www.pnas.org/cgi/doi/10.1073/pnas.

1

Supplementary Information for Insulin Promoter in Human Pancreatic β Cells Contacts Diabetes Susceptibility

Loci and Regulates Genes Affecting Insulin Metabolism

Xing Jian and Gary Felsenfeld*

Gary Felsenfeld Email: garyf@intra.niddk.nih.gov

This PDF file includes:

Figs. S1 to S7 Tables S1 to S5 References for SI reference citations

1803146115

2

0 10 20 30 40 50

0

2000000

4000000

6000000

8000000

10000000

12000000

14000000

SIZ

E (n

t)

SITE NUMBER

Fig. S1. Size distribution of the interchromosomal interactions of INS promoter that are present in EndoC-βH1 cells but not in HeLa cells.

3

NELFB

MSI1

TRIM56

H19

VGF

SSTR5-AS1

SRCAP

INS

MKNK2

GPX4

SDF4

4

VEGFB

SNX4

RCN2

TRIAP1

EIF5

DLK1

TVP23B

SLC39A13

CDIPT

Fig. S2. UCSC genome browser (http://genome.ucsc.edu/) (1, 2) graphs showing CHIP-seq data of histone mark H3K27Ac (upper track) of the genes affected by INS promoter shRNA (Fig. 4B). The lower two tracks are DNase I hypersentivity clusters and transcription factor CHIP-seq from ENCODE project (3).

5

NELFB

MSI1

6

TRIM56

H19

7

VGF

SSTR5-AS1

8

SRCAP

INS

9

MKNK2

GPX4

10

SDF4

VEGFB

11

SNX4

RCN2

12

TRIAP1

EIF5

13

DLK1

TVP23B

14

SLC39A13

CDIPT

15

Fig. S3. Genomic features of the genes affected by INS promoter shRNA (Fig. 4B), retrieved from the Islet Regulome Browser (http://gattaca.imppc.org/isletregulome/home) (4). The top parts of the graphs show the association between SNPs and T2D susceptibility; most highly associated SNPs are labeled. The lower parts of the graphs show transcription factor binding sites and chromatin classes.

16

17

Fig. S4. RNA-seq differential expression analysis for Foxo1 regulated genes SLC2A2/GLUT2, SOD1 and CAT (5), and IRE-BP1 regulated genes PPIA, RPN2, GNB2L1/RACK1 (6)in EndoC-βH1 cells upon INS promoter knockdown by shRNA. Blue bar: knock-down cells. Red bar: control cells. Y-axis: Fragments Per Kilobase of transcript per Million mapped reads.

18

Fig. S5. After INS promoter shRNA knockdown, SSTR5-AS1 level does not change after restoring the extracellular insulin level (n = 4). Condition a: knockdown cells. Condition b: knockdown cells culturing with medium from non-knockdown cells. GAPDH endogenous control gene was used to normalize gene expression for RT-qPCR.

0

0.5

1

1.5

a b

Rela

tive

SSTR

5-AS

1le

vel

19

Fig. S6. RNA-seq differential expression analysis for HLA-A gene in EndoC-βH1 cells upon INS promoter knockdown by shRNA. Blue bar: knock-down cells. Red bar: control cells. Y-axis: Fragments Per Kilobase of transcript per Million mapped reads.

20

Fig. S7. Relationship between SSTR5-AS1, SSTR5, SST28 and insulin.

21

• Table S1A. List of long-range interactions detected in the 4C-seq experiment

in EndoC-βH1 cells.

Start (bp) End (bp) Span (bp) chr11 60246 174680 114434 chr11 4195332 4425148 229816 chr11 9172334 10216846 1044512 chr11 17045011 17820131 775120 chr11 18304347 18766621 462274 chr11 32966639 34592300 1625661 chr11 44774073 48086220 3312147 chr11 61036207 61573234 537027 chr11 62258814 62658221 399407 chr11 63412401 64252836 840435 chr11 67283008 67942358 659350 chr11 71130077 71788230 658153 Non Specific chr11 1.17E+08 1.17E+08 534414 chr11 1.18E+08 1.19E+08 1175418 chr1 13699 4529608 4515909 Non Specific chr1 1.21E+08 1.51E+08 29861435 Non Specific chr1 2.24E+08 2.25E+08 1414244 chr12 6374103 9953279 3579176 chr12 48085479 51716023 3630544 chr12 55060960 58665288 3604328 chr12 1.12E+08 1.14E+08 2588488 chr12 1.2E+08 1.24E+08 4751289 chr14 1.02E+08 1.07E+08 4646476 chr15 76339580 77742441 1402861 chr16 63380 5873016 5809636 chr16 13609329 17248796 3639467 chr16 27140431 32251345 5110914 Non Specific chr17 16917764 21075237 4157473 chr17 35951901 38673683 2721782 chr19 62328 4946479 4884151 chr19 46372780 51370006 4997226 Non Specific chr2 96481317 98661207 2179890

22

chr20 30085098 36340836 6255738 chr20 59845137 62964795 3119658 chr21 43658652 47144116 3485464 chr3 46511307 52632724 6121417 chr3 74524116 76643052 2118936 chr3 1.25E+08 1.27E+08 2258826 chr3 1.28E+08 1.31E+08 3780708 chr3 1.36E+08 1.38E+08 1838281 chr3 1.82E+08 1.85E+08 2421891 chr3 1.96E+08 1.98E+08 2271773 chr4 14190 5888056 5873866 chr4 6694310 11150612 4456302 chr4 52800295 54249341 1449046 chr5 1.75E+08 1.81E+08 5958824 chr6 29647329 35797697 6150368 chr7 3824870 8108712 4283842 chr7 54897214 62406318 7509104 chr7 71339212 76304458 4965246 Non Specific chr7 96620142 1.04E+08 7573484 Non Specific chr8 1.42E+08 1.46E+08 3998120 chr9 66388203 69144883 2756680 chr9 1.29E+08 1.41E+08 12078986 chrX 46796971 50197689 3400718 chrX 55915235 57353129 1437894 Non Specific chrX 71505399 74489743 2984344 Non Specific

Total Contact Span 214412973 Intra-chromosomal Contact Span 12368168 Inter-chromosomal Contact Span 202044805

Non Specific Contact 62104605 Specific Intra-chromosomal Contact Span

11710015

Specific Inter-chromosomal Contact Span

140598353

23

• Table S1B. List of diabetes susceptibility loci overlapping with INS 4C contact region.

