ADAR A830080D01RIK CD40LG DKKL1 CAMK2N1 FOXP1 PLD1 MAF CX3CR1 CDCA5 FRMD4A ATP11B BMP2 BC016495 AI837181 ALAD ADC AA388235 CD5 DUSP7 CAPN3 GAS7 PRKCA MARK2 CXCR3 CENPE FRMD6 ATP1B1 BMP7 BC018473 AK3 ALDH5A1 ADCK1 AAAS CD6 EDARADD CAR2 GIMAP4 PRR5L MATN2 DAPK2 CENPM FSTL4 ATP1B3 BVES BC031181 AKR1B10 ALDOA ADCY6 AATF CD81 ELL2 CASZ1 GIMAP8 PSTPIP2 MICAL2 DENND4A CHAF1A FUT7 ATP6V0A2 BZW2 BCL2A1C ALG5 ALDOC ADD3 ABAT CD9 EMB CCDC104 GM11435 PTPRR MMP25 DOPEY2 CHN1 FXYD7 ATP8B4 CACNA1D BCL2A1D ALKBH4 ANXA1 ADI1 ABCA5 CDC6 EMP3 CCDC134 GM156 PYROXD2 NR1D1 DSE CHN2 GM10791 AW146020 CALCA BMP4 ANAPC4 ANXA2 ADK ABCB6 CDCA5 EPAS1 CCDC136 GM4759 SCN8A OLFR60 ELOVL7 CMTM4 GM2A B3GNT5 CAR13 BTBD19 ANKRD24 ANXA6 ADPRHL2 ABCC4 CDCA7 ERO1L CCDC80 GPR174 SESN3 PEX26 EOMES CNGA1 GM9961 B4GALT5 CCL1 BTRC ANUBL1 AP3S1 ADRBK2 ABCC5 CDK1 ESYT2 CCL3 GRAMD3 SLC29A1 PLCB4 FAM26F DDC HGSNAT BC017643 CCR4 C130039O16RIK ANXA1 APAF1 AFF4 ABCC8 CDKN2C ETV6 CCL4 GVIN1 SMPDL3B PLEKHB2 FAM65B DDX19A HMGCL BC094916 CCR8 C4A ANXA2 APBB1IP AGER ABCD3 CENPE F2RL2 CCL5 GZMA SP6 PLIN2 FASL DENND2D HS3ST1 BCL9L CD24A C4B AOAH APH1A AGPAT2 ABCE1 CENPH FAM117A CCNI GZMB STARD10 PLXND1 FCER1G DEPDC1A IL17RE BID CD6 CABLES1 APBB1IP APH1B AHNAK ABCF2 CENPK FAM124B CCNO GZMC TESC PON2 FGD5 DLEC1 IL1R1 BOD1 CD81 CAP2 ARHGAP25 APOL7E AI413582 ABHD15 CEP55 FAM169B CCRL2 H2-AA TIAM1 RAMP3 FGL2 DNAHC8 IL23R C030039L03RIK CDH2 CAPG ARHGAP30 APOLD1 AI462493 ABI3 CES2D-PS FAM65B CD101 HOPX TRIM13 RARA FGR DNM3 INTS7 C1GALT1 CHD7 CAV2 ARHGEF18 APP AI467606 ABI3BP CHDH FCHO2 CD200R1 HRH4 TUBA3A RORC FILIP1L DUSP10 KCNK1 C630004H02RIK CHDH CCDC55 ARHGEF2 APPL1 AI854703 ABL2 CHEK1 FLOT1 CD200R2 HSD11B1 ZCCHC12 SDC1 FKBP8 DYRK4 LAPTM4B CAR5B CHSY3 CCNE2 ARL4D AQP9 AK2 ACAD9 CHST15 FOSB CD200R4 IFITM1 SEC11C FOXP1 E2F7 LDHD CASC5 CSF1 CCNG2 ARL6IP5 ARAP2 AKAP7 ACOT10 CHST2 FSTL4 CD244 IFITM2 SERINC5 GAS7 ENC1 LINGO4 CASP2 CSF2 CCNI ARPC5L AREG AKAP8 ACSL1 CKS1B GAB3 CD38 IFITM3 SLC11A2 GIMAP4 ESCO2 LMO4 CBFA2T3 CXCL1 CCR1 ARRDC1 ARF6 AKAP8L ACSL3 CKS2 GABBR1 CD3E IFNG SLC35F2 GIMAP8 EXO1 LTA CCL5 CXCL2 CCR9 ARSB ARHGAP18 AKR1C12 ACTL6A CMTM7 GALM CD7 IL4RA SMOX GM10640 EZH2 LY6G5B CCM2 CYBB CD164 AS3MT ARHGAP19 AKR1C13 ACTR1B CNTNAP1 GGT1 CD72 IRF8 SMYD1 GM11435 F13A1 MAF CCNA2 CYP2D22 CD38 ASAP2 ARHGAP29 AKT1S1 ACTR3B CPNE7 GLIPR2 CD8A ITGA1 SPSB3 GM12250 F630042J09RIK MANF CCNB2 CYP2W1 CD4 ATG4D ARHGEF5 ALDH1B1 ACVR1 CSF1 GLT25D2 CD96 ITM2A STAB2 GM14005 FABP7 MARK2 CCNE1 CYP51 CD83 ATG5 ARHGEF6 ALKBH4 ADAM12 CTLA2A GM2A CDH1 KCNJ8 SUSD2 GM156 FAM169B MATN2 CCNJ CYSLTR1 CD93 ATP11B ARID5B ALKBH7 ADAM19 CX3CR1 GM527 CDYL2 KLRA1 TACSTD2 GM4759 FAM55B MICAL2 CCR5 D330045A20RIK CD96 ATP1B1 ARL5A ALOX5AP ADAM1A CXXC5 GOLM1 CELA1 KLRA3 TDRKH GPR174 FAM55C MMP25 CD160 DACH2 CDC42EP2 ATP1B3 ARL8B ALOX8 ADAM9 CYCS GPR132 CHST12 KLRA5 TICAM1 GRAMD3 FAM71F2 MTSS1 CD1D1 DENND5A CDH17 ATP6V0A2 ARRB1 ALS2CL ADAMTS13 D030056L22RIK GPR183 CHSY1 KLRA8 TM2D3 GVIN1 FLRT2 MUS81 CD1D2 DGAT2 CDH20 ATP8B4 ARRDC3 AMPD3 ADAMTS6 DEPDC1A GPR44 CLDND2 KLRA9 TMEM149 GZMA FOXN2 NDUFS3 CD2 DHCR24 CDK14 AW146020 ARSB ANGPTL6 ADARB1 DFNA5 GPRIN3 CLIP2 KLRC1 TMEM176B GZMB FRMD7 NR1D1 CD22 DHX40 CHAD B3GNT5 ASAH2 ANK ADARB2 DLGAP5 H60B CLNK KLRC2 TNFSF14 GZMC GABRR2 NUDT14 CD247 DIP2C CHST12 B4GALT5 ASAP1 ANKRD23 ADCY4 DNA2 HBB-B1 CLSTN1 KLRC3 TRPV2 H2-AA GATA1 OLFR60 CD28 DMXL2 CKB BAIAP3 ASNS AP3D1 ADCY9 DNAHC8 HBB-B2 CNIH2 KLRD1 UCP2 HIGD1A GEN1 PAOX CD3D DOCK1 CLIC4 BC017643 ATF6 AP4S1 ADH4 DPP4 HLF CNNM2 KLRG1 ZBTB7C HOPX GM129 PEX26 CD3E DPH5 CLNK BC094916 ATP11B APOL7C ADPGK DSTN HNRPLL COPZ2 KLRI1 HRH4 GM14085 PFKP CD3G DUSP10 CNKSR3 BID ATP13A3 AQP11 AFAP1 DTL IFI203 CREB3L1 KLRI2 HSD11B1 GM4841 PLCB4 CD47 EBI3 CNN3 BLOC1S3 ATP1A3 AR AFF1 DUSP2 IFNGR1 CRTAM KLRK1 IFITM1 GM8096 PLEKHB2 CD48 EEF1B2 CORO2B C030039L03RIK ATP1B2 ARHGAP4 AFF3 DUT IGF1R CTLA4 LAIR1 IFITM2 GM973 PLIN2 CD52 EEPD1 CPA3 C1QL3 ATP2B1 ARHGEF1 AGAP1 EIF3M IL17F CTNNBIP1 LAT2 IFITM3 GNAS PLXND1 CD55 EFNB2 CPD CALM1 ATP2B4 ARHGEF10 AGAP3 ENG IL17RA CYP2J6 LPAR6 IFNG GPR97 PON2 CD7 ELOVL5 CRYAA CAPN2 ATP6V1D ARHGEF18 AHCTF1 EPHA3 IL17RC CYP2J9 LRRC8C IL4RA GPRASP2 POP1 CD9 ENAH CSTAD CAR5B ATP8A1 ARID4B AHR ERH IL17RE CYP51 LRRK1 IRF8 GSN PSD2 CD97 EPAS1 CTLA4 CARD6 ATP8A2 ARL4A AHRR ESCO2 IL1R1 CYTH3 LY6C1 ITGA1 HC PSEN2 CDC14B EPB4.1L4A CTSA CBFA2T3 ATP8B4 ARL4C AHSA1 ETV5 IL23R D8ERTD82E LY6C2 ITM2A HECW2 PUSL1 CDC25A EPHA2 CTSB CCDC88A AW112010 ARL6IP5 AIDA EXO1 IL2RA DAPK2 LY6I KBTBD2 HEY1 RAMP3 CDC25B ETS2 CXCL9 CCL5 AZIN1 ASB13 AIF1L EZH2 IL7R DCBLD2 MAN1C1 KCNJ8 HIF1A RARA CDC42SE1 F630111L10RIK CXCR5 CCM2 B2M ASB2 AIFM1 F630043A04RIK IRAK3 DDC MAP3K8 KLF2 HIST2H2BE RORA CHORDC1 FAAH CYP2J6 CCNA2 B3GNT3 ASB6 AK1 FABP7 ITGA5 DDX28 MBNL1 KLF3 HMGN2 RORC CHPT1 FAM169B CYP2J9 CCNB2 B3GNT5 ASPSCR1 AK4 FAIM ITGB5 DENND4A MCOLN2 KLRA1 IFI27L1 SCPEP1 CHSY1 FAM183B CYP4F16 CCNE1 B430306N03RIK ASS1 AKAP1 FAM20A KBTBD11 DHCR24 MS4A6C KLRA3 IIGP1 SDC1 CLDND2 FAM194A D16ERTD472E CCNJ B4GALNT4 ATF3 AKAP12 FAM49A KCNA3 DHCR7 NCALD KLRA5 IL17RB SEC11C CLEC2I FAM55D DBF4 CCR2 BAG3 ATF5 AKAP13 FAM54A KCNK1 DISP1 NCR1 KLRA8 IL21 SERINC5 CLN3 FAM71F2 DHRS11 CCR5 BASP1 ATG16L1 AKAP2 FAM60A KLF2 DOK1 NEURL3 KLRA9 IL4 SLC11A2 CLOCK FBXL21 DHRS4 CD1D1 BATF3 ATG4C AKAP5 FAM81A KLF3 DSP NKG7 KLRC1 IL6RA SLC27A6 CMAH FBXO34 DKKL1 CD1D2 BBC3 ATN1 AKR1B8 FBXO5 LAPTM4B DTX1 NR4A2 KLRC2 KHDRBS3 SLC35C2 CNGA1 GALC DLG5 CD2 BC022687 ATOX1 ALCAM FCRL1 LINGO4 DUSP10 P2RY13 KLRC3 KIF23 SLC35F2 CNR2 GALNT3 DMRTA1 CD247 BC052040 ATP10D ALDOART1 FGF2 LONRF3 DUSP5 PGLYRP1 KLRD1 KLRA6 SLC41A3 COPA GAS2L3 DNAHC6 CD28 BC068157 ATP13A1 ALG3 FHL2 LPCAT2 DUSP6 PIK3R5 KLRG1 LCK SMOX CRIP1 GATA3 DNAJB5 CD300LF BCL2L11 ATP1A1 ALG8 FIGNL1 LRRC25 EEF2K