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Supplemental Data Article TCF7L2 is a master regulator of insulin production and processing ZHOU, Yuedan, et al. Abstract Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of [...] Reference ZHOU, Yuedan, et al. TCF7L2 is a master regulator of insulin production and processing. Human Molecular Genetics, 2014, vol. 23, no. 24, p. 6419-6431 DOI : 10.1093/hmg/ddu359 PMID : 25015099 Available at: http://archive-ouverte.unige.ch/unige:45177 Disclaimer: layout of this document may differ from the published version. 1 / 1 Gene ID log(Fold Change) logCPM Likelihood ratio P Value value FDR correc Description Gene Symbol ENSRNOG00000020811 -1.884144098 6.14183448 182.8588856 1.15E-41 1.74E-37 Interleukin-6 receptor subunit alpha [Source:UniProtKB/Swiss-Prot;Acc:P22273] Il6r ENSRNOG00000017619 3.250568327 6.22643 180.5260665 3.72E-41 2.80E-37 Retinal dehydrogenase 1 [Source:UniProtKB/Swiss-Prot;Acc:P51647] Aldh1a1 ENSRNOG00000003251 -2.048987017 4.87056849 136.3135032 1.70E-31 6.42E-28 beta-1,3-galactosyltransferase 2 [Source:RefSeq peptide;Acc:NP_001102962] B3galt2 ENSRNOG00000007512 1.692218023 6.29829189 136.3430377 1.68E-31 6.42E-28 signal recognition particle 14 kDa protein [Source:RefSeq peptide;Acc:NP_001099967] Srp14 ENSRNOG00000033531 -2.18464309 7.80561272 133.5052453 7.01E-31 2.08E-27 Voltage-dependent calcium channel subunit alpha-2/delta-1Voltage-dependent calcium channel subunit alpha-2-1Voltage- Cacna2d1 dependent calcium channel subunit delta-1 [Source:UniProtKB/Swiss-Prot;Acc:P54290] ENSRNOG00000018082 -1.833829027 6.88465482 133.1739369 8.28E-31 2.08E-27 Sulfate transporter [Source:UniProtKB/Swiss-Prot;Acc:O70531] Slc26a2 ENSRNOG00000014550 -1.427981119 6.21976673 124.1122101 7.96E-29 1.72E-25 RGD1308448 ENSRNOG00000020578 -1.468888395 6.16475527 118.3789909 1.43E-27 2.70E-24 Carcinoembryonic antigen-related cell adhesion molecule 1 [Source:UniProtKB/Swiss-Prot;Acc:P16573] Ceacam1 ENSRNOG00000014740 -3.095060926 3.57761596 116.0514741 4.63E-27 7.76E-24 GastrinBig gastrinGastrin [Source:UniProtKB/Swiss-Prot;Acc:P04563] Gast ENSRNOG00000011352 1.472419643 7.49273232 115.8194425 5.21E-27 7.85E-24 Furin [Source:UniProtKB/Swiss-Prot;Acc:P23377] Furin ENSRNOG00000007583 1.189980628 7.6066405 108.6959566 1.89E-25 2.59E-22 Glycogen phosphorylase, brain form [Source:UniProtKB/Swiss-Prot;Acc:P53534] Pygb ENSRNOG00000031163 2.731920784 3.69878814 101.875131 5.91E-24 7.43E-21 NF-kappa-B inhibitor zeta [Source:RefSeq peptide;Acc:NP_001100565] Nfkbiz ENSRNOG00000003492 -1.680421521 5.9035401 98.91506493 2.64E-23 3.06E-20 Growth arrest-specific protein 7 [Source:UniProtKB/Swiss-Prot;Acc:O55148] Gas7 ENSRNOG00000034025 -1.685605215 5.49014494 98.20133676 3.78E-23 4.07E-20 protein tyrosine phosphatase, receptor type, J [Source:MGI Symbol;Acc:MGI:104574] Ptprj ENSRNOG00000010915 -1.365012655 7.59666154 96.93629925 