Location Gene Notes 3p21.31 SCAP T2D 4p16.3 MAEA T2D Important to β-cell Function 4p16.1 WFS1 Neonatal Diabetes, MODY, T2D Important to β-cell Function 6P21.3 MHC locus T1D 6p21.33 HLA-B T2D 6p21.33 POU5F1/TCF19 T2D Important to β-cell Function 6p21.33 NEU1 T2D 6p21.32 HLA-DRB5 T2D 6p21.32 HLA-DQA1 T2D 9q34.13 CEL MODY 9q34.2 ABO T2D 9q34.3 GPSM1 T2D Important to β-cell Function 12p13.31 CD69 T1D 12q13.2 IKZF4 T1D 12q13.3 ERBB3 T1D 12q24.11 CUX2 T1D 12q24.12 SH2B3 T1D 12q24.31 HNF1A MODY, T2D Important to β-cell Function 12q24.31 MPHOSPH9 T2D 12q24.31 CCDC92 T2D 14q32.2 MEG3 T1D 15q24.3 HMG20A T2D Important to β-cell Function 16p13.3 ITFG3 T2D 16p11.2 IL27 T1D Contact region not cell type-specific 17q12 IKZF3, ORMDL3 T1D 17q12 HNF1B MODY, T2D Important to β-cell Function 17q21.2 CCR7 T1D 19q13.32 PRKD2 T1D Contact region not cell type-specific 19q13.33 FUT2 T1D Contact region not cell type-specific 21q22.3 UBASH3A T1D 21q22.3 ICOSLG T1D Xp11.23 FOXP3 Neonatal Diabetes

• MODY, maturity-onset diabetes of the young.

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• Table S2. List of top 2% histone H3K27Ac sites in EndoC-βH1 cells.

chr11 2180650 2183800 chr7 1.3E+08 1.3E+08 chr2 2.08E+08 2.08E+08 chr11 2172100 2174650 chr20 20524900 20538900 chr11 65263100 65271800 chr7 1.58E+08 1.58E+08 chr20 34328150 34332300 chr2 2.2E+08 2.2E+08 chr20 379100 391500 chr20 20383450 20397050 chr19 6062800 6070350 chr20 44599100 44601900 chr20 30696650 30698950 chr11 2007000 2015950 chr17 75277300 75285500 chr9 97667350 97678650 chr20 62818400 62824150 chr20 358400 364900 chr5 1.24E+08 1.24E+08 chr20 31145850 31151300 chr5 33998050 34009400 chr19 13260400 13267200 chr14 90976100 90985200 chr6 32934800 32941700 chr20 40718900 40732250 chr20 30189750 30197700 chr1 2.03E+08 2.03E+08 chr4 71757350 71765050 chr20 10196200 10202750 chr7 1.55E+08 1.55E+08 chr7 1.58E+08 1.58E+08 chr15 66120650 66130650 chr3 1.93E+08 1.93E+08 chr8 37738050 37745300 chr16 4663150 4672350 chr20 20416250 20439300 chr5 1.72E+08 1.72E+08 chr7 1E+08 1E+08 chr19 46219100 46222650 chr19 12898600 12906500 chr4 1.87E+08 1.87E+08

chr20 57933900 57948850 chr2 2.2E+08 2.2E+08 chr6 42748800 42752650 chr12 1.31E+08 1.31E+08 chr20 22500050 22508050 chr8 29591300 29602850 chr2 2.33E+08 2.33E+08 chrX 41189100 41195200 chr9 79197900 79207050 chr17 73639500 73644650 chr2 2.39E+08 2.39E+08 chr3 1.39E+08 1.39E+08 chr2 2.32E+08 2.32E+08 chr20 11666200 11671050 chr15 74602800 74615050 chr3 57581850 57585150 chr11 64900700 64903650 chr6 81345350 81351050 chr14 55281000 55288000 chr19 50378850 50382250 chr18 68039200 68049600 chr19 54958850 54965150 chr8 11311150 11317650 chr17 39048100 39062450 chr4 1.4E+08 1.4E+08 chr16 3743100 3747800 chr12 53398050 53401600 chr14 1.01E+08 1.01E+08 chr17 77781950 77788300 chr2 6696900 6705800 chr2 1.78E+08 1.78E+08 chr20 31959300 31963750 chr19 18389500 18394650 chr17 57694650 57699000 chr5 95318500 95328000 chr7 1.39E+08 1.39E+08 chr17 57904500 57908950 chr1 2.35E+08 2.35E+08 chr1 22737550 22746300 chr1 2.36E+08 2.36E+08 chr20 21500300 21506500 chr15 79163650 79167350

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chr8 22623400 22628850 chr2 25193550 25196500 chr1 2.22E+08 2.22E+08 chr9 1.12E+08 1.12E+08 chr7 1.08E+08 1.08E+08 chr6 31701600 31709150 chr6 1.39E+08 1.39E+08 chr19 13952900 13962950 chr19 47613450 47618400 chr11 72488250 72500400 chr1 1.13E+08 1.13E+08 chr17 36570350 36573350 chr8 54568350 54573150 chr14 93381250 93393650 chr7 44221600 44232750 chr7 99612300 99616200 chr1 16389800 16396550 chr17 48941650 48946200 chr20 48530650 48535900 chr5 1.39E+08 1.39E+08 chr1 2.35E+08 2.35E+08 chr20 326300 330400 chr1 78442850 78446300 chr8 53157500 53170150 chr12 1.09E+08 1.09E+08 chr2 916750 923200 chr17 62156000 62163900 chr2 70311050 70317250 chr14 77383000 77394100 chr14 90845950 90851200 chr5 64328550 64332750 chr6 32162600 32165500 chr4 1.41E+08 1.41E+08 chr22 29194300 29198800 chr14 75641450 75644400 chr14 55517100 55520550 chr20 57588200 57594350 chr2 8816800 8826200 chr5 1.24E+08 1.24E+08 chr6 1.39E+08 1.39E+08 chr11 1.19E+08 1.19E+08 chr20 42837950 42841400 chrX 24071400 24074150 chr20 62127500 62137250