PLEKHM3 KLRI1 LIMS1 SMYD1 CRTAM GCFC1 DNAJC12 CD47 BCL7C ATP1B3 ALMS1 FLRT2 LRRC8B EFCAB4B PPM1J KLRI2 LRP11 SPSB3 CSPRS GFI1 DPEP2 CD48 BEND6 ATP2A3 AMACR FOLR4 LRRN4 EFHD2 PRF1 KLRK1 LRRC49 SSR1 CST7 GFPT2 DSTN CD52 BHLHE40 ATP5E AMOTL1 FZD6 LTB4R1 EHD1 PTPN4 LAIR1 LXN STAB2 CTSD GLB1 DUS2L CD55 BMF ATP6V0B AMPH GADL1 LY6A ELMO2 QRFP LAT2 LYPD6B SUSD2 CYB5B GLRX DUSP4 CD68 BMP2K ATP6V0E ANAPC13 GAS5 LY6G5B ENPP5 RECK LITAF LZTFL1 TACSTD2 CYM GM7257 E2F3 CD7 BNIP3 AUH ANGPTL2 GEMIN6 MATN2 ENTPD1 RGS1 LPAR6 MAGED2 TCEAL3 D10WSU102E GM889 EGFL6 CD9 BRDT AVIL ANKLE1 GEN1 MGAT5 EPB4.1 RGS18 LRRC8C MAPK11 TCEB3 D14ABB1E GRIN2D EIF2C4 CD97 BRE AW549877 ANKRD13B GM12238 MIF4GD EPCAM RNF13 LRRK1 MBOAT1 TDRKH D1ERTD622E H2-OA EMD CDAN1 BSPRY AXIN2 ANKRD17 GM4759 MIR202 ERRFI1 SAMD3 LY6C1 MCM10 TICAM1 D330012F22RIK HAVCR2 EMP1 CDC14B BST1 B3GALT4 ANKRD26 GM885 MIR344 EXOC3 SEPN1 LY6C2 MGST2 TM2D3 D4WSU53E HBA-A1 ENTPD1 CDC25B BTBD1 B3GALT5 ANKRD37 GMNN MMP14 FABP2 SERPINA3H LY6I MTX2 TMEM149 D8ERTD82E HBA-A2 EPB4.1L5 CDC34 BTG1 B3GAT3 ANKRD50 GNPNAT1 MMP25 FADS1 SERPINB9 LYZ1 NAA20 TMEM176B D930015E06RIK HDAC5 EPS8 CDC42SE1 BTLA B4GALT5 ANKRD52 GPNMB MTSS1 FADS2 SERPINB9B LYZ2 NBR1 TNFSF14 DAPL1 HDC EPS8L3 CDCA7L C1QTNF1 B4GALT7 ANP32A GPR155 NAV2 FAM109B SERPINI1 MAGOHB NCAPG2 TNS4 DDX39 HDX ETV5 CDH22 C1QTNF6 BAIAP2 AOAH GPR174 NPL FAM135B SIDT1 MAN1C1 NCAPH TRPV2 DDX43 HES1 F2R CDK2AP1 C330007P06RIK BATF AP1AR GTF2IRD1 NR1D1 FAM46C SLAMF7 MAP3K8 NRP2 TUBE1 DEF6 HGF F2RL2 CDKN2C CAB39 BBS9 APEX2 GYPC NR1D2 FASL SNX10 MBNL1 NTRK3 UCP2 DENND2D HIST1H2BC FAH CDKN2D CABLES1 BC021614 APITD1 H19 ODC1 FCER1G SPIN2 MCOLN2 NUDT7 UTP11L DGKA HIST1H2BE FAM134B CGGBP1 CACNB3 BC037034 APLF H1F0 OLFR525 FCGR3 SRC MS4A6C NUP153 ZBTB7C DGKZ HIST1H2BG FAM184B CHPT1 CACNB4 BCAM APLP2 HC OLFR527 FDFT1 STYK1 NCALD OLFML3 ZFP459 DIDO1 HIST2H2BB FAM20A CHRNE CAGE1 BCKDHB APOL9B HDC P2RY1 FDPS SYTL2 NCR1 ORC1 DNAHC8 HLF FAM46C CHSY1 CAPN2 BCL11B APOO HDDC2 PCSK1 FES SYTL3 NEDD4 PABPC1 DOCK11 HMCN1 FAM82A1 CLDND2 CAR11 BET1L AQP3 HELLS PDE5A FGL2 TACC1 NEURL3 PCSK1 DOCK9 HOMER2 FAM98B CLEC2D CARD11 BHLHE41 ARGLU1 HEY1 PI4K2A FGR TBX21 NKG7 PDE4C DPH2 HPGDS FBXL17 CLEC2I CASP1 BID ARHGAP12 HHEX PISD-PS1 FOSL2 TMEM2 NR4A2 PDE7B DPY19L1 HPN FFAR2 CLEC4E CASP3 BIN1 ARHGAP21 HIBCH PLIN3 FOXO3 TMEM37 OASL1 PECAM1 DSCAM HS3ST1 FGF16 CLIP3 CASP4 BMP7 ARHGAP27 HIF1A PLP2 FRMD4B TNFSF8 P2RY13 PGAM2 DTX3L HSPB11 FHL2 CLOCK CASS4 BOLA2 ARHGAP31 HIST1H1A PLXDC2 FRMD5 TSC22D3 PANK3 PGCP EFCAB4B HTR1B FNBP1L CMA1 CAV2 BRAP ARHGAP32 HIST1H2AB PLXNA1 GABARAPL1 TSPAN4 PDE7A PGK1 EFHC2 IFNGR2 FRYL CMAH CBLB BRI3 ARHGAP33 HIST1H2BB PLXND1 GALNS TXNIP PEA15A PHGDH EFHD2 IGFBPL1 GABARAPL1 CMKLR1 CBX3 BSCL2 ARHGAP39 HIST1H2BF PRELID2 GBP5 TYROBP PGLYRP1 PLAC8 EHD3 IL13 GATAD1 CRIP1 CCDC102A BTC ARHGAP5 HIST1H2BG PROS1 GCA WIPF1 PIK3R5 PLAUR ELOVL7 IL17RB GCNT2 CRTAM CCDC136 BTG2 ARHGDIG HIST1H2BJ PRSS12 GCET2 XCL1 PITPNC1 PLD1 ELTD1 IL1RL1 GDA CSDA CCDC92 C030006K11RIK ARHGEF19 HIST1H2BK RAMP3 GCNT1 ZCCHC18 PLEKHM3 PPIC ENPP1 IL4 GJB2 CSPRS CCL5 CACNA1C ARHGEF9 HIST1H2BL RAPGEF4 GCNT2 POGK PRDX2 ENTPD4 IL5 GLT25D2 CST7 CCND3 CACNB1 ARMC9 HIST1H2BN RARG GFI1 PPM1J PRG4 EOMES IL6 GM11818 CSTF2T CCNI CALCRL ARMCX2 HIST1H4A RASA3 GGTA1 PRF1 PRKCA EPSTI1 IL9R GM166 CTLA2A CCR5 CAMK1D ARMCX4 HIST1H4B RASA4 GIMAP3 PTPN4 PRR5L ESYT1 INPP4B GM5635 CTSC CCRL2 CAMK2B ARMCX6 HIST1H4C RASGRP2 GIMAP6 PTPN6 PSTPIP2 EYA1 IPMK GNA13 CTSD CD163L1 CAMK2N1 ARNTL HIST1H4D RASSF3 GIMAP7 QRFP PTGIR F2RL1 IRF4 GNG12 CUEDC1 CD164 CAMTA2 ART2A-PS HIST1H4F RBPMS2 GKAP1 RCBTB2 PTPLAD1 FAM120B ITK GNG2 CX3CR1 CD200R1 CAR2 ASB14 HIST1H4K RET GLCCI1 RECK PTPN5 FAM33A JDP2 GNG5 CYM CD200R4 CARD6 ASH2L HIST1H4M RORC GLP1R RGS1 PTPRR FAM53B KCNA4 GOLIM4 CYP17A1 CD28 CARHSP1 ASPH HIST2H2BB S100A4 GM11435 RGS18 PXMP3 FAM65B KCNN4 GPNMB D1ERTD622E CD38 CATSPERB ASXL1 HIST4H4 S100A6 GM12253 RNF13 PYROXD2 FAM78A KCNQ5 GPR146 D330012F22RIK CD8A CBR1 ATAD2 HIVEP3 S1PR1 GM156 SAMD3 RCAN3 FAM78B KIF23 GPR157 D4WSU53E CD9 CBX4 ATAD3A HMGA2 SAMHD1 GM4956 SEPN1 RCBTB1 FBXL2 KLF5 GPR183 D8ERTD82E CD93 CBX7 ATAD5 HMGB3 SCPEP1 GNAS SERPINA3H RGS12 FBXO22 KLK8 GPR34 D930015E06RIK CDC14A CCDC101 ATAT1 HMMR SDC1 GNB5 SERPINB9 RPRM FCGR2B KLRG1 GPR97 DAPK2 CDK14 CCDC115 ATP1A2 HRH4 SELL GNGT2 SERPINB9B RRM2 FCHSD2 KRT80 GRAMD1B DCXR CDK19 CCDC22 ATP1B1 HSPD1 SEMA4B GOLIM4 SERPINI1 SAMHD1 FGF13 LGALS7 GRB7 DDX39 CDKN2A CCDC32 ATP2A2 I830012O16RIK SEMA4F GP49A SIDT1 SCD1 FGR LGMN GSTM4 DGKH CDKN2C CCDC88B ATP6V0A1 ID3 SEPP1 GPD2 SLAMF7 SCD2 FLNA LMO4 GSTM5 DGKZ CDKN3 CCDC9 ATP6V0D2 IFI27L1 SERPINB1A GPR18 SLC2A3 SCN8A G3BP2 LPCAT2 GSTT2 DNAHC8 CDNF CCIN ATP6V1G2 IFI27L2A SGK1 GPR34 SMAP2 SDHB GAS7 LPHN2 GZMB DNAJC15 CDS2 CCM2 ATP7B IFI30 SH3BGRL2 GPR55 SNX10 SEC63 GBP5 LRRC34 GZMC DOCK11 CELF2 CCNO ATPIF1 IFI44 SH3PXD2B GPR56 SPAG9 SESN3 GDF11 LRRC52 GZMD DOK2 CELSR1 CCR1 ATR IFIT1 SLAMF1 GPX8 SPIN2 SETX GIMAP8 LY6A GZME DPH2 CENPA CCR8 ATRN IFIT2 SLC27A6 GRB7 SRC SGK3 GM11435 LY6C1 H1F0 DPY19L1 CENPM CD1D1 ATRNL1 IFIT3 SLC35F2 GZMA ST3GAL4 SGOL1 GNPNAT1 LY6C2 HBP1 DUSP2 CEP170 CD3D ATXN10 IGF2BP3 SLC9A2 GZMB STYK1 SLC22A3 GNPTAB MAP4K3 HERPUD1 DUSP22 CHD7 CD79B ATXN2 IGFBP4 SMOX GZMK SYTL2 SLC29A1 GOLGA1 MBOAT1 HK2 EFCAB4B CHPT1 CD82 AVPI1 IIGP1 SOCS3 HECTD2 SYTL3 SMC2 GOLM1 MC5R HMGB3 EFHD2 CHST11 CD83 AXL IL13 SOX13 HEYL TACC1 SMPDL3B GOLPH3L MED12L HOXA5 EHD3 CHST15 CD96 B230319C09RIK IL17RB SPOCK2 HIC1 TAPBPL SNX10 GPR137B MICAL3 HOXA6 EIF5A2 CHST2 CDC42BPG B3GALNT2 IL21 SSH2 HIP1 TBX21 SOX4 GPR15 MNS1 HPSE ELOVL7 CHSY1 CDC42SE2 B3GNT8 IL4 ST3GAL6 HMGCR TGFBR2 SP6 GPR155 MRAS HS6ST2 ELTD1 CKB CDH1 B4GALNT2 IL6RA STOM HMGCS1 TMEM2 SPNB2 GPR174 MUC1 HSD17B11 ENPP1 CLEC12A CHN2 B4GALT2 INPP4B STX1A HPGDS