7.16E-23 7.20E-20 Endoplasmic reticulum metallopeptidase 1 [Source:UniProtKB/Swiss-Prot;Acc:Q6UPR8] Ermp1 ENSRNOG00000007808 -2.423152566 4.22623711 95.66550493 1.36E-22 1.28E-19 Nucleosome assembly protein 1-like 5 [Source:UniProtKB/Swiss-Prot;Acc:Q5PPG6] Nap1l5 ENSRNOG00000025406 -2.126140228 4.61588368 92.80178369 5.78E-22 5.13E-19 Protein LOC100360623 [Source:UniProtKB/TrEMBL;Acc:F1LW74] Iqgap2 ENSRNOG00000008401 1.661230655 5.10569967 92.52384436 6.65E-22 5.57E-19 caspase recruitment domain-containing protein 10 [Source:RefSeq peptide;Acc:NP_001124026] Card10 ENSRNOG00000008088 -1.41145632 5.61211989 89.99888389 2.38E-21 1.89E-18 BTB/POZ domain-containing protein 3 [Source:RefSeq peptide;Acc:NP_001101252] Btbd3 ENSRNOG00000012181 -1.935960177 5.93691867 89.04029023 3.87E-21 2.92E-18 Lipoprotein lipase [Source:UniProtKB/Swiss-Prot;Acc:Q06000] Lpl ENSRNOG00000011439 -1.830216615 4.57317382 88.19842921 5.92E-21 4.25E-18 G protein-coupled receptor kinase 5 [Source:UniProtKB/Swiss-Prot;Acc:Q62833] Grk5 ENSRNOG00000012235 -2.895221597 2.85748939 87.89385692 6.91E-21 4.73E-18 G-substrate [Source:RefSeq peptide;Acc:NP_703197] Gsbs ENSRNOG00000011522 -2.391710509 3.22495114 81.45312465 1.79E-19 1.18E-16 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 [Source:UniProtKB/Swiss- Hcn1 ENSRNOG00000036661 -1.46704422 5.15806374 81.13873348 2.10E-19 1.32E-16 ras-related protein Rab-40B [Source:RefSeq peptide;Acc:NP_001100546] Rab40b ENSRNOG00000006523 -1.145210832 7.27846694 80.86454888 2.42E-19 1.46E-16 ADP-ribosylation factor-like 6 interacting protein 2 [Source:RefSeq peptide;Acc:NP_001094141] Atl2 ENSRNOG00000002654 2.102935356 3.62821177 80.31720584 3.19E-19 1.85E-16 Protein FAM120C [Source:UniProtKB/TrEMBL;Acc:D3ZNI4] FAM120C ENSRNOG00000026277 1.93434437 4.31273257 79.71236406 4.33E-19 2.42E-16 zinc finger CCCH domain-containing protein 6 [Source:RefSeq peptide;Acc:NP_001101242] Zc3h6 ENSRNOG00000024346 -2.637854506 2.86869803 79.4445456 4.96E-19 2.58E-16 Placenta-expressed transcript 1 protein [Source:UniProtKB/Swiss-Prot;Acc:Q5HZW7] LOC363060 ENSRNOG00000028169 1.345026004 7.40201982 79.45114326 4.94E-19 2.58E-16 protein phosphatase 1L [Source:RefSeq peptide;Acc:NP_001101151] Ppm1l ENSRNOG00000010086 1.611745287 5.42399559 79.2901701 5.36E-19 2.65E-16 pleiomorphic adenoma gene-like 2 [Source:RefSeq peptide;Acc:NP_001099998] Plagl2 ENSRNOG00000031997 -1.532688187 6.12050701 79.26019727 5.44E-19 2.65E-16 tubulin tyrosine ligase-like family, member 7 [Source:MGI Symbol;Acc:MGI:1918142] Ttll7 ENSRNOG00000016210 -1.650728107 4.42459748 77.41710161 1.38E-18 6.52E-16 MICAL C-terminal-like protein [Source:UniProtKB/Swiss-Prot;Acc:Q4G091] Micalcl ENSRNOG00000007427 1.334437858 5.2330087 76.78368015 1.91E-18 8.72E-16 Ectonucleoside triphosphate diphosphohydrolase 6 [Source:UniProtKB/Swiss-Prot;Acc:Q9ER31] Entpd6 ENSRNOG00000004747 -1.460640406 8.5304176 