chr14 75723500 75728350 chr11 65243600 65248450 chr17 48784000 48787250 chr14 70463050 70477400 chr12 1.21E+08 1.21E+08 chr12 1.21E+08 1.21E+08 chr14 77668650 77674400 chr17 206250 210600 chr20 34558300 34562750 chr14 70232800 70235950 chr22 23860450 23867050 chr6 1.14E+08 1.14E+08 chr17 79476950 79483300 chr16 88568700 88574100 chr17 77964150 77969600 chr11 17228100 17231900 chr22 44987900 44997500 chr17 46945100 46952800 chr2 42271800 42277100 chr3 1.27E+08 1.27E+08 chr3 1.48E+08 1.48E+08 chr20 17948000 17950850 chr11 17453500 17463600 chr19 39172550 39178550 chr12 13250500 13257250 chr7 91761950 91765700 chr9 97699200 97710600 chr17 72424750 72430950 chr9 3523900 3529500 chr1 2.45E+08 2.45E+08 chr7 41022800 41029550 chr21 32669550 32673100 chr2 70006150 70010750 chr19 33920900 33929650 chr13 1.14E+08 1.14E+08 chr2 2325700 2338550 chr11 65624200 65629650 chr1 2.41E+08 2.41E+08 chr20 18486750 18489700 chr4 1.53E+08 1.53E+08 chr9 97823800 97829800 chr14 1.01E+08 1.01E+08 chr6 1.23E+08 1.23E+08 chr10 89375350 89381600

26

chr10 74078050 74084050 chr5 59664200 59671100 chr6 26222700 26226100 chr2 69988550 69996200 chr4 1.41E+08 1.41E+08 chr13 35038650 35046250 chr4 77994700 77998900 chr1 59348350 59353350 chr3 71253500 71260900 chr15 40383700 40396450 chrX 39332750 39340200 chr17 230750 236800 chr2 65355700 65358650 chr2 85763350 85767900 chr2 2.18E+08 2.18E+08 chr20 20539000 20549750 chr20 47834800 47837650 chr19 54366950 54373600 chr6 43797600 43807450 chr17 7588100 7591750 chr9 2296600 2302250 chr17 7385700 7389000 chr11 20018400 20028000 chr11 61519750 61526950 chr4 1.04E+08 1.04E+08 chr2 2.39E+08 2.39E+08 chr17 197600 206200 chr13 1.14E+08 1.14E+08 chr13 1.14E+08 1.14E+08 chr4 83292450 83296650 chr20 22486450 22498550 chr5 31729400 31734550 chr12 212650 216600 chr20 34540100 34544100 chr20 30157300 30162650 chr7 1.08E+08 1.08E+08 chr6 30821800 30827200 chr16 81649600 81655350 chr1 30054900 30060950 chr13 50696850 50701400 chr17 3789850 3797950 chr5 1.38E+08 1.38E+08 chr8 1.31E+08 1.31E+08 chr8 17175300 17183000

chr6 41485000 41493000 chr13 34727500 34738850 chr8 59938100 59945550 chr9 1.15E+08 1.15E+08 chr14 23589800 23593700 chr2 28969850 28976650 chr19 10763550 10766850 chr20 57390050 57402150 chr11 1.18E+08 1.18E+08 chr1 1.69E+08 1.69E+08 chr10 1.06E+08 1.06E+08 chr19 49998450 50000750 chr13 91791400 91799200 chr20 31121450 31126450 chr7 1.51E+08 1.51E+08 chr3 48699350 48702400 chr17 43223950 43227350 chr20 1164750 1171150 chr20 49545850 49549150 chr2 21552700 21559100 chr21 34913000 34917000 chr6 33953450 33965100 chr12 54552500 54558850 chr20 38499850 38510950 chr7 86780550 86784450 chr4 41976550 41982250 chr16 14733200 14736900 chr2 43203300 43208900 chr1 27849700 27857400 chr16 20908750 20914050 chr7 1.07E+08 1.07E+08 chr14 68203800 68207250 chr11 46637100 46640150 chr16 85475500 85488050 chr11 33911400 33916650 chr8 95250850 95258100 chr7 1.39E+08 1.39E+08 chr12 31381000 31383750 chrX 48753400 48756600 chr1 1.1E+08 1.1E+08 chr7 95872550 95879250 chr21 40163200 40171500 chr6 24718950 24722900 chr10 70087250 70093500

27

chrX 24041700 24046000 chr17 78873200 78877000 chr9 93694800 93700800 chr1 1.85E+08 1.85E+08 chr15 66161050 66164000 chr9 34664700 34667050 chr11 1.23E+08 1.23E+08 chr1 2.04E+08 2.04E+08 chr1 1.6E+08 1.6E+08 chr17 25619600 25624000 chr21 43651750 43657850 chr17 72368150 72372200 chr2 2.28E+08 2.28E+08 chr12 1.25E+08 1.25E+08 chr13 45008250 45012100 chr12 53318500 53322700 chr15 93445700 93448850 chr1 40504200 40507750 chr1 2.02E+08 2.02E+08 chr20 17548600 17552500 chr7 1.41E+08 1.41E+08 chr1 41805750 41810700 chr17 17593750 17599050 chr19 13742250 13746700 chr19 46381700 46387250 chr2 1.7E+08 1.7E+08 chr2 46529950 46538350 chr5 51783550 51791350 chr2 1.49E+08 1.49E+08 chr8 1.02E+08 1.02E+08 chr20 23340900 23344350 chr6 1.23E+08 1.23E+08 chr17 13339550 13344100 chr17 71059950 71067750 chr1 33806300 33816700 chr14 69220700 69230850 chr7 1.51E+08 1.51E+08 chr14 21736350 21738950 chr6 43769850 43781900 chrX 49605200 49612800 chr2 2.19E+08 2.19E+08 chr19 14115750 14118650 chr1 1.56E+08 1.56E+08 chr2 19808900 19814600