TMEM37 ST13 GPR18 MXI1 HSPA13 ENTPD1 CLEC2I CHPF2 B4GALT4 IPCEF1 SUSD2 HSD17B7 TNFRSF18 ST8SIA6 GPR21 MYO1D HTRA1 EOMES CLIC1 CHST10 BACH2 ITGA4 SYNE2 HSPA2 TNFSF8 STARD10 GPR68 NAIP1 ICOS EPSTI1 CLIC4 CHURC1 BAZ1A JUB SYNJ2 HVCN1 TPM1 STMN1 GPRIN3 NAIP5 IER5L ESD CLIP2 CIB2 BBS5 JUP TASP1 IDH1 TPM4 TCF25 GRAMD3 NAIP6 IFI30 ESYT1 CLNK CISD2 BBS7 KCNN2 TBXA2R IDI1 TSC22D3 TCF7 GRAMD4 NAV2 IFNGR1 EYA1 CLSTN3 CISH BC018473 KIF11 TDRKH IER5L TSPAN4 TESC GSG2 NCKAP5 IGFBP4 F2RL1 CMAH CITED2 BC030476 KIF15 THY1 IGF2R TXNIP THEMIS GTDC1 NEB IGFBP7 FAM105B CMAS CKLF BC030867 KIF20A TLR1 IGSF5 TYROBP TIAM1 GVIN1 NEO1 IL17RE FAM26F CNRIP1 CLCF1 BC068281 KIF2C TMEM176A IL12RB2 UBLCP1 TNFRSF4 GZMA NFIX IL1R1 FAM53B COBLL1 CLCN3 BCAR1 KIF4 TMEM176B IL21R UIMC1 TOP2A GZMM NFKB1 IL1R2 FAM65B COPS2 CLCN4-2 BCAT1 KLF12 TMEM65 IL2RB WHSC1L1 TPMT H2-OB NHS IL1RL2 FAM69A COPS4 CLCN5 BCL2A1B KLRA1 TNFRSF25 IL34 WIPF1 TRIM13 H2-T24 NMUR1 IL22 FBXL2 CORO2A CLEC2D BCL2A1C KLRA10 TNFRSF26 IL6ST XCL1 TRP53BP1 H6PD NPNT IL23R FCGR2B COX5A CLN3 BCL2A1D KLRA3 TSC22D1 INPP4A ZCCHC18 TSPAN32 HAAO NUCB2 ING3 FCRL6 CPM CLN5 BCL2L2 KLRA6 TSPAN31 INSIG1 ZFP36L2 TTC3 HERC3 OLFR1009 ING5 FLNA CPNE3 CMPK2 BDP1 KLRA9 TUBA8 INTU ZYX TUBA3A HIST1H2AK OLFR1037 INPP4A FRY CS CMTM3 BEGAIN KLRB1B ZDHHC2 IRF8 TUBB5 HIST1H2BN OLFR1134 INTS12 GALNT6 CSF1 CMTM8 BEND3 KLRB1C ZFP462 ITGA1 TWSG1 HN1 OLFR1168 IRAK3 GAS7 CSF2 CNGA1 BEND4 KLRC1 ZFP516 ITGAD TYMS HOPX OLFR1173 IRF5 GEMIN7 CSRP2 CNIH4 BHLHB9 KLRC2 ZNRF1 ITGAE USP38 HS3ST3B1 OLFR1226 IRF8 GGCT CTDSP2 CNP BIRC3 KLRC3 ITGAM XKR8 HSD11B1 OLFR1245 ISCU GIMAP1 CTLA2A CNR2 BLCAP KLRI2 ITGAX ZCCHC12 I830012O16RIK OLFR1372-PS1 ITGB3BP GM11435 CTSB CNST BMP1 KNTC1 ITIH5 IFI44 OLFR1384 ITGB5 GNPNAT1 CUTA CNTROB BMPR2 KPNA2 JDP2 IFI47 OLFR340 JMJD1C GNPTAB CXCR1 COL11A2 BPTF LCLAT1 JUNB IFIT2 OLFR478 KCNK1 GOLM1 CXCR2 COL1A1 BRCA2 LEF1 KCNG3 IFNAR2 OLFR706 KRT4 GOLPH3L CXCR3 COL23A1 BRD3 LGI2 KIT IKZF1 OLFR714 L1CAM GPC1 CXCR6 COMMD2 BRD7 LPCAT4 KLHL4 IL10RB OTX1 LANCL2 GPR137B CYB5R4 COMMD6 BRIX1 LRRC6 KLRB1A IL16 P4HA2 LARGE GPR160 CYP4F39 COMMD7 BRMS1L LRRTM1 KLRD1 IL17RA PAPSS2 LGALS3 GPR174 CYP51 CORO7 BRPF3 MAGOH KLRI1 IL18RAP PARD3 LIN7C GPR25 CYSLTR2 COX11 BUD31 MARCKSL1 KY IL20RA PCSK1 LINGO4 GPRIN3 CYTH3 COX16 BZW2 MBOAT1 LAG3 IL21R PDCD1 LITAF GPX8 CYTIP CR1L C1QBP MCM5 LASS6 IRGM1 PDCD1LG2 LRRC49 GRAMD3 D16ERTD472E CREG1 C1S MCM7 LAT2 ITGA2 PDE4D LRRC8B GRAMD4 D8ERTD82E CRIP1 C330024D21RIK MGST2 LDLR ITGAM PDE7B LRRK2 GSG2 D930015E06RIK CRLF2 C330027C09RIK MIR181A-1 LGALS2 ITGAX PENK LTA GSTM1 DAP CRTC1 CACNB2 MIR181B-1 LILRB4 ITGB1 PGCP LY6G5B GTDC1 DAPK2 CSK CACYBP MKI67 LIMK1 ITGB1BP1 PKIA LY86 GVIN1 DCUN1D3 CST6 CALHM2 MPP6 LITAF ITGB2 PLAUR LYSMD2 GZMA DDAH2 CST7 CAMKK2 MPP7 LPIN2 ITM2A PLCL1 LYSMD3 GZMB DDX60 CTAGE5 CAMSAP1 MRPS6 LRRC8C JAK1 PLSCR2 MAF GZMK DENND4A CTSE CAPG MSRA LRRC9 KBTBD4 PLXDC1 MAFF GZMM DENND4C CTSF CAPN11 MTX2 LRRK1 KCNAB2 POPDC3 MAPK10 H2AFZ DEPDC1B CTTN CAPRIN2 MX2 LSS KCNIP3 POU2F2 MARCKSL1 HAAO DES CXCR4 CAPSL MYB LTA4H KCNJ8 PPARG MARVELD1 HERC3 DGAT1 CXX1C CAR12 NANOS1 LYN KIFC3 PPM1L MBD2 HEXB DGKH CYB561D2 CAR13 NCAPG MAP4K1 KLF12 PPP2R3A MDFIC HGSNAT DHCR7 CYBRD1 CAR5B NCAPG2 MAPK3 KLHL20 PRNP METTL4 HHEX DHX58 CYP4F16 CARM1 NCAPH MAPRE2 KLHL4 PSMC5 MGAT4A HIST1H1B DISP1 CYP4V3 CASK NCR1 MAX KLHL6 PTGIR MICAL2 HIST1H2AF DKKL1 CYSLTR1 CASKIN2 NDUFB6 MBD2 KLRA1 PTK2 MINA HIST1H2AK DLG3 D630039A03RIK CASP7 NDUFC2 MCAM KLRA10 PTP4A1 MMP23 HIST1H2AN DNAJB13 DAND5 CASZ1 NEIL3 MCART6 KLRA3 PTPN13 MPZL3 HIST1H2BB DNAJC15 DAPK1 CBX2 NEK2 MCOLN3 KLRA5 PTPN9 MSRA HIST1H2BC DNM1 DAPK3 CCAR1 NETO2 MCTP2 KLRA6 RAB11FIP5 MTAP7D3 HIST1H2BL DOCK9 DBNDD2 CCBL2 NIPAL1 METRNL KLRA8 RAB27B MYO5A HIST1H3G DOK1 DCAF4 CCDC112 NME1 MLKL KLRA9 RAB30 NCOA7 HN1 DPY19L1 DCLK2 CCDC116 NOP10 MLLT4 KLRB1A RAB4A NDRG1 HSD11B1 DPYSL2 DDC CCDC122 NPAS4 MRAS KLRB1C RAD51L1 NEDD9 HYLS1 DSE DDIT3 CCDC132 NPM3 MRGPRA9 KLRC1 RASGRP4 NEIL1 I830012O16RIK DSG2 DDX26B CCDC137 NPM3-PS1 MTA3 KLRC2 RBM47 NFAM1 IFI47 DYNLRB2 DEDD2 CCDC157 NRGN MYO1E KLRC3 REM2 NFE2L2 IFIT2 DYRK2 DENND1A CCDC30 NRP1 MYO6 KLRD1 RET NIF3L1 IL10RA DZIP1 DENND1C CCDC34 NSG2 NAAA KLRE1 RETNLB NLRP1B IL10RB E330009J07RIK DENND3 CCDC57 NTRK3 NAIP5 KLRI1 RGS12 NMBR IL16 ECE1 DFFB CCDC58 NUDCD2 NAIP6 KLRI2 RIPK4 NOX1 IL17RA EDEM1 DGKA CCDC63 NUF2 NAPSA KLRK1 RNF128 NPAS2 IL18RAP EEFSEC DHRS11 CCDC74A OAS2 NCALD LAT2 RPL11 NR1D1 IRGM1 EFCAB10 DHRS3 CCDC88A OASL2 NCF1 LAX1 RPL19 NRGN ITGA2 EFHD2 DHRSX CCL3 OLFR161 NEDD4L LCN4 RPL22 NT5E ITGA6 EFNA1 DMD CCL4 ORC6 NEDD9 LDLRAP1 RPL24 OASL2 ITGAD EFR3A DNAJB9 CCNE1 PACSIN1 NEURL3 LEF1 RPL26 OAT ITGAM EHD1 DNASE1L2 CCNE2 PAK1 NFIL3 LFNG RPL27 OCRL ITGAX EID1 DNASE2A CCNYL1 PARD6G NKG7 LGALS1 RPL27A OGFRL1 ITGB1 EIF2AK2 DOCK2 CCR3 PBK NLRP1B LIMD2 RPL30 OLFR1342 ITGB1BP1 EIF4E3 DOK2 CCRN4L PDCD1 NMB LIMS1 RPL31 OLFR46 ITGB2 ELOVL5 DPP7 CCT3 PDCD1LG2 NOD1 LPAR5 RPL35 OLFR60 ITM2A ELOVL6 DTWD2 CCT6A PGCP NR4A1 LRMP RPL35A OPTN JAK1 EMB DTX4 CCT8 PHGDH NR4A2 LRRK1 RPL36 ORAI1 KBTBD4 EMILIN2 DUSP1 CD101 PITPNM2 NR4A3 LY6C1 RPL36A OSGIN2 KCNAB2 ENPP1 DUSP10 CD109 PLA2G7 NRCAM LY6C2 RPL37A P2RX7 KCNIP3 ENPP4 DUSP2 CD200 PLAC8 NSDHL LYST RPLP1 PARP1 KCNJ8 ENPP5 DUSP23 CD209C PLEKHO1 NTAN1 MFSD8 RPRL2 PARP12 KCTD1 EPHX4 DUSP6 CD24A PLK1 NUMBL MKI67 RPS13 PDE4B KHDC1A EPS8 E130311K13RIK CD300A PLK2 OPTN MS4A4B RPS17 PDE5A KHDC1B EPSTI1 E4F1 CD33 PLXNA3 OS9 MS4A4C RPS21 PDP1 KLF12 ERAP1 EAR2 CD3EAP POLE OSGIN1 MS4A6B RPS24 PDZD2 KLF2 ERI2 ECM1 CD40 POMP OSTF1 MS4A6C RPS27A PEX13 KLHL20 ERMN EFNA5 CD5 PPA1 P2RX7 MTERF RPS28 PGM1 KLHL30 ERMP1 EHHADH CD5L PPIC PACSIN2 MTIF3 RPS3 PGM2L1 KLHL4 ERO1LB EIF5 CD74 PPIL1 PADI2 MYB RPS8 PHYH KLHL6 ERRFI1 ELF1 CDC123 PRC1 PALM MYO1F RPS9 PIK3C2B KLRA1 