76.3103252 2.42E-18 1.08E-15 Zinc transporter 8 [Source:UniProtKB/Swiss-Prot;Acc:P0CE46] Slc30a8 ENSRNOG00000019559 -1.24220285 6.41624815 75.5102877 3.64E-18 1.57E-15 ELL-associated factor 1 [Source:RefSeq peptide;Acc:NP_001100763] Eaf1 ENSRNOG00000018911 -1.077842242 6.19674891 75.27551277 4.09E-18 1.71E-15 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 36-phosphofructo-2-kinaseFructose-2,6-bisphosphatase Pfkfb3 [Source:UniProtKB/Swiss-Prot;Acc:O35552] ENSRNOG00000016704 -1.322711989 7.17712665 74.95251575 4.82E-18 1.97E-15 Prenylcysteine oxidase [Source:UniProtKB/Swiss-Prot;Acc:Q99ML5] Pcyox1 ENSRNOG00000008055 -1.13286363 6.45256662 73.33881001 1.09E-17 4.33E-15 G1/S-specific cyclin-E2 [Source:RefSeq peptide;Acc:NP_001102126] Ccne2 ENSRNOG00000007989 1.573907077 4.95414373 72.25411701 1.89E-17 7.32E-15 Carbohydrate sulfotransferase 1 [Source:UniProtKB/Swiss-Prot;Acc:Q5RJQ0] Chst1 ENSRNOG00000010389 1.825619605 4.45619599 72.16015284 1.98E-17 7.48E-15 Protein NDRG2 [Source:UniProtKB/Swiss-Prot;Acc:Q8VBU2] Ndrg2 ENSRNOG00000003873 -1.258524309 8.27317166 69.9225615 6.17E-17 2.27E-14 Carboxypeptidase D [Source:UniProtKB/Swiss-Prot;Acc:Q9JHW1] Cpd ENSRNOG00000020151 -1.082052889 9.38456979 69.86331384 6.36E-17 2.28E-14 Cadherin-1E-Cad/CTF1E-Cad/CTF2E-Cad/CTF3 [Source:UniProtKB/Swiss-Prot;Acc:Q9R0T4] Cdh1 ENSRNOG00000021182 1.152885053 7.85036331 69.12500674 9.24E-17 3.24E-14 Synaptic vesicle glycoprotein 2A [Source:UniProtKB/Swiss-Prot;Acc:Q02563] Sv2a ENSRNOG00000027230 -1.621175318 5.39870771 68.17640157 1.50E-16 5.12E-14 formin homology 2 domain containing 3 (Fhod3), mRNA [Source:RefSeq mRNA;Acc:NM_001271332] Fhod3 ENSRNOG00000017983 1.064445121 6.12881425 67.90526741 1.72E-16 5.75E-14 Ubiquitin-associated domain-containing protein 1 [Source:UniProtKB/Swiss-Prot;Acc:Q5XIR9] Ubac1 ENSRNOG00000042246 -1.06814083 8.2185739 67.84660453 1.77E-16 5.79E-14 RCG54937Uncharacterized protein [Source:UniProtKB/TrEMBL;Acc:D3ZI94] LOC690918 ENSRNOG00000027514 0.985567875 7.0962325 67.55145813 2.05E-16 6.59E-14 NEDD8-conjugating enzyme Ubc12 [Source:RefSeq peptide;Acc:NP_001101941] Ube2m ENSRNOG00000013774 0.948789382 7.13294968 67.2392396 2.40E-16 7.56E-14 Lamin-B1 [Source:UniProtKB/Swiss-Prot;Acc:P70615] Lmnb1 ENSRNOG00000009029 -1.212945481 6.59228518 67.13631457 2.53E-16 7.80E-14 Neuroplastin [Source:UniProtKB/Swiss-Prot;Acc:P97546] Nptn ENSRNOG00000002922 -1.451922294 4.29423384 66.6764751 3.20E-16 9.65E-14 Adenosine receptor A2b [Source:UniProtKB/Swiss-Prot;Acc:P29276] Adora2b ENSRNOG00000004828 -2.269841398 3.35863648 66.58233116 3.36E-16 9.73E-14 Activin receptor type-1C [Source:UniProtKB/Swiss-Prot;Acc:P70539] Acvr1c ENSRNOG00000005609 -1.193132577 6.80065742 66.61173486 3.31E-16 9.73E-14 Neurogenic differentiation
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  • Supplemental Information
    Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig.
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  • Breast Cancer Antiestrogen Resistance-3 Expression Regulates Breast Cancer Cell Migration Through Promotion of P130cas Membrane Localization Andmembrane Ruffling
    Research Article Breast Cancer Antiestrogen Resistance-3 Expression Regulates Breast Cancer Cell Migration through Promotion of p130Cas Membrane Localization andMembrane Ruffling Randy S. Schrecengost,1 Rebecca B. Riggins,2 Keena S. Thomas,1 Michael S. Guerrero,1 and Amy H. Bouton1 1Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia and 2Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia Abstract antiestrogen resistance-1 (BCAR1; also known as p130Cas; refs. 2, 3). Antiestrogens such as tamoxifen are widely used in the clinic A second protein, BCAR3 (the human homologue of the murine to treat estrogen receptor–positive breast tumors. Resistance protein AND-34), was identified in a genetic screen along with to tamoxifen can occur either de novo or develop over time in BCAR1 as a gene product whose overexpression conferred tamoxifen resistance in vitro (4). BCAR3 is a member of the novel a large proportion of these tumors. Additionally, resistance is S p associated with enhanced motility and invasiveness in vitro. rc homology 2 (SH2)–containing rotein (NSP) family that One molecule that has been implicated in tamoxifen resis- includes two other members, Chat/SHEP1 and NSP1. These tance, breast cancer antiestrogen resistance-3 (BCAR3), has proteins share a common domain structure consisting of an also been shown to regulate migration of fibroblasts. In this amino-terminal SH2 domain and a carboxyl-terminal domain with study, we investigated the role of BCAR3 in breast cancer cell sequence homology to the Cdc25-family of guanine nucleotide exchange factors (GEF). Several studies have shown that BCAR3 migration and invasion.
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  • 9-Azido Analogs of Three Sialic Acid Forms for Metabolic Remodeling Of
    Supporting Information 9-Azido Analogs of Three Sialic Acid Forms for Metabolic Remodeling of Cell-Surface Sialoglycans Bo Cheng,†,‡ Lu Dong,†,§ Yuntao Zhu,†,‡ Rongbing Huang,†,‡ Yuting Sun,†,‖ Qiancheng You,†,‡ Qitao Song,†,§ James C. Paton, ∇ Adrienne W. Paton,∇ and Xing Chen*,†,‡,§,⊥,# †College of Chemistry and Molecular Engineering, ‡Beijing National Laboratory for Molecular Sciences, §Peking−Tsinghua Center for Life Sciences,‖Academy for Advanced Interdisciplinary Studies, ⊥Synthetic and Functional Biomolecules Center, and #Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China ∇Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide SA 5005, Australia Page S1 Table of Contents: Scheme S1.……………………………………………………….........……………. S3 Figure S1……………………………………………………..………..……………. S3 Figure S2……………………………………………………..………..…………… S4 Figure S3……………………………………………………..………..…………… S4 Figure S4……………………………………………………..………..…………… S5 Figure S5……………………………………………………..………..…………… S6 Figure S6……………………………………………………..………..…………….S7 Figure S7……………………………………………………..………..…………….S8 Figure S8……………………………………………………..………..…………….S9 Experimental Procedures……………………………….…........…………....S10-S27 Table S1………………………………………………..………..…………….S28-S48 Supporting Reference……………………………………………….......………...S49 Page S2 Scheme S1. Synthesis of 9AzNeu5Gc Figure S1: a, b, c, d) Representative scatter plots (FSC vs. SSC) and histograms of flow cytometry analysis
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  • Whole Proteome Analysis of Human Tankyrase Knockout Cells Reveals Targets of Tankyrase- Mediated Degradation
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