chr8 1.25E+08 1.25E+08 chr1 10741100 10749200 chrX 48857350 48859900 chr6 19801550 19807250 chr5 1.78E+08 1.78E+08 chr22 42227050 42231250 chr3 1.57E+08 1.57E+08 chr17 43237550 43239350 chr21 43942750 43949150 chr19 58897100 58899400 chr11 61733800 61736650 chr22 29178150 29182200 chr5 1.4E+08 1.4E+08 chr4 71766900 71770650 chr20 523350 525250 chr20 20347000 20358250 chr10 33241600 33248950 chrX 16736550 16738800 chr1 27236000 27244050 chr11 1.17E+08 1.17E+08 chr11 43850850 43858850 chr17 66506400 66512150 chr19 49464400 49470200 chr16 2801000 2804100 chr12 6861200 6863700 chr1 1.54E+08 1.54E+08 chr7 1.01E+08 1.01E+08 chr17 39843750 39847750 chr15 41407250 41409850 chr20 19736550 19740200 chr8 22549200 22554200 chr2 70350350 70353650 chr9 1.36E+08 1.36E+08 chr3 19187500 19190850 chr5 1.38E+08 1.38E+08 chr1 52342600 52346000 chr12 62995400 62998700 chr3 1.7E+08 1.7E+08 chr7 73154800 73159050 chr2 1.57E+08 1.57E+08 chr20 21512700 21520100 chr11 60807950 60812350 chr19 18844750 18855950 chrX 47091400 47094300

28

chr12 1.06E+08 1.06E+08 chr2 2.2E+08 2.2E+08 chr17 34979700 34985350 chr11 1967450 1977400 chr19 56110150 56112700 chr19 55727550 55729700 chr6 31668100 31672050 chr6 30714500 30720500 chr17 41321100 41324700 chr21 39196300 39205100 chr20 57464150 57472050 chr4 76596900 76600300 chr1 1.55E+08 1.55E+08 chr1 94079000 94089550 chr20 20365350 20372850 chr1 8220500 8232800 chr5 66434250 66442000 chr5 1.79E+08 1.79E+08 chr15 23930700 23939600 chr6 1.55E+08 1.55E+08 chr17 2294700 2306200 chr12 6640200 6645650 chr2 2.02E+08 2.02E+08 chr17 7736900 7749200 chr12 72232400 72235500 chr1 21587100 21595900 chr1 1.56E+08 1.56E+08 chr20 5589950 5592750 chr10 1.02E+08 1.02E+08 chr7 1.11E+08 1.11E+08 chr1 27424300 27428500 chr1 21346800 21350100 chr17 72752900 72761800 chr11 65183750 65191100 chr16 3183650 3186050 chr16 71841300 71844100 chr8 81078550 81085400 chr20 1304800 1307450 chr20 19942200 19951200 chr1 35657350 35659750 chr12 90022900 90029850 chr22 18120200 18122750 chr19 42578600 42581250 chr10 93168450 93171400

chr15 93424700 93429250 chr12 49625600 49629350 chr1 2.35E+08 2.35E+08 chr19 59083250 59088150 chr6 43788950 43797100 chr12 1.25E+08 1.25E+08 chr11 16759100 16761550 chr11 10951650 10954750 chr11 1.17E+08 1.17E+08 chr8 29846000 29853100 chr7 50595350 50604700 chr3 50268700 50273100 chr1 2.1E+08 2.1E+08 chr6 1.44E+08 1.44E+08 chr17 62500750 62504300 chr14 68160400 68162850 chr9 2240500 2245000 chr2 28837550 28847550 chr9 33288950 33291950 chr12 1.26E+08 1.26E+08 chr20 62794300 62802150 chr1 59247850 59251700 chr16 4991750 4999350 chr12 57912700 57918950 chr11 1.26E+08 1.26E+08 chr20 3201550 3206350 chr20 22479550 22486150 chr20 5890700 5893800 chr16 9581250 9586900 chr16 758000 762150 chr6 30292450 30296150 chr19 45614500 45618800 chr16 2516500 2522500 chr9 1.32E+08 1.32E+08 chr3 48513200 48517000 chr6 39305050 39311500 chr7 1.3E+08 1.3E+08 chr3 1.94E+08 1.94E+08 chr6 1.59E+08 1.59E+08 chr2 26100100 26102850 chr2 2.42E+08 2.42E+08 chr6 27439150 27441700 chr2 11882300 11889650 chr17 2828150 2837150

29

chr7 1.3E+08 1.3E+08 chr2 21021150 21023800 chrX 47880000 47882200 chr1 33115350 33118050 chr15 66082500 66086100 chr19 36235500 36237350 chr7 1.59E+08 1.59E+08 chr6 70504700 70507750 chr19 46008900 46013900 chr12 57538850 57544000 chrX 37705000 37708250 chr6 27803750 27807400 chr4 83820250 83823500 chr3 1.6E+08 1.6E+08 chr11 92680150 92683000 chr1 3163200 3170100 chr15 24039050 24046300 chr7 74069950 74073600 chr17 2495750 2498950 chr19 18866400 18870300 chr2 1.13E+08 1.13E+08 chr2 47570900 47573750 chr5 1.34E+08 1.34E+08 chr1 2.36E+08 2.36E+08 chr5 95193650 95203350 chr13 28483100 28499500 chr7 92391050 92400400 chr1 2.29E+08 2.29E+08 chr12 16034150 16036850 chr3 50481550 50489800 chr1 45271900 45276450 chr4 69212300 69216800 chr17 47790650 47795850 chr14 77498000 77502350 chr1 1.54E+08 1.54E+08 chr17 57440100 57449000 chr4 13702650 13709450 chr4 90214200 90230050 chr11 1.21E+08 1.21E+08 chr6 2987900 2992200 chr14 1.02E+08 1.02E+08 chr12 98986350 98988800 chr19 50431350 50433800 chr19 41768550 41772200

