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