ESPN ELF2 CDC14B PRDX1 PDE4A NBEAL2 RPSA PIK3R1 KLRA10 ESPNL EMG1 CDC25A PRG4 PDZD2 NCK1 RRP15 PLCB4 KLRA3 ESR1 EMILIN1 CDC42BPA PRIM1 PGM1 NEBL RUNX1T1 PLCXD2 KLRA5 ETV3 EML1 CDC42BPB PSAT1 PHKA1 NOD1 RXRG PLEKHG1 KLRA6 ETV5 EML3 CDC42EP4 PSMB6 PHOSPHO1 OAS1A SCAMP1 PLEKHM3 KLRA8 EXOC6 EMP3 CDC45 PSMG1 PIK3AP1 OAS1B SCEL PLK3 KLRA9 EZR ENGASE CDC6 PSMG2 PIK3CB OGT SEMA3E PLK4 KLRB1A F2RL1 ENTHD1 CDC7 PTPN13 PIK3R6 ORAI2 SERPINE1 PLTP KLRB1C FADS2 ENTPD1 CDCA7 PXMP3 PKD2 ORMDL1 SLAIN1 PODNL1 KLRC1 FAH ENTPD6 CDH23 RAD54L PKP2 OSBPL5 SLC18A2 POP4 KLRC2 FAM102B EOMES CDK16 RALYL PKP4 OXSM SLC6A12 PPP1R11 KLRC3 FAM107B EPAS1 CDK2 RAP1A PLCG2 PAM SLC7A5 PPP1R2 KLRD1 FAM110A EPB4.1L1 CDK2AP1 RAP2C PLCL2 PARP11 SLC7A8 PPP1R3B KLRE1 FAM114A1 EPCAM CDK5 RAPH1 PLEK PDE2A SOAT1 PRAM1 KLRI2 FAM122B EPHA2 CDK6 RASA1 PLTP PDGFB SOCS5 PRC1 KLRK1 FAM132A EPHX1 CDK8 RBPMS PMEPA1 PGLYRP1 SPCS3 PRELID2 KPNA2 FAM168A ERN1 CDKL3 RCBTB1 PNPLA7 PHF11 SPNS3 PRR5 KTI12 FAM20A ESCO1 CDKL5 RILPL2 PPM1H PIK3R5 SPRY1 PRRG1 LACTB2 FAM26F ESRRA CDKN1A RIN2 PPP1R3B PILRB1 SSXB10 PRRG4 LAIR1 FAM49A EYA2 CDR2 RNF2 PPP2R2C PION ST6GALNAC5 PSAP LASS2 FAM63B F2RL3 CDR2L RNU12 PPP2R5C PJA2 STAB2 PSD2 LAT2 FAM64A FAAH CDV3 RNU73B PPP3CC PLEK STXBP6 PTGES LAX1 FASL FADD CDYL ROCK2 PRDM1 PLEKHA5 SV2B PTMS LDLRAP1 FBLN1 FAM101B CELA1 RPL23A PRF1 PLXNC1 SYNE1 PTPN3 LFNG FBXL5 FAM105A CELF1 RPS12 PRR5 POGK TANC2 PTPRA LGALS1 FBXO28 FAM117A CELSR2 RPS17 PRR5L POLE2 TCP11L1 PTPRM LIMS1 FCER1G FAM117B CENPH RPS27L PTP4A3 POT1A TGM2 RAB7 LPIN1 FCHO2 FAM120A CENPI RRM2 PTPN11 POT1B THSD4 RABGEF1 LRMP FDPS FAM129C CENPT SAMD3 PTPN12 PPARGC1A TKTL1 RAI14 LRRK1 FFAR2 FAM160B2 CEP110 SCCPDH PTPN22 PQLC3 TLE1 RASA2 LY6C1 FGGY FAM19A3 CEP135 SGK3 PTPN4 PRF1 TLR1 RASGEF1B LY6C2 FGL2 FAM20B CEP152 SH2D1A PTPN5 PRKCB TMEM146 RASGRP3 LYRM2 FGR FAM46A CEP170 SHCBP1 PTPRJ PRKCQ TMEM164 RASL11A LZTS1 FHL2 FAM63A CEP250 SHMT1 PYGL PRR5L TNFRSF10B RBBP8 MAG FILIP1 FAM65C CEP290 SLAMF6 RAB11FIP4 PTCD2 TNFSF18 RBM11 MCAM FKBP5 FAM83H CEP350 SLC12A2 RAB20 PTPN12 TPH1 RBM24 MED30 FNDC3A FAU CEP57 SLC14A1 RACGAP1 PTPN4 TSPAN13 RBPMS2 MED8 FNTB FBRS CEP78 SLC15A1 RAI14 PTPRC UBA52 RCBTB2 MEF2C FOXJ1 FBRSL1 CERK SLC16A1 RASGRF1 PYCARD UBB RFK METTL5 FRMD4B FBXO17 CERKL SLC22A3 RASGRF2 PYHIN1 UBC RGNEF MOCS2 FURIN FBXO27 CFDP1 SLC25A13 RASL11B QRFP UBE2E2 RGS9 MORC3 FUT4 FBXO31 CHAF1A SLC25A17 RCN1 RAB7L1 UBE2L6 RHOBTB1 MS4A4B FUT8 FBXO33 CHCHD4 SLC25A5 RFC2 RACGAP1 UNC5B RHOC MS4A4C FXYD1 FBXO4 CHD1 SLC29A1 RGS1 RANBP10 VIPR2 RHOD MS4A6C FXYD5 FCGRT CHD9 SLC44A1 RHOB RAP1A VMN1R179 RIN2 MTERF FXYD7 FCHSD2 CHEK1 SLC5A3 RHOC RAP2B VMN1R6 RIPK2 MTIF3 FYN FCRLS CINP SLC7A5 RIN3 RAPH1 YPEL2 RNF24 MYB FZD5 FGFR1 CIRH1A SLC9A7 RIPPLY3 RARG ZC3H12C RNFT1 MYLIP GAB3 FILIP1L CKS2 SLFN1 RNF149 RASA1 ZDBF2 RORC NAGK GADD45G FLAD1 CLASP1 SLFN3 RNF169 RASA3 ZFP92 RPN1 NBEAL2 GALE FLCN CLEC2L SMC2 RNF180 RASGRP2 RPS7 NCALD GALNS FLT3L CLGN SMTN RNF19B RELT RSU1 NCK1 GALNT3 FN3K CLSPN SNHG1 RPTOR RFX3 RYBP NHP2L1 GALNT7 FOXN3 CLUAP1 SNORA16A RRAS2 RGS3 RYK NIP7 GAPDH FPGT CMKLR1 SNORA23 RTN4RL1 RHOQ S100A1 NKG7 GAS2L3 FRAT1 CNDP2 SNORA34 RUNX3 RNF144A S1PR3 NOD1 GAS7 FRAT2 CNIH3 SNORA44 S100A1 RNF219 SAP30 NPC1 GATAD1 FRMPD1 CNKSR3 SNORA65 S1PR3 RRAGB SAT1 NRARP GATSL2 FRY CNNM4 SNORA69 SC4MOL RRAS2 SCPEP1 NT5C GBE1 FTL1 CNOT10 SNORA74A SCIN RRM2 SCRT1 OAS1B GBP2 FUT11 CNTLN SNORD104 SCLY RSL1 SDC1 ORAI2 GBP3 FYB COL15A1 SNORD118 SEC14L1 RTP4 SDC2 ORMDL1 GBP4 FZD10 COL5A1 SNORD15A SELENBP1 RTTN SEC24D OSBPL5 GBP6 GABARAPL2 COLEC12 SNORD15B SELENBP2 S100A6 SELM PAM GCA GABRB3 COPS5 SNORD16A SELM S1PR1 SEMA4F PDCD10 GCAT GAL3ST1 COPS7B SNORD1C SERPINA3F S1PR4 SEPP1 PDE2A GDF11 GALNT10 COQ3 SNORD22 SERPINB6A S1PR5 SERINC2 PDGFB GFPT1 GATA1 COQ7 SNORD35A SFT2D2 SAMD3 SERPINB1A PEX5L GGTA1 GATA3 COX6C SNORD38A SH2D1B1 SAMD9L SERPINB6A PGLYRP1 GIMAP4 GATSL3 COX7A1 SNORD47 SH2D1B2 SASH3 SERPINB6B PHF11 GIMAP5 GEMIN8 CPD SNORD49A SH2D3C SASS6 SERPINB9 PIK3R5 GIMAP6 GFI1 CPE SNORD49B SH3TC1 SCARB2 SERPINE2 PION GIMAP7 GGCX CPEB3 SNORD55 SIPA1L1 SCML4 SESTD1 PLA2G4B GIPC1 GIGYF1 CPNE2 SNORD61 SLC26A10 SCRN3 SGTB PLD3 GLA GLIPR2 CPNE8 SNORD68 SLC28A2 SEC24A SLC16A10 PLEK GLG1 GLTSCR1 CPOX SNORD82 SLC35F5 SELL SLC16A6 PLSCR4 GLRX GM12191 CPSF2 SNORD85 SLC36A1 SEMA4A SLC22A15 PNRC2 GLTP GM13051 CPT1C SNORD87 SLC38A8 SETBP1 SLC31A1 POGK GM12070 GM13251 CRABP2 SNRPE SLC39A4 SGK1 SLC35B1 POLE2 GM12185 GM15760 CRAMP1L SNRPF SLC46A3 SGK3 SLC41A3 POLR3K GM12250 GM2382 CRLS1 SOX4 SLC9A3R1 SH2D1A SLC6A20A POT1A GM14005 GM5134 CRTAM SPINK5 SNAP23 SH2D1B2 SLC7A6OS POT1B GM14085 GM5148 CRTC3 ST8SIA1 SNX18 SH2D3C SLC7A7 PPARGC1A GM16515 GM561 CRY1 ST8SIA6 SNX9 SH3BP2 SLC9A2 PPM1J GM8979 GM711 CSAD STEAP3 SOAT2 SIDT1 SMAP2 PQLC3 GNAQ GM973 CSE1L STIL SPATS2 SIKE1 SMOX PRF1 GNB2 GM996 CSPG5 STMN1 SPP1 SIRT3 SMYD2 PRKCB GNB5 GMFG CSRNP2 STYK1 SQLE SLAMF6 SNTB1 PRKCQ GNG2 GMIP CSTF3 TAF1D SREBF2 SLC12A7 SNX18 PRR5L GPC1 GNA15 CTBP2 TBC1D4 ST3GAL5 SLC14A1 SPRED2 PSIP1 GPLD1 GPBP1L1 CTDSPL TCEAL3 ST6GALNAC2 SLC26A11 SPSB1 PTCD2 GPNMB GPM6B CTH TDGF1 STARD4 SLC9A7 SQLE PTER GPR114 GPR132 CTLA2B TGM3 STK32C SLCO3A1 SRGAP2 PTP4A3 GPR141 GPR137B-PS CTNNAL1 THBS1 STK39 SLFN1 SSX2IP PTPN12 GPR18 GPR179 CTNND1 TIPIN STXBP5 SLFN2 ST14 PTPN4 GPR55 GPR97 CTPS TIRAP SULF2 SLFN8 ST3GAL3 PTPRC GPT2 GRAP CTSC TLR7 SULT2B1 SLFN9 ST6GALNAC6 PTRH2 GRIN1 GRASP CTTNBP2NL TMEM38B SUSD4 SMEK2 STAP1 PXMP3 GRXCR2 GRIK5 CUBN TMEM48 SYTL2 SNAI3 STOM PYCARD GSTM4 GRIN2D CUL1 TOP2A SYTL3 SNAPC3 STX11 PYHIN1 GTF2I GRTP1 CUL7 TPX2 TBC1D24 SOAT2 SUMO1 QRFP GVIN1 GSTM5 CUX1 TREML2 TBX21 SP100 SUSD2 RAB31 GYG GZMA CWC22 TRIM36 TCF4 SPATA13 SUSD3 RAB7L1 GZMB H2-DMA CWC27 TRIP13 TESC ST3GAL4 TACSTD2 RAC3 H1FX H2-DMB2 CWH43 TRPM6 TESK2 ST8SIA4 TCEAL1 RACGAP1 H2-AB1 H2-KE6 CX3CR1 TSPAN32 TEX2 STIM2 TCN2 RAP1A H2-D1 H2-OA CXCR5 TTC39C TGFB3 STK38 TCP11L2 RAP1GAP2 H2-K1 H2AFJ CYB5 TWSG1 TGM2 STYK1 TDRD3 RAP2B H2-M3 HADH CYP1A1 TXN1 TIGIT SULF2 TDRKH RAPH1 H2-Q10 HC CYP1B1 UBE2V2 TIPARP SYTL2 THY1 RASA1 H2-Q2 HCST D11WSU47E UCK2 TM7SF3 TBC1D10C TIFA RASA3 H2-Q7 HEMGN D19BWG1357E UGCG TMCC3 TBC1D2B TIMP2 RASGEF1A H2-Q8 HEXIM1 D630003M21RIK UHRF1 TMEM149 TBRG3 TIPRL RASGRP2 H2-T10 HGF D630045J12RIK USMG5 TMEM38B TGFB3 TLCD1 RASL12 H2-T22 HIF3A D930048N14RIK VAULTRC5 TMEM59L TGFBR1 TMEM123 REEP5 H2-T23 HIP1 DAB2 VDR TMPRSS6 TIRAP TMEM149 RELT H2-T9 HIST1H1C DACT3 WFIKKN2 TMTC4 TLR4 TMEM154 RHOQ H2AFX HIST1H1D DALRD3 ZBTB16 TNFAIP3 TM6SF1 TMEM176A RNF157 H2AFY HPGD DARS2 ZCWPW1 TNFSF10 TMEM163 TMEM176B RNF216 H2AFZ HPGDS DBH ZFP536 TNFSF13B TMEM165 TMEM5 RPA2 HAAO HPS3 DBR1 TNFSF8 TNFRSF13C TMEM59 RPGR HACL1 HRH4 DCBLD2 TNKS1BP1 TNFRSF26 TMTC2 RPL38 HDAC7 HS1BP3 DCDC2C TRDN TNFSF8 TNF RRAGB HDGFRP3 HS6ST1 DCLK1 TRIB1 TPM1 TNFRSF21 RRAS2 HDHD3 HSD11B1 DCLRE1C TRIO TRAF3IP3 TNS3 RSL1 HEATR5A HSD17B10 DCTD TSGA10 TRAT1 TNS4 S100A6 HEATR5B HSD17B11 DDHD1 TSPAN9 TREML2 TOR1AIP1 S1PR1 HECTD1 HSD3B7 DDI2 TXK TRIM21 TOX S1PR4 HECTD2 HSPA1A DDR1 TYROBP TTC13 TRF S1PR5 HELB HUNK DDX1 UBAC2 TTC9C TRP53INP1 SAMD3 HERC1 ICA1L DDX11 UBE2L6 TUBGCP5 TTLL1 SAMD9L HEXB ICAM2 DDX18 USP11 TXNIP TTYH2 SAP18 HIBCH ICOSL DDX21 USP46 TYROBP TXNDC12 SASS6 HIC2 IER2 DDX27 VAV3 UBASH3A UBE2B SCARB2 HIF1A IFFO1 DDX31 VIPR2 UGCG UBE2J1 SCD2 HK1 IFI30 DENND2C VPS37B VEGFC UCP3 SCRN3 HLX IFLTD1 DERL3 ZBED3 VIPR1 UPP1 SEC61B HMGCR IFNGR2 DGCR8 ZBTB38 WIPF1 VAMP4 SELL HMGCS1 IKBKB DGKG ZCCHC18 WWP1 VAV3 SEMA4A HMOX1 IKBKE DHFR ZFP395 XAF1 VDR SERPINB9B HMX2 IL17RB DHRS13 ZMAT4 XCL1 VEGFA SETBP1 HN1 IL19 DHRS4 XRN2 VPS37A SGK1 HNRNPUL1 IL24 DHX15 XYLT1 WARS SGK3 HOPX IL27RA DHX29 ZBTB8A WBP1 SH2D1A HPSE IL4 DHX33 ZC3H12D WDR90 SH2D1B1 HS3ST3B1 IL4RA DHX9 ZDHHC15 WIPI1 SH2D1B2 HSD17B7 IL9R DIABLO ZFP157 XKRX SH2D3C HSPA13 IMPACT DIAP2 ZFP260 ZBTB25 SH3BP2 HSPA2 INADL DIDO1 ZFP273 ZDHHC14 SIDT1 HSPB11 INPP4B DIS3 ZFP277 ZFP414 SIKE1 HSPB6 INPP5D DKC1 ZFP418 ZFP462 SLAMF6 I830012O16RIK IRAK3 DLG2 ZFP422 ZFP57 SLC12A7 ICAM1 IRF6 DMWD ZFP512 ZMAT4 SLC14A1 ID2 IRF9 DMXL2 ZFP563 SLC25A30 IDH1 IRS2 DNA2 ZFP597 SLC37A2 IDI1 ISCA1 DNAJA1 ZFP7 SLC41A2 IER5L ITGA7 DNAJB5 ZFP709 SLC9A7 IFI203 ITGB3 DNAJC11 ZFP71-RS1 SLFN2 IFI204 ITGB7 DNAJC2 ZFP719 SLFN8 IFI44 ITPKB DNAJC21 ZFP759 SLFN9 IFIH1 ITPR1 DNAJC27 ZFP760 SNAPC3 IFIT1 ITSN2 DNAJC6 ZFP763 SNAPIN IFIT2 IZUMO4 DNAJC9 ZFP825 SNX10 IFIT3 JDP2 DNM1L ZKSCAN3 SNX11 IFITM1 JMJD4 DNM3 ZYX SOAT2 IFITM2 JUND DNPEP SORD IFITM3 KBTBD3 DNTT SP100 IFNG KCNA2 DNTTIP2 SPATA13 IFNGR1 KCNH2 DOCK3 SPN IFT20 KCNK5 DOCK4 SRPX IFT52 KCNN4 DOCK6 ST3GAL4 IFT80 KCTD12 DOT1L ST5 IGF2BP2 KDM4A DPF1 STEAP3 IGF2BP3 KDM6B DPH5 STIM2 IGFL3 KDSR DPM2 STK32C IIGP1 KIFC2 DPY30 STK38 IKZF1 KLF2 DRG2 STYK1 IKZF2 KLF3 DRP2 SULF2 IL12RB2 KLHDC1 DSCC1 SYNE2 IL18R1 KLHDC2 DSEL SYPL IL18RAP KLHL21 DSN1 SYT11 IL1RL2 KLHL32 DST SYTL2 IL2RB KLHL35 DSTYK TADA1 IL34 KLK8 DTL TAF1B IL6ST KPNA4 DTYMK TBC1D10C IMPA2 KRBA1 DUS4L TBC1D2B IMPAD1 KREMEN2 DUSP4 TIGIT INPP1 KRT18 DYRK3 TIRAP INSIG1 KRT80 DYRK4 TLR4 INSL6 L1CAM DZIP3 TM6SF1 IPCEF1 LAIR1 E130308A19RIK TM6SF2 IQGAP1 LAMP1 E2F3 TMEM163 IQSEC1 LAPTM4B E2F6 TMEM165 IRF2 LCMT1 E2F8 TMEM171 IRF8 LDB1 E330020D12RIK TMEM37 IRGM1 LEFTY1 EBF1 TMSB15A IRGM2 LEMD2 EBNA1BP2 TNFRSF26 ISG15 LEPROT EEA1 TRAF3IP3 ITGA2 LGALS7 EFCAB5 TRAF5 ITGA6 LGMN EFCAB7 TREML2 ITGAL LHFP EFTUD2 TRIM21 ITGAM LIMD1 EGR2 TRIM27 ITGAV LLGL2 EGR3 TRMT11 ITGB5 LMBR1L EHBP1 TSC22D1 ITIH5 LMBRD1 EHD4 TSPAN5 JARID2 LPAR2 EIF2AK4 TSTD2 JUN LPAR5 EIF2B3 TTBK2 KATNAL1 LPCAT4 EIF3B TTC39C KATNB1 LRRC32 EIF4A1 TWF2 KCNAB3 LRRC8A EIF4G1 TXNIP KCNC1 LSM1 EIF5A TYROBP KCNJ8 LSP1 ELK3 UBA3 KCNK7 LUM ELP4 UBLCP1 KCTD7 LY6G5B EML4 UBXN2B KDELC2 LYNX1 EMP1 UGCG KHDRBS1 LYPLA2 ENDOD1 UTP23 KIF14 LYRM5 ENO2 VEGFC KIF1A LYRM7 ENPP2 VTI1B KIF2A MAN1C1 ENY2 WIPF1 KIF3C MAN2B1 EPB4.1L2 WTAP KIF9 MANSC1 EPN2 XAF1 KIT MAP1LC3B EPRS XRN2 KITL MAP2K6 ERC1 YWHAQ KLF6 MAP3K15 ERH ZBTB8A KLF7 MAP3K2 ERMAP ZDHHC15 KLHL25 MAP3K9 ERV3 ZEB2 KLHL4 MAP4K2 ESF1 ZFP105 KLHL6 MAPK1IP1 ETV1 ZFP128 KLRB1F MAPRE2 EVPL ZFP157 KLRC1 MAST3 EXO1 ZFP160 KLRD1 MAST4 EXOC6B ZFP235 KLRK1 MATK EXOSC2 ZFP251 LAG3 MBOAT1 EXOSC7 ZFP260 LAMA5 MCL1 EXOSC8 ZFP273 LAMB3 MCTP1 EXT1 ZFP277 LAMC1 MCTS2 EZH2 ZFP300 LASP1 MDP1 F3 ZFP382 LAT2 MED26 F730043M19RIK ZFP418 LBH MEPCE FABP4 ZFP456 LCA5 METRNL FABP5 ZFP512 LCN4 METTL8 FAM107A ZFP54 LDLR MFNG FAM124B ZFP563 LFNG MGAT3 FAM129B ZFP595 LGI4 MGMT FAM131B ZFP597 LILRB4 MICALL1 FAM133B ZFP637 LIMS1 MICALL2 FAM135A ZFP7 LIN7C MIDN FAM161B ZFP708 LIPA MIRLET7B FAM184B ZFP709 LITAF MLLT3 FAM193A ZFP719 LNPEP MLYCD FAM20C ZFP748 LPIN1 MOSPD3 FAM53B ZFP759 LPIN2 MOXD1 FAM57A ZFP760 LRMP MPL FAM73B ZFP763 LRP12 MRPL35 FAM83D ZFP780B LRRC3B MRPL55 FAM83E ZFP825 LRRC8B MRPS12 FAM98A ZFP85-RS1 LRRC8C MRPS24 FANCA ZFP87 LRRK1 MTG1 FANCB ZFP873 LSR MTMR10 FANCG ZKSCAN3 LSS MUC19 FANCI ZKSCAN6 LTA4H MXD4 FANCM ZYX LTB4R1 MYEOV2 FARSB LTK MYO6 FASTKD3 LY6A MYO9B FBL LY6C1 N6AMT1 FBXL12 LY6C2 NAB1 FBXL19 LY6E NAGA FBXO2 LY75 NBEAL2 FBXO5 LYN NCEH1 FBXW7 LYPD6B NCKAP5L FCRL1 LYRM1 NCLN FEN1 LYSMD2 NCOA3 FERMT1 LYZ2 NCOA7 FGD1 LZTS1 NDFIP1 FGF13 MAML3 NDUFA6 FGF2 MAN1A NEU1 FGFR1OP MAN2B2 NFE2 FIGNL1 MAP1LC3A NFIA FIP1L1 MAP2K5 NFIL3 FJX1 MAP3K5 NFX1 FKBP1A MAP3K8 NIPAL1 FKBP1B MAP4K5 NPM3 FKTN MAPK3 NPTN FLNB MAPRE1 NR1D2 FNBP1L MAPRE3 NRBP2 FNDC3B MATN2 NRGN FNIP2 MBNL1 NRIP1 FOXD2 MCTP2 NRP2 FOXF2 MEF2A NSMCE1 FOXP3 METTL9 NTRK3 FPGS MFSD6 NUDT19 FRMD4A MGAM NUFIP2 FRMD5 MGST2 OAS1B FRMD6 MID1IP1 OAS1C FSCN1 MLKL OAS2 FSD1L MORN4 OLFR60 FSTL4 MOSPD2 ORAI2 FTSJ3 MPP1 ORC4 FTSJD2 MPZL2 OSBPL7 FUBP1 MPZL3 OTUD1 FUS MRVI1 OXCT1 FUT10 MS4A4B P2RX4 FUT7 MS4A4C P2RX7 FXR2 MS4A4D P2RY1 FZD7 MS4A6D P2RY10 GABARAPL1 MSH5 PADI4 GABRR2 MSMB PANX1 GAD2 MT1 PARD6B GADD45A MT3 PAX9 GALM MTHFD2 PCF11 GALNT14 MTMR6 PCGF2 GAN MUC13 PDCD2 GAP43 MVD PDCD4 GAR1 MVK PDE4A GART MXD1 PDLIM2 GAS5 MXRA8 PDLIM4 GATAD2B MYADM PDXK GATM MYCN PDZRN3 GCLM MYD88 PEPD GCNT2 MYO1E PEX19 GCSH MYO1F PFDN5 GDF6 MZT2 PHF1 GDPD5 NAA50 PHLDA3 GEMIN4 NAB2 PHLDB1 GEMIN6 NACC2 PHLDB3 GFM1 NAPRT1 PIGM GFOD1 NCALD PIM3 GFPT2 NCAPH2 PIP5K1B GGA2 NCF1 PIP5K1C GINS1 NDN PISD-PS1 GINS3 NDRG1 PJA1 GJA3 NDRG2 PLA2G12A GJA5 NDRG3 PLA2G6 GK5 NEB PLCB4 GKAP1 NEDD4 PLCD1 GLCCI1 NEIL1 PLCL1 GLCE NGLY1 PLXDC1 GLI3 NICN1 PLXDC2 GLS2 NIPA1 PLXNA1 GM10033 NKG7 PMM2 GM10069 NLRC5 PNKP GM10845 NLRP1A PNPLA7 GM13034 NLRP1B PNPO GM3002 NLRP3 PNRC1 GM5124 NMNAT2 PNRC2 GM5177 NOD1 PODNL1 GM527 NOXO1 POGZ GM5434 NPHP4 POLE4 GM5643 NR2F6 POLM GM5803 NRM POLR1A GM6642 NRN1 PON3 GM6682 NSDHL PORCN GM7102 NSG2 POT1B GM8994 NUAK2 POU4F1 GMNN NUCB1 PPARG GNA12 NUCKS1 PPCS GNL2 NUDT21 PPP1R11 GNL3 NUDT4 PPP1R15A GOLGA1 NUMBL PPP1R9B GOLGA4 NXNL2 PPP2R3A GOLIM4 NXT2 PPP2R5A GOLM1 OAS3 PPP3CC GPATCH4 OASL2 PQLC1 GPD2 OBFC1 PRKAG1 GPR125 OGFRL1 PRKCQ GPR15 OLFM1 PRKCZ GPR162 OSBPL8 PRKD2 GPR65 OTUD7B PRKD3 GPRASP2 P2RX3 PRKDC GPS1 P2RY14 PRODH GRHL1 P4HA1 PROS1 GRIA3 P4HA2 PRR13 GRK1 PADI2 PRR14 GRK4 PAK6 PRSS32 GRWD1 PAOX PSEN2 GSG1L PAPSS1 PTGER2 GSG2 PAQR7 PTGIR GSPT1 PARD6A PTPN13 GTF2F2 PARP12 PTPN18 GTF2H5 PARP14 PTPN7 GTF2IRD1 PARP8 PTPRCAP GTSE1 PARVG PYCARD H19 PBX4 PYGM HAP1 PCBP4 QPRT HARS PCCA QRFP HAS3 PCYT1A RAB19 HAUS1 PDE2A RAB20 HAUS4 PDE5A RAB32 HAUS5 PEA15B RAB37 HAUS6 PGM2 RAB3A HAX1 PHF11 RAB4A HCFC1 PHLPP1 RABAC1 HCFC2 PHYH RAMP3 HCN3 PI4KB RANBP6 HDAC2 PICALM RAP1B HEATR3 PIGZ RAP1GAP HECW2 PIK3AP1 RAP1GAP2 HELLS PIK3R5 RAP2B HELQ PIM2 RAPGEF5 HIC2 PKD1L2 RAPSN HIRA PKIB RARA HIRIP3 PKIG RASA3 HIST1H3E PLAC8 RASAL3 HIST1H4K PLAT RASGRP1 HIST2H2BB PLCG2 RASGRP2 HIST2H4 PLCL2 RASGRP4 HIVEP3 PLD2 RASSF5 HMBOX1 PLD4 RASSF8 HMGB1-RS17 PLEKHH3 RBAK HMGB3 PLEKHM3 RBM12B HMGN1 PML RCHY1 HMGN3 PMVK RDH10 HMGN5 POR REC8 HN1L POU6F1 RERE HNRNPA2B1 PPM1H RGL2 HNRNPD PPM1J RGS1 HNRNPH1 PPP1R12A RGS14 HNRNPL PPP1R3B RHBDL1 HNRNPM PRCP RING1 HOOK1 PRDM1 RLTPR HOOK2 PRDX4 RNF111 HSF2 PRELID1 RNF123 HSF2BP PRELID2 RNF128 HSP90AA1 PRF1 RNF144A HSPA4L PRKCA RNF152 HSPA9 PRKCE RNF167 HSPD1 PRNP RNF19B HSPH1 PRPF18 RNF217 HTRA2 PRPH ROM1 HTT PRR5 RPL12 HUS1 PRR7 RPL13A HYOU1 PRRC1 RPL14 IARS PRRG4 RPL17 IBTK PRSS16 RPL18 ICA1 PRSS35 RPL19 ID1 PSG17 RPL22 IDE PSMB8 RPL22L1 IDI2 PSMB9 RPL27 IFRD2 PTDSS2 RPL27A IFT74 PTEN RPL32 IGF1R PTGER3 RPL34 IGLON5 PTMS RPL36 IGSF3 PTPN14 RPL36AL IKZF3 PTPN22 RPL37A IKZF4 PTPN5 RPL38 IL17RC PTPRE RPL39 IL17RE PVR RPL9 IL1F9 PXMP4 RPLP1 IL1R1 PXT1 RPLP2 IL1RN PYGL RPS10 IL21 PYHIN1 RPS12 IL23R QARS RPS13 IL2RA RAB27B RPS14 IL9 RAB28 RPS15A ILTIFB RAB31 RPS18 IMPG2 RAB3D RPS19 INPP5F RAP2A RPS21 INTS10 RAPGEF4 RPS23 INTS2 RASA4 RPS24 INTS4 RASGRF2 RPS27A INTS7 RASL11A RPS27L INTU RASSF3 RPS28 IPMK RASSF4 RPS3 IPO4 RBMS2 RPS6KA5 IPO5 RBPMS RPS6KL1 IPO9 RCBTB2 RPS7 IQCB1 RCN1 RREB1 IRAK1BP1 RCN2 RTF1 IRF4 RDH11 RTN4RL1 IRGQ RDM1 RUNX1 ISCA2 RECK RUSC1 ITGA3 RELL1 RXRB ITGA5 RET RYR3 ITPA RFK S100A1 ITPR3 RFX2 S100A13 IVNS1ABP RGAG4 S100A6 IWS1 RGS3 S1PR1 JAM3 RHOB S1PR4 JMJD1C RHOC SAG JMJD6 RILPL2 SAMD9L JMY RIMS2 SARS2 JPH4 RIN3 SATB1 JUP RIOK1 SAV1 KANK3 RNF130 SBF1 KAT5 RNF141 SCAI KCNC3 RNF157 SCAND1 KCNH5 RNF26 SDF2 KCNIP2 ROPN1L SEC16B KCNMB4 RPA1 SEC61B KCTD11 RPGRIP1L SELM KCTD14 RRAS SEMA4B KDELC1 RRAS2 SEMA4F KDM2B RSPH1 SEMA6C KIF1B RSPH9 SEPP1 KIF20B RTBDN SERPINF1 KIF3B RTN3 SEZ6L2 KIF4 RTP4 SFT2D2 KIF5C RUFY4 SGCE KIFAP3 RUNX3 SGMS1 KIFC3 RYR1 SGSH KLC1 S100A11 SH3TC1 KLHL12 S100A4 SIGIRR KLHL23 SAMHD1 SIKE1 KLHL8 SAP30L SIPA1L3 KLRC2 SCARB2 SIRT5 KLRC3 SCD1 SIRT7 KLRG2 SCD2 SIT1 KNG2 SCLY SLA KPNA2 SCPEP1 SLC10A3 KRT6B SCRN3 SLC12A5 KTN1 SCRT1 SLC12A9 L2HGDH SDC3 SLC16A2 L7RN6 SDCBP2 SLC17A6 LAMC2 SELL SLC17A9 LAMP3 SEMA3B SLC25A37 LAP3 SEMA3F SLC25A45 LARP1 SEMA4A SLC26A11 LARP7 SEMA4G SLC27A1 LARS2 SEPN1 SLC29A4 LAS1L SERPINB5 SLC2A6 LBP SERPINB6A SLC35B4 LDHB SERPINB6B SLC35C1 LDLRAD3 SERPINB9 SLC35C2 LENG8 SERPINE2 SLC36A1 LEO1 SETD7 SLC37A1 LEPRE1 SGIP1 SLC37A3 LGR4 SH3BP2 SLC38A9 LHX6 SH3BP5 SLC39A11 LIF SH3GLB1 SLC39A6 LIG1 SHF SLC39A7 LIPG SHISA2 SLC41A2 LIPT2 SIAH3 SLC41A3 LMLN SIPA1L1 SLC4A4 LMNA SKAP2 SLC4A7 LMO4 SLAMF1 SLC8A3 LOC380994 SLAMF7 SLC9A6 LONP1 SLC11A2 SLC9A8 LONP2 SLC12A8 SLCO4A1 LONRF3 SLC16A1 SLFN2 LOXL2 SLC20A1 SLFN5 LPGAT1 SLC25A1 SMAD5 LPXN SLC25A23 SMG7 LRFN4 SLC25A24 SNAP47 LRIG1 SLC25A30 SNAPC4 LRP1 SLC30A4 SNRPG LRP2BP SLC35F5 SNX33 LRPPRC SLC46A3 SOCS1 LRRC49 SLC7A3 SORBS3 LRRC58 SLC7A5 SP6 LRRC59 SMAGP SPATC1 LRRC7 SMCHD1 SPATS2L LRRK2 SMPDL3A SPCS3 LSM14B SNAI3 SPINT2 LSM3 SND1 SPR LTA SNTB1 SPSB1 LTV1 SNTB2 SPTLC3 LUC7L3 SNX10 SRGN LUM SNX18 SRPK1 LUZP1 SNX9 SSR4 LY6K SORCS2 ST3GAL1 LYAR SORD ST3GAL5 LYRM4 SOS2 ST6GAL1 LZIC SP100 ST6GALNAC1 LZTS2 SP110 ST8SIA4 MAD1L1 SP140 ST8SIA6 MAFF SPARC STBD1 MAGED1 SPATA13 STC1 MAGED2 SPATA6 STK11IP MAGI3 SPRED2 STK38 MAGOH SPRY2 STX1A MALAT1 SPRYD4 SUFU MALT1 SPT1 SUN1 MAML2 SPTY2D1 SUPT3H MAOA SQLE SUV420H1 MAP2K3 SSBP2 SV2C MAP3K7 SSR1 SVAL1 MAPK8 SSRP1 SYPL MAPKAPK3 ST14 SYS1 MAPKAPK5 ST3GAL4 SZT2 MAPKBP1 ST3GAL6 TAF1C MARCKSL1 ST8SIA1 TANC2 MARVELD1 STAP1 TAZ MAST2 STARD4 TBC1D10A MAT2A STAT1 TBC1D2 MC2R STIM2 TBCD MCM10 STK17B TBRG1 MCM2 STK24 TBX6 MCM3 STK32C TCIRG1 MCM4 STK39 TCTN3 MCM5 STON2 TDGF1 MCM6 STXBP5 TDRKH MCM8 STYK1 TEP1 MDFIC SUGT1 TESC MDN1 SULF2 TET2 ME2 SULT2B1 TEX264 MEAF6 SUSD3 TGFB1I1 MECR SWAP70 THY1 MED14 SYNE2 TIGIT MED18 SYTL1 TIMM10 MEGF11 SYTL2 TJP3 MEGF8 SYTL3 TK2 METAP1D TAGLN2 TKTL1 METTL1 TANC1 TLR1 METTL13 TAP1 TM2D1 MEX3A TAX1BP1 TM2D3 MEX3C TBC1D19 TMC6 MFHAS1 TBC1D22B TMC8 MFSD2A TBC1D2B TMEM141 MFSD2B TBC1D30 TMEM160 MFSD7B TBKBP1 TMEM161B MFSD7C TBL1X TMEM185B MGAT5 TBX21 TMEM191C MGST3 TCP11L1 TMEM208 MIB1 TET1 TMEM221 MICAL2 TGM1 TMEM223 MICAL3 TGTP1 TMEM41B MID1 THEMIS TMEM50A MID2 THRA TMEM60 MIF4GD THRB TMEM63A MIR17HG TIFAB TMEM64 MIR615 TIRAP TMEM81 MKI67 TKT TMEM87B MLF1 TLE3 TMIE MLH1 TMCO4 TMSB4X MLLT1 TMED10 TMUB1 MMP11 TMED8 TNFAIP3 MORC2A TMEM106A TNFSF13B MORF4L2 TMEM107 TNFSF8 MOV10 TMEM108 TNP2 MPHOSPH10 TMEM143 TOB1 MPHOSPH6 TMEM151B TOMM20 MPZL1 TMEM158 TOMM34 MRPL37 TMEM159 TPP1 MRPL38 TMEM163 TPRGL MRPL42 TMEM170B TRAF5 MRPL45 TMEM180 TRAT1 MRPL47 TMEM205 TRIAP1 MRPS10 TMEM26 TRIB3 MRPS22 TMEM30A TRIM16 MRPS27 TMEM45A TRIM39 MRPS5 TMEM51 TRIM65 MRPS6 TMEM66 TRIM8 MRRF TMEM71 TRIP6 MRTO4 TMEM9 TSHZ3 MS4A8A TMOD3 TSPAN17 MSC TNFRSF1A TSPAN32 MSH6 TNFRSF1B TSPAN9 MSL3 TNFRSF9 TTC28 MSRB3 TNFSF10 TUBA4A MST1 TNKS1BP1 TUG1 MTBP TNS1 UAP1L1 MTCP1 TNS4 UBA52 MTHFD1 TPD52 UBL3 MTHFD2L TPP2 UBXN6 MTHFSD TPST2 UCP2 MTMR11 TRAF1 ULK3 MTO1 TRAFD1 UNC119 MTOR TREX1 UNC5A MTSS1 TRIB2 UQCRH MTX1 TRIM12A USE1 MTX2 TRIM13 USP20 MUC6 TRIM14 UVRAG MURC TRIM30A VAMP5 MYB TRIM36 VAMP8 MYBBP1A TRIM46 VILL MYBL2 TRIM59 VKORC1 MYEF2 TRP53INP1 VMAC MYH11 TSPAN3 VPS11 MYO10 TSPAN31 VPS33B MYO19 TTC39B WDFY2 MYO1C TTC7B WDR12 MYO1D TTLL12 WDR26 MYO3B TTYH3 WDR41 MYO5A TUBA1A WDR6 MYO9A TUBA1B WDR81 N4BP1 TUBA1C WFIKKN2 N4BP3 TUBA8 WNT9A NAA15 TUBB5 XLR3B NAA16 TUBD1 XLR4B NAA25 TULP4 XLR4C NAA35 TUSC3 XPC NAA40 TXK YOD1 NAF1 TXNDC16 YPEL3 NARS2 UBAC2 YTHDF3 NASP UBE2C ZADH2 NAT10 UBE2F ZBTB10 NAV1 UBE2H ZBTB37 NAV2 UBE2L6 ZBTB6 NBN UBE2S ZFAND2B NCBP1 UEVLD ZFHX2 NCBP2 UGCG ZFP109 NCKAP1 UHRF1BP1L ZFP160 NCLN UNC119B ZFP182 NCS1 UNC93B1 ZFP263 NDEL1 USP12 ZFP273 NDST1 USP18 ZFP280B NDUFA12 USP3 ZFP316 NDUFA5 VARS ZFP317 NDUFAF2 VAV2 ZFP36 NDUFAF4 VCAN ZFP362 NDUFC1 VIPR1 ZFP36L2 NEDD8 VOPP1 ZFP40 NEFH VPS13A ZFP420 NEIL3 VPS37B ZFP442 NEK6 VPS8 ZFP456 NEK8 VWA5A ZFP467 NELF WBP5 ZFP472 NETO2 WDR19 ZFP51 NEU3 WDR31 ZFP551 NFAT5 WDR44 ZFP558 NFE2L3 WDR78 ZFP579 NFIX WDR82 ZFP646 NFKB1 WDTC1 ZFP654 NFKB2 WNK1 ZFP658 NFKBIA WNK2 ZFP677 NFKBID WRN ZFP68 NFKBIZ XCR1 ZFP703 NFXL1 XDH ZFP707 NHS XKR5 ZFP709 NHSL1 XPR1 ZFP746 NIF3L1 YIPF4 ZFP773 NINJ1 YPEL4 ZFP777 NINL YWHAG ZFP780B NKD2 ZBP1 ZFP784 NKRF ZDHHC21 ZFP827 NMD3 ZEB2 ZFP831 NME1 ZFP287 ZFP84 NME4 ZFP36L1 ZFP865 NME6 ZFP395 ZGPAT NMT2 ZFP608 ZMYND8 NNT ZKSCAN17 ZRSR1 NOC3L ZNRF2 ZSCAN10 NOC4L ZYG11B ZSCAN22 NOL10 NOL11 NOL8 NOLC1 NOM1 NOP14 NOP16 NOP2 NOP58 NOV NPAS4 NR1D1 NR4A1 NR4A2 NR4A3 NR6A1 NRARP NRD1 NRIP3 NSF NSFL1C NSMCE4A NSUN2 NSUN4 NT5DC3 NT5E NUAK1 NUCB2 NUDC NUDCD1 NUDT1 NUDT5 NUF2 NUP133 NUP155 NUP205 NUP210L NUP43 NUP54 NUP85 NUP88 NUP93 NUP98 NUTF2 NYNRIN OAZ3 OCIAD2 OCRL ODC1 ODF2L OGDHL OLFR1033 OLFR856-PS1 OPTN ORC1 ORC2 ORC6 ORM2 OSBPL11 OSGEPL1 OSGIN2 OTUD6B PA2G4 PABPN1 PAK1IP1 PALB2 PANK4 PAPD7 PAPSS2 PAQR8 PARD6G PARP1 PARP2 PAXIP1 PCBP3 PCDH7 PCGF6 PCNT PDAP1 PDCD1 PDCD11 PDCD5 PDE4C PDE6D PDGFB PDGFC PDIA2 PDIA5 PDIA6 PDK3 PDLIM5 PDPN PDXDC1 PDZD4 PDZK1 PECR PELI2 PELP1 PER2 PERP PFAS PFDN1 PFDN4 PFKFB1 PHACTR2 PHACTR4 PHB PHF14 PHTF2 PIAS2 PID1 PIGG PIGL PIK3C2B PIK3R1 PIK3R3 PIN4 PINX1 PIPOX PITPNM2 PKHD1L1 PLA2G4C PLAGL1 PLAGL2 PLEKHA1 PLEKHA8 PLEKHB1 PLEKHB2 PLEKHF2 PLEKHG4 PLEKHO1 PLOD2 PLS1 PLS3 PLSCR1 PLSCR4 PLXNA3 PLXNB1 PMEPA1 PNCK PNMA1 PNN PNO1 PNPT1 POGK POLA2 POLD3 POLE POLE3 POLQ POLR1B POLR2K POLR3D POLR3G POP1 POP4 POU2AF1 PPA1 PPAPDC1B PPFIA3 PPFIBP1 PPID PPM1F PPME1 PPP1CC PPP1R12B PPP1R3C PPP1R3D PPP1R8 PPP2R1B PPP4R4 PPRC1 PPTC7 PRDM10 PRDM4 PRDM5 PRIM1 PRKAR1B PRKCI PRKRIR PRLR PRMT1 PRMT5 PRMT7 PROCA1 PRPF19 PRPF3 PRPF31 PRPF38B PRPF4B PRPS1 PRR18 PRR5L PRRT2 PRSS12 PSD3 PSMC1 PSMC2 PSMC4 PSMC5 PSMD1 PSMD12 PSMD6 PSMD7 PSME3 PSPC1 PSTPIP2 PTCD3 PTGER4 PTGFRN PTK2 PTK7 PTOV1 PTPN1 PTPN23 PTPRF PTPRJ PTPRS PUS10 PUS7 PWP1 PWWP2A PWWP2B PYCRL PYROXD2 QRSL1 QSER1 QSOX2 QTRTD1 R3HDM1 RAB11FIP3 RAB23 RAB26 RAB38 RAB3IP RABGGTB RABL2 RAC3 RAD1 RAD50 RAD51AP1 RAD52 RAD54B RAD54L RAD54L2 RALGPS1 RANBP1 RANGRF RARB RARG RARS RARS2 RASA1 RASAL2 RASGEF1B RASGRP3 RASL11B RBBP7 RBBP8 RBFOX2 RBM17 RBM18 RBM19 RBM25 RBM28 RBM4B RBMX RBMX2 RBP4 RCAN1 RCAN3 RCCD1 RCL1 RDH1 RDX RECQL4 REEP1 REEP2 RELB REP15 REV1 REXO2 REXO4 RFC3 RFX5 RFX8 RGAG4 RGMB RGS16 RGS2 RHEBL1 RHOT1 RIF1 RIN2 RIOK2 RMRP RNASEH2B RNF149 RNF19A RNF208 RNF216 RNF8 RNFT1 RNFT2 RNMT RNMTL1 RNPS1 RNU12 ROCK2 RORA RORC RPAP3 RPP30 RPRD1A RPS27L RPS6KC1 RPUSD2 RRAGA RRAGD RRP1 RRP12 RRP15 RRP1B RRP9 RSAD1 RSL1D1 RSRC2 RTEL1 RTKN RTN2 RTN4IP1 RUFY1 RUFY3 RUVBL1 RUVBL2 RYBP S100PBP SAP30 SARNP SASS6 SBK1 SCARNA17 SCLT1 SCN1B SCN4B SCRIB SDAD1 SDC1 SDC2 SDHAF1 SEC1 SEC24A SEC61A2 SELP SEMA3D SEMA6D SEMA7A SERF1 SERINC5 SERP2 SERPINE1 SERTAD4 SET SETD6 SF3A3 SFPQ SFRP2 SGK1 SGOL1 SH3BGRL2 SH3BP4 SH3PXD2B SH3RF1 SHB SHMT1 SHMT2 SHQ1 SIAH1A SIAH1B SIGMAR1 SIM2 SKI SKIV2L2 SKP2 SLC12A2 SLC15A3 SLC16A10 SLC16A4 SLC18A2 SLC19A1 SLC19A2 SLC1A4 SLC22A17 SLC25A13 SLC25A15 SLC25A18 SLC25A19 SLC25A27 SLC25A42 SLC27A6 SLC29A1 SLC29A2 SLC34A3 SLC35D3 SLC37A2 SLC38A6 SLC39A1 SLC39A10 SLC39A14 SLC41A1 SLC43A1 SLC43A3 SLC44A1 SLC46A1 SLC4A11 SLC4A2 SLC4A8 SLC5A3 SLC7A14 SLC7A6 SLC9A5 SLC9A7 SLC9A9 SLFN10-PS SLMO2 SLTM SMARCAD1 SMARCC1 SMARCE1 SMG5 SMGC SMN1 SMPD4 SMYD2 SMYD5 SNHG1 SNHG8 SNORA21 SNORA3 SNORD104 SNRNP70 SNRPA1 SNRPD1 SNX16 SNX27 SOCS2 SORBS1 SORT1 SOX12 SOX4 SPAG1 SPATA5 SPDEF SPECC1 SPG20 SPINT1 SPIRE1 SPON1 SRC SRD5A1 SRL SRM SRRT SRSF10 SSB SSBP1 SSX2IP ST13 ST3GAL3 ST5 ST6GALNAC3 ST6GALNAC4 ST7 STARD13 STARD7 STAT3 STAT5A STIP1 STK35 STK38L STON1 STX11 STX12 STXBP3A STXBP4 SULT1A1 SUPT16H SUPV3L1 SUV39H1 SUV39H2 SYCE2 SYDE2 SYN3 SYNCRIP SYNGR2 SYP SYT11 TADA2A TAF1D TAF4B TAF9 TALDO1 TANC2 TARDBP TARS TARSL2 TBC1D16 TBC1D24 TBC1D30 TBCE TBL3 TCEA2 TCERG1 TCF19 TCF7L1 TDP2 TDRKH TEAD3 TEC TECPR2 TERF2 TFDP1 TFDP2 TFF1 TFRC TGFBI TGFBR1 TGIF1 TGM2 TGS1 THG1L THOP1 TIA1 TICAM2 TIMD2 TIMELESS TIMM17A TIMM17B TIMM23 TIMM44 TIMM50 TIMM8A1 TIMM9 TIMP1 TIPIN TJP2 TLCD1 TLE2 TLN2 TM9SF1 TM9SF4 TMCC2 TMEFF1 TMEM120B TMEM131 TMEM132A TMEM136 TMEM144 TMEM17 TMEM176B TMEM190 TMEM201 TMEM216 TMEM55B TMEM63B TMEM86B TMTC2 TMTC3 TMTC4 TNF TNFAIP1 TNFRSF10B TNFRSF13B TNFRSF21 TNFRSF23 TNFRSF25 TNFRSF8 TNFSF4 TNIP1 TNIP2 TNIP3 TNK1 TNPO3 TOMM40 TOP1 TOP1MT TOPBP1 TOX TPD52L2 TPM1 TRA2A TRAF3 TRAF3IP1 TRAF6 TRAIP TRAP1 TRERF1 TRIM2 TRIM3 TRIM44 TRIP13 TRMT5 TRMT6 TRP53 TRPS1 TRUB1 TSC22D1 TSEN2 TSFM TSKU TSPAN2 TSPAN6 TSPYL2 TSR2 TTBK1 TTC21B TTC27 TTC3 TTC8 TTI1 TTK TTL TTLL4 TUBB2B TUBB6 TUBGCP3 TULP3 TXLNA TXNRD1 TXNRD3 TYMS TYR TYRO3 U2AF1 UBA2 UBAP2 UBASH3B UBE2CBP UBE2E2 UBE2M UBE2Q2 UBE4B UBQLN4 UBR3 UBR4 UBR5 UBTD2 UCHL1 UCHL3 UCHL5 UHRF1 UHRF1BP1 UIMC1 UMPS UNG UPF2 UPF3B UPP1 URB2 USP1 USP10 USP11 USP22 USP27X USP31 USP33 USP40 USP46 USP49 USP6NL UST UTP14A UTP18 UTP20 UTP6 VAC14 VANGL2 VAX2 VCL VDR VKORC1L1 VMN1R58 VMN2R96 VWA1 WDFY4 WDHD1 WDR3 WDR35 WDR36 WDR43 WDR47 WDR60 WDR61 WDR62 WDR75 WDR92 WDYHV1 WFDC16 WHRN WNT2B WRB WWC2 XKRX XPO5 XRCC1 XRCC2 XYLB XYLT2 YARS2 YBX2 YDJC YEATS2 YLPM1 ZADH2 ZBTB17 ZBTB46 ZC3H12A ZC3H12C ZC3H12D ZC3H8 ZCCHC14 ZCRB1 ZDHHC13 ZDHHC14 ZDHHC6 ZFC3H1 ZFHX3 ZFP101 ZFP131 ZFP28 ZFP318 ZFP382 ZFP410 ZFP428 ZFP449 ZFP451 ZFP488 ZFP518B ZFP52 ZFP609 ZFP667 ZFP85-RS1 ZFP870 ZFP9 ZFP90 ZFYVE26 ZFYVE9 ZGPAT ZIK1 ZMAT3 ZMYM1 ZMYND19 ZNHIT6 ZSCAN21 ZSCAN22 ZWILCH ZZZ3 Supplementary Table 2. List of shared upstream regulators and canonical pathways in each group. Numbers indicate –logP values of an enrichment score of each upstream regulator or canonical pathways. The list shows ones highly significant to all subsets in each group (–logP>3 or P<0.001 for upstream regulators and –logP>1.3 or P<0.05 for canonical pathways). For L2 and L3 groups, canonical pathways significantly shared by three out of four subsets are shown. Group Upstram Regulator NKT1 ILC1 V5 Th1 NK Group Canonical Pathway NKT1 ILC1 V5 Th1 NK ITK 30.10 12.31 10.66 13.83 11.15 Natural Killer Cell Signaling 10.86 8.52 6.27 5.43 9.39 IL2 18.61 9.79 13.85 14.82 11.72 Pathogenesis of Multiple Sclerosis 4.65 2.10 3.44 2.34 1.95 IL12 (complex) 18.16 7.51 7.83 21.00 8.73 Crosstalk between Dendritic Cells and Natural Killer Cells 3.50 2.56 1.75 4.19 2.18 IL21 14.90 12.67 12.60 8.84 10.31 Production of Nitric Oxide and Reactive Oxygen Species in Macrophages 2.84 1.58 4.12 4.16 1.64 IL15 14.23 8.58 12.37 12.91 8.36 Integrin Signaling 2.60 7.54 6.31 6.47 9.46 IFNG 12.96 8.35 14.35 29.79 9.73 Germ Cell-Sertoli Cell Junction Signaling 2.35 2.99 4.00 3.96 1.95 TCR 11.53 5.25 9.68 17.82 6.68 Type I Diabetes Mellitus Signaling 2.21 3.47 1.41 5.00 1.76 IL4 11.16 11.71 11.25 15.19 6.69 PKCθ Signaling in T Lymphocytes 2.07 3.20 4.39 3.38 1.58 IL10 10.34 4.90 6.25 10.44 6.69 Erythropoietin Signaling 1.96 1.63 2.95 3.31 1.39 TGFB1 9.29 11.09 10.18 23.16 12.61 Leukocyte Extravasation Signaling 1.95 2.87 2.62 1.72 2.81 TNF 9.24 6.64 12.47 20.31 7.01 CCR5 Signaling in Macrophages 1.89 4.72 5.40 3.12 2.60 CSF2 8.74 5.16 5.73 7.30 4.99 L1 Chemokine Signaling 1.88 1.54 3.58 3.07 1.89 CD28 8.70 3.47 6.57 9.39 3.14 TREM1 Signaling 1.86 3.76 3.55 3.64 3.28 FAS 8.17 5.23 5.95 10.38 4.15 Reelin Signaling in Neurons 1.82 3.65 3.44 2.89 2.46 CD3 7.99 5.29 10.75 7.65 5.24 Ceramide Signaling 1.75 2.71 4.94 2.17 3.02 IL5 7.79 6.92 7.85 15.14 8.45 Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells 1.73 5.07 3.75 3.62 2.56 STAT3 7.50 3.77 7.73 20.16 3.65 Virus Entry via Endocytic Pathways 1.61 4.78 2.28 4.56 5.82 IL1B 7.40 4.07 4.69 9.28 4.57 NF-κB Signaling 1.57 1.75 2.60 1.64 1.38 ESR1 7.33 5.60 8.50 12.79 3.74 Paxillin Signaling 1.54 5.42 5.11 4.26 5.56 L1 TLR4 7.24 4.35 9.20 9.16 3.46 Pancreatic Adenocarcinoma Signaling 1.47 2.17 1.45 1.51 1.30 CREBBP 7.08 6.83 9.60 11.52 7.29 Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses 1.31 2.47 2.29 3.79 1.54 ID2 7.04 4.45 8.90 11.03 5.80 p70S6K Signaling 1.31 1.88 5.07 3.79 2.63 Interferon alpha 6.73 6.23 4.58 20.54 4.50 NKT2 ILC2 V6 Th2 IFN alpha/beta 6.30 3.04 3.68 6.68 3.39 cAMP-mediated signaling 2.24 3.46 0.00 1.86 SATB1 6.13 8.71 5.78 4.84 6.76 Protein Kinase A Signaling 2.07 2.09 0.66 3.35 ID3 5.85 4.29 9.51 10.59 5.60 G-Protein Coupled Receptor Signaling 1.90 3.48 0.00 1.53 ERBB2 5.78 6.80 3.42 15.57 5.67 L2 T Helper Cell Differentiation 1.81 3.68 2.42 0.51 ETS1 5.32 5.05 6.08 5.45 5.51 Altered T Cell and B Cell Signaling in Rheumatoid Arthritis 1.58 3.20 2.77 0.35 IgG 5.15 4.62 3.62 5.44 3.89 Airway Inflammation in Asthma 1.45 4.79 2.70 0.75 IRF3 5.13 4.60 3.54 12.98 3.24 NKT17 ILC3 V2 Th17 IFNA2 5.10 5.46 3.80 24.48 3.36 Inhibition of Matrix Metalloproteases 1.77 1.53 3.57 1.18 CD40LG 4.69 3.41 7.58 13.93 3.96 L3 Type I Diabetes Mellitus Signaling 1.75 1.95 1.25 1.85 IRF7 4.21 7.03 3.67 17.35 4.59 CSF3 4.18 4.60 6.57 4.84 6.76 FOXO1 3.69 4.00 3.61 5.85 3.63 PI3K (complex) 3.53 6.96 5.15 3.45 7.79 CD38 3.43 5.60 3.82 12.86 5.52 CCL5 3.04 4.18 3.97 3.52 4.55 EP300 3.04 9.57 3.64 8.79 6.66 NKT2 ILC2 V6 Th2 TP53 12.31 6.72 23.02 7.46 CSF2 11.46 8.29 25.52 5.93 ID2 7.60 12.20 13.82 5.95 ID3 7.42 12.96 14.51 5.66 RRP1B 6.39 7.88 8.03 4.17 L2 TGFB1 5.84 6.31 15.00 6.31 ESR1 5.77 5.35 6.73 3.83 CD3 5.15 9.98 11.15 4.43 ERBB2 4.51 6.17 13.15 3.77 TCR 3.72 6.73 12.59 5.88 MYC 3.27 3.85 10.69 3.13 NKT17 ILC3 V2 Th17 ID3 5.76 6.11 7.11 4.75 ID2 4.84 7.12 7.28 3.78 L3 BCL6 3.35 3.51 4.16 4.90 EP300 3.19 6.25 16.43 5.53 IL4 3.06 4.92 6.00 7.43