chr2 1.45E+08 1.45E+08 chr5 1.34E+08 1.34E+08 chr6 70489650 70492600 chr11 1.11E+08 1.11E+08 chr6 3226600 3233000 chr16 52590250 52600800 chr11 1.3E+08 1.3E+08 chr3 47420800 47423750 chr14 91929800 91934950 chr1 2.45E+08 2.45E+08 chr5 1.71E+08 1.71E+08 chr19 55848150 55853150 chr7 73235350 73239800 chr7 91669700 91673950 chr1 1.8E+08 1.8E+08 chr7 1.27E+08 1.27E+08 chr13 27824050 27827100 chr19 35738100 35741050 chr2 1.36E+08 1.37E+08 chr2 2466500 2469850 chr5 1.02E+08 1.02E+08 chr9 1.11E+08 1.11E+08 chr16 57637650 57646600 chr17 27275750 27280400 chr2 2614800 2618050 chr14 60309600 60314800 chr16 11889250 11892750 chr13 1.15E+08 1.15E+08 chr17 7475000 7477550 chr2 55842950 55846200 chrX 48455400 48457450 chrX 49002000 49006150 chr3 49043300 49046150 chr17 41444150 41447450 chr5 32172600 32175900 chr17 73552150 73555950 chr3 1.42E+08 1.42E+08 chr5 1.49E+08 1.49E+08 chr20 61150550 61158500 chr13 77403750 77409850 chr1 52519850 52523700 chr13 31734450 31737900 chr20 32412200 32422100 chr7 1.27E+08 1.27E+08

30

chr20 44561750 44564800 chr15 89109700 89119300 chr11 12109500 12114750 chrX 39306350 39315000 chr17 8053500 8061100 chr19 50706000 50710400 chr2 30368200 30371400 chr4 83349650 83353050 chr1 19810250 19813900 chr1 1.92E+08 1.92E+08 chr5 95765500 95771700 chr17 49195500 49200300 chr17 55737900 55742800 chr12 1.07E+08 1.07E+08 chr11 61593800 61600100 chr4 37430650 37436300 chr11 62647450 62650600 chr2 2.4E+08 2.4E+08 chr20 43149500 43151950 chr7 1.14E+08 1.14E+08 chr5 1.43E+08 1.43E+08 chr19 57900050 57902750 chr11 1.08E+08 1.08E+08 chr4 87278600 87282450 chr17 7956850 7966650 chr16 75466450 75469200 chr4 1.84E+08 1.84E+08 chr3 42065000 42068950 chr5 43311150 43317100 chr20 6681450 6687450 chr12 2189900 2196850 chr14 23788950 23792400 chr11 2227000 2236250 chr17 1617100 1621950 chr6 31937950 31941400 chr17 79789450 79792450 chr15 69108050 69114000 chr20 36660950 36663300 chr17 17738650 17744900 chr15 72764850 72768700 chr20 22467700 22476850 chr20 22390550 22397800 chr8 36866950 36880600 chr18 74192250 74209050

chr6 1.5E+08 1.51E+08 chr1 1.75E+08 1.75E+08 chr19 39896300 39905150 chr14 89813800 89820400 chr1 17229600 17232750 chr2 28112400 28115150 chr6 1.01E+08 1.01E+08 chr1 1.15E+08 1.15E+08 chr9 86593600 86597150 chr1 1.87E+08 1.87E+08 chr19 39880250 39883000 chr2 1.75E+08 1.75E+08 chr22 38900350 38904150 chr8 26305400 26308550 chr4 99489850 99497300 chr4 1.85E+08 1.85E+08 chr16 70321200 70324750 chr12 38515250 38520150 chr19 49374750 49380650 chr1 2.22E+08 2.22E+08 chr11 45917200 45923200 chr20 50382700 50385300 chr3 1.71E+08 1.71E+08 chr4 1.29E+08 1.29E+08 chr20 32148450 32152650 chr1 2.23E+08 2.23E+08 chr8 60553000 60559000 chr20 35232550 35235250 chr7 1.13E+08 1.13E+08 chr11 61558600 61561450 chr17 27052050 27056450 chr5 95293000 95299150 chr3 1.97E+08 1.97E+08 chr6 1.36E+08 1.36E+08 chr1 16159700 16163700 chrX 40032200 40037050 chr10 80731050 80735700 chr4 48832650 48834600 chr14 1.01E+08 1.01E+08 chr21 43978500 43984300 chr20 39314850 39319650 chr11 17433500 17439200 chr3 1.93E+08 1.93E+08 chr22 41839850 41846200

31

chr11 95521750 95525450 chr2 2.2E+08 2.2E+08 chr1 1.54E+08 1.54E+08 chr3 50245400 50251000 chr9 1.36E+08 1.36E+08 chr6 1.37E+08 1.37E+08 chr5 1.76E+08 1.76E+08 chr6 82458300 82465750 chr20 47598750 47601600 chr20 32140150 32145700 chr5 16878100 16883350 chr2 20248400 20253500 chr6 42708900 42715950 chr1 51699850 51704550 chr1 1.65E+08 1.65E+08 chr11 1.28E+08 1.28E+08 chr2 2.08E+08 2.08E+08 chr2 1.02E+08 1.02E+08 chr2 2.17E+08 2.17E+08 chr6 37068450 37075300 chr18 77606550 77611100 chr17 33306500 33309950 chr2 67262650 67270600 chr7 1.02E+08 1.02E+08 chr9 79070250 79076700 chr19 11198400 11204750 chr7 1.55E+08 1.55E+08 chr10 74031400 74036850 chr1 2.35E+08 2.35E+08 chr14 96556400 96564900 chr1 22509850 22514000

chr1 42799550 42809000 chr3 1.77E+08 1.77E+08 chr12 6720350 6724600 chr6 31619000 31621800 chr17 7144150 7147400 chr5 1.09E+08 1.09E+08 chrX 48431650 48434500 chr16 19077950 19080450 chr10 64664200 64669850 chr4 1.29E+08 1.29E+08 chr8 22221500 22226250 chr22 41486500 41489500 chr14 64969100 64972200 chr5 1.32E+08 1.32E+08 chr12 53296600 53299900 chr20 36154900 36157550 chr17 53191600 53200150 chr20 3183350 3185750 chr13 74860950 74866250 chr18 8498250 8502700 chr3 39218300 39223550 chr5 74630800 74636350 chr6 32143150 32147300 chr8 61819900 61827550 chr11 71821700 71825050 chr12 92529200 92541800 chrX 15691950 15694700 chr16 1988500 1993950 chr10 97888000 97891400 chr19 58608600 58610850 chr1 2.13E+08 2.13E+08

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• Table S3. List of genes that are significantly affected by shRNA targeting INS promoter in EndoC-βH1 cells.

1 VWA1 chr1 1372702 1372864 * 2 MANEAL chr1 38265516 38267278 3 PTPRF chr1 44087606 44089343 4 ALG6 chr1 63902494 63904233 5 FAM73A chr1 78340531 78345225 6 DNAJB4 chr1 78481698 78482995 7 ABCD3 chr1 94982608 94984219 8 HIST2H2A chr1 1.50E+08 1.50E+08 * 9 KIAA1614 chr1 1.81E+08 1.81E+08

10 TIMM17A chr1 2.02E+08 2.02E+08 11 SNRPE chr1 2.04E+08 2.04E+08 12 LYPLAL1 chr1 2.19E+08 2.19E+08 13 BROX chr1 2.23E+08 2.23E+08 14 SRP9 chr1 2.26E+08 2.26E+08 15 GUK1 chr1 2.28E+08 2.28E+08 16 SDF4 chr1 1167272 1167447 * 17 DVL1 chr1 1284276 1284492 * 18 GPR15 chr1 6320885 6321035 19 MYOM3 chr1 24438521 24438665 20 STMN1 chr1 26232880 26232993 21 SDC3 chr1 31381296 31381480 22 PABPC4 chr1 40041431 40042521 23 PIGK chr1 77684995 77685132 24 CTBS chr1 85039922 85040163 25 15-Sep chr1 87379711 87380107 26 GSTM3 chr1 1.10E+08 1.10E+08 27 BCAS2 chr1 1.15E+08 1.15E+08 28 TSPAN2 chr1 1.16E+08 1.16E+08 29 FAM189B chr1 1.55E+08 1.55E+08 30 TAGLN2 chr1 1.60E+08 1.60E+08 31 DENND1B chr1 1.98E+08 1.98E+08 32 ZNF22 chr10 45498728 45500777 33 CISD1 chr10 60047321 60049019 34 PTEN chr10 89725044 89728532 35 GSTO1 chr10 1.06E+08 1.06E+08 36 IDI1 chr10 1094804 1095061 37 NEBL chr10 21462694 21463116 38 MMS19 chr10 99258453 99258551 39 SLC39A13 chr11 47436839 47438051 * 40 C11orf84 chr11 63594400 63595190 * 41 VEGFB chr11 64005828 64006736 *

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42 FAM89B chr11 65340873 65341669 43 SPCS2 chr11 74687902 74690076 44 EI24 chr11 1.25E+08 1.25E+08 45 KCNJ5 chr11 1.29E+08 1.29E+08 46 RNH1 chr11 507113 507283 47 H19 chr11 2017989 2018061 * 48 ASCL2 chr11 2290963 2292182 * 49 MTRNR2L chr11 10529434 10530723 50 LIN7C chr11 27528263 27528326 51 PRPF19 chr11 60673836 60674061 52 NDUFC2 chr11 77790625 77791265 53 H2AFX chr11 1.19E+08 1.19E+08 * 54 PVRL1 chr11 1.20E+08 1.20E+08 55 H2AFJ chr12 14927270 14930936 56 IAPP chr12 21531171 21532914 57 ETNK1 chr12 22837816 22843608 58 MED21 chr12 27181218 27183606 59 CAND1 chr12 67706386 67708388 60 SLC25A3 chr12 98995146 98995778 61 FAM222A chr12 1.10E+08 1.10E+08 62 SDSL chr12 1.14E+08 1.14E+08 * 63 TMTC1 chr12 29936383 29936743 64 ZCRB1 chr12 42719726 42719932 65 MSI1 chr12 1.21E+08 1.21E+08 * 66 TRIAP1 chr12 1.21E+08 1.21E+08 * 67 NCOR2 chr12 1.25E+08 1.25E+08 68 SAP18 chr13 21721325 21723224 69 PAN3 chr13 28866519 28869475 70 POMP chr13 29252172 29253093 71 DNAJC15 chr13 43681314 43683306 72 TM9SF2 chr13 1.00E+08 1.00E+08 73 LAMP1 chr13 1.14E+08 1.14E+08 74 COMMD6 chr13 76111900 76112008 75 TEX30 chr13 1.03E+08 1.03E+08 76 LRP10 chr13 23346149 23347291 77 CGRRF1 chr14 55004781 55005334 78 LINC00643 chr14 62594741 62600903 79 CHGA chr14 93401146 93401638 80 DLK1 chr14 1.01E+08 1.01E+08 * 81 EIF5 chr14 1.04E+08 1.04E+08 * 82 RPPH1 chr14 20811230 20811570 83 CNIH1 chr14 54907965 54908148

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84 GMFB chr14 54955643 54955744 85 KLF13 chr15 31664213 31670102 86 BAHD1 chr15 40758140 40760441 87 RAB11A chr15 66180039 66184329 88 ARID3B chr15 74887952 74890472 89 RCN2 chr15 77241411 77242601 * 90 MESDC1 chr15 81293295 81296345 91 FURIN chr15 91424516 91426688 92 SRP14 chr15 40331294 40331389 93 GTF2A2 chr15 59949605 59949737 94 COX5A chr15 75230256 75230495 95 IDH2 chr15 90645508 90645786 96 ADAMTS1 chr15 1.01E+08 1.01E+08 97 CAPN15 chr16 603339 604636 * 98 GLIS2 chr16 4386726 4389598 99 SRCAP chr16 30748370 30751450 *

100 ITGAX chr16 31393124 31394318 * 101 IST1 chr16 71961517 71964540 102 GABARAPL chr16 75611177 75611779 103 HSBP1 chr16 83845026 83846607 104 KLHL36 chr16 84695184 84695916 105 SSTR5-AS1 chr16 1128458 1128731 * 106 HAGH chr16 1876713 1877195 * 107 CDIPT chr16 29874136 29874609 * 108 ST3GAL2 chr16 70472852 70472991 109 GCSH chr16 81129736 81129980 110 ARRB2 chr17 4624241 4624795 111 TVP23B chr17 18708854 18710026 * 112 MTRNR2L chr17 22022437 22023991 113 GRN chr17 42430029 42430470 114 NFE2L1 chr17 46135657 46138907 115 AMZ2 chr17 66252955 66253305 116 UNK chr17 73789524 73790279 117 CBX2 chr17 77757531 77761449 118 MAFG-AS1 chr17 79887352 79888629 119 DERL2 chr17 5389389 5389494 120 LOC72 chr17 5403351 5404319 121 SREBF1 chr17 17740041 17740325 * 122 JUP chr17 39942840 39942964 123 FASN chr17 80055997 80056106 124 USP14 chr18 211133 213739 125 NDUFV2 chr18 9134184 9134343

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126 SNRPD1 chr18 19209023 19210206 127 ELAC1 chr18 48512989 48514490 128 IER3IP1 chr18 44702558 44702745 129 GPX4 chr19 1106539 1106788 130 CLEC4GP1 chr19 7854646 7855898 131 ZNF791 chr19 12738535 12740676 132 PIK3R2 chr19 18279897 18281343 133 SIPA1L3 chr19 38696737 38699012 134 ZNF526 chr19 42728539 42732353 135 SNAR-C3 chr19 48453553 48453671 * 136 C19orf68 chr19 48697910 48700877 * 137 ZNF880 chr19 52887102 52889046 138 TMEM259 chr19 1020771 1021141 * 139 MKNK2 chr19 2051095 2051243 * 140 TMIGD2 chr19 4302337 4302428 * 141 MLLT1 chr19 6279784 6279959 142 ELAVL3 chr19 11591415 11591803 143 PRDX2 chr19 12912554 12912724 144 LPHN1 chr19 14316797 14316997 145 CEBPA chr19 33790840 33793470 146 ZFP82 chr19 36909394 36909550 147 CAPN12 chr19 39234569 39235114 148 DEDD2 chr19 42721784 42721944 149 OPA3 chr19 46087881 46088122 150 GP6 chr19 55549571 55549632 151 PPP1CB chr2 29022065 29025806 152 HAT1 chr2 1.73E+08 1.73E+08 153 BZW1 chr2 2.02E+08 2.02E+08 154 DNAJB2 chr2 2.20E+08 2.20E+08 155 CALM2 chr2 47403580 47403740 156 MOGS chr2 74692441 74692537 157 TXNDC9 chr2 99952702 99952860 158 HS6ST1 chr2 1.29E+08 1.29E+08 159 MMADHC chr2 1.50E+08 1.50E+08 160 ATP5G3 chr2 1.76E+08 1.76E+08 161 CNPPD1 chr2 2.20E+08 2.20E+08 162 PDE6D chr2 2.33E+08 2.33E+08 163 SRSF6 chr20 42089343 42092244 164 PFDN4 chr20 52835558 52836492 165 SLC2A4RG chr20 62374232 62375403 166 CENPB chr20 3764498 3767337 167 NOL4L chr20 31071165 31071385 *

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168 SOGA1 chr20 35487977 35488276 * 169 CDH22 chr20 44936894 44937137 170 EEF1A2 chr20 62130411 62130668 171 SMIM11 chr21 35760927 35761452 172 CCDC117 chr22 29182077 29185289 173 SH3BP1 chr22 38051279 38052050 174 GTPBP1 chr22 39126617 39129592 175 HIRA chr22 19418963 19419219 176 C22orf42 chr22 32554971 32555243 177 TMEM184 chr22 38668890 38669040 178 CBX6 chr22 39268127 39268258 179 CYB5R3 chr22 43045301 43045405 180 PLXNB2 chr22 50745982 50746001 181 PCNP chr3 1.01E+08 1.01E+08 182 HIGD1A chr3 42845928 42846027 183 ARF4 chr3 57582801 57583215 184 SNX4 chr3 1.25E+08 1.25E+08 * 185 ANAPC13 chr3 1.34E+08 1.34E+08 186 FGFR3 chr4 1808843 1810599 * 187 COPS4 chr4 83996450 83996971 188 MRPS18C chr4 84382274 84382929 189 ELMOD2 chr4 1.41E+08 1.41E+08 190 TMEM129 chr4 1722360 1723084 * 191 CLOCK chr4 56412949 56413076 192 EIF4E chr4 99850046 99850243 193 MAD2L1 chr4 1.21E+08 1.21E+08 194 SUB1 chr5 32601111 32604185 195 MRPS36 chr5 68525035 68525985 196 PTCD2 chr5 71654030 71655180 197 AP3S1 chr5 1.15E+08 1.15E+08 198 NDFIP1 chr5 1.42E+08 1.42E+08 199 NEURL1B chr5 1.72E+08 1.72E+08 200 UNC5A chr5 1.76E+08 1.76E+08 * 201 SLC12A7 chr5 1111983 1112172 202 LOC64671 chr5 36871463 36876796 203 MOCS2 chr5 52405542 52405602 204 ARL15 chr5 53606262 53606403 205 ZCCHC10 chr5 1.32E+08 1.32E+08 206 C5orf15 chr5 1.33E+08 1.33E+08 207 SKP1 chr5 1.34E+08 1.34E+08 208 HLA-A chr6 29913228 29913661 * 209 PPARD chr6 35392106 35393173 *

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210 ZFAND3 chr6 38120011 38122399 211 EFHC1 chr6 52357068 52360583 212 PPP1R18 chr6 30654891 30655093 * 213 TEAD3 chr6 35464675 35464861 * 214 CCND3 chr6 41909190 41909586 215 ME1 chr6 84140596 84140938 216 NDUFAF4 chr6 97345542 97345767 217 NPY chr7 24331282 24331484 218 SLC12A9 chr7 1.00E+08 1.00E+08 * 219 TRIM56 chr7 1.01E+08 1.01E+08 * 220 CAPZA2 chr7 1.17E+08 1.17E+08 221 C7orf73 chr7 1.35E+08 1.35E+08 222 ATP6V0E2 chr7 1.50E+08 1.50E+08 223 CHPF2 chr7 1.51E+08 1.51E+08 224 CYCS chr7 25164819 25164980 225 LSM5 chr7 32529932 32530023 226 PSMA2 chr7 42971717 42971805 227 TMEM60 chr7 77427571 77427747 228 BET1 chr7 93633510 93633690 229 PDK4 chr7 95225476 95225925 230 VGF chr7 1.01E+08 1.01E+08 * 231 NDUFA5 chr7 1.23E+08 1.23E+08 232 KCNH2 chr7 1.51E+08 1.51E+08 233 UBE2V2 chr8 48973242 48974454 234 PLEKHF2 chr8 96166259 96168913 235 MRPS28 chr8 80942271 80942506 236 ZNF706 chr8 1.02E+08 1.02E+08 237 MRPL13 chr8 1.21E+08 1.21E+08 238 CHMP5 chr9 33280807 33282067 239 TESK1 chr9 35608859 35610038 240 NIPSNAP3 chr9 1.08E+08 1.08E+08 241 RXRA chr9 1.37E+08 1.37E+08 * 242 NELFB chr9 1.40E+08 1.40E+08 * 243 TMEM261 chr9 7799461 7799799 244 NDUFB6 chr9 32572879 32573182 245 RMRP chr9 35657748 35658015 246 CDC26 chr9 1.16E+08 1.16E+08 247 SAPCD2 chr9 1.40E+08 1.40E+08 * 248 EFNB1 chrX 68060085 68062006 249 PRPS1 chrX 1.07E+08 1.07E+08 250 ATG4A chrX 1.07E+08 1.07E+08 251 HPRT1 chrX 1.34E+08 1.34E+08

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252 DUSP9 chrX 1.53E+08 1.53E+08 253 PLXNA3 chrX 1.54E+08 1.54E+08 254 SH3KBP1 chrX 19817752 19817917 255 DYNLT3 chrX 37706734 37706889 256 C1GALT1C chrX 1.20E+08 1.20E+08 257 MOSPD1 chrX 1.34E+08 1.34E+08 258 IRAK1 chrX 1.53E+08 1.53E+08 259 EIF1AY chrX 22754227 22755040

The genes located within 4C-contact regions (Table S1A) are marked by asterisks (*).

39

Table S4. 60 Random Loci Retrieved from the Islet Regulome Browser (4). ADGRF1 * DCD * KRTAP5-2 SNORD152 ADIPOR2 DGCR6L LINC01342 SNORD16 ADRA1D DOCK4-AS1 * MAPK12 SPATA25 AMPD2 * EXOSC9 MIER3 SPINK4 ATRNL1 FAM133B MTMR4 TAS2R4 CCDC37-AS1 FGGY * NDC80 * TOLLIP-AS1 CCDC59 GABRG1 NDUFB8 TRAJ52 CELA2B GDAP2 NOC3L * TRL-TAA4-1 CFAP126 GPD1L * NUCB1-AS1 * TRM-CAT3-1 CLDN18 HPS6 PADI2 * TRN-GTT2-1 CREB5 * IGSF21 * PLPP1 USF2 * CRYM INTS10 SCARNA4 * VIPR2 CST7 IQCK SDC1 * WARS2-IT1 CYP11B1 ITGB1BP1 * SDR42E2 ZNF107 DBI * KRTAP22-1 SLC16A3 * ZNF460 The genes located within 100kb of an enhancer cluster are marked by asterisks (*).

40

• Table S5. Sequences of the oligonucleotides used in this study. 4C-seq barcode primers: BglII primer AATGATACGGCGACCACCGAACACTCTTTCCCTACACGACGCTCTTCCGATCT ATCACG GCTGACGACCAAGGAGATCT

AATGATACGGCGACCACCGAACACTCTTTCCCTACACGACGCTCTTCCGATCT CGATGTGCTGACGACCAAGGAGATCT

AATGATACGGCGACCACCGAACACTCTTTCCCTACACGACGCTCTTCCGATCT TTAGGCGCTGACGACCAAGGAGATCT

AATGATACGGCGACCACCGAACACTCTTTCCCTACACGACGCTCTTCCGATCT TGACCAGCTGACGACCAAGGAGATCT

AATGATACGGCGACCACCGAACACTCTTTCCCTACACGACGCTCTTCCGATCT ACAGTGGCTGACGACCAAGGAGATCT

AATGATACGGCGACCACCGAACACTCTTTCCCTACACGACGCTCTTCCGATCT GCCAATGCTGACGACCAAGGAGATCT

NlaIII primer CAAGCAGAAGACGGCATACGATGTCCCCAGTCCCGGATG

3C-PCR primer:

INS locus CCCTGGTTAAGACTCTAATG Site 1 - 1.48 Mb TCTGTCTCCCACTGCCC Site 2 – 1.712 Mb TCCCCGGACACTGCTCA Site 3 – 1.715 Mb GTATCAGAGTGTTCCAGGC Site 4 – 1.77 Mb AGCCCCAGGATACACGA Site 5 – 2.02 Mb CATGACACTGAAGCCCTC Site 6 – 2.16 Mb TGCGCTCGCTCCTGCT Site 7 – 2.22 Mb CATCTAGGGAAGGACAGTG

41

Site 8 – 2.29 Mb ACAGGAAGTTCTGGGGTG Site 9 – 2.43 Mb CTGCTGCACCCCCATGA Site 10 – 2.44 Mb TCAGGACTATCTGGATGAGC

Tet-pLKO-puro sequencing primer: GGCAGGGATATTCACCATTATCGTTTCAGA

INS promotor shRNA target sequence: AGGGAAATGGTCCGGAAATTG

INS promotor shRNA cloning primer:

shRNA-1-tet-f CCGG AGGGAAATGGTCCGGAAATTG CTCGAG CAATTTCCGGACCATTTCCCT TTTTTG

shRNA-1-tet-r AATTCAAAAA AGGGAAATGGTCCGGAAATTG CTCGAG CAATTTCCGGACCATTTCCCT

SSTR5-AS1 shRNA target sequence: GAACCAAACTCAGGAAACAGC

SSTR5-AS1 shRNA cloning primers: shRNA672-f CCGG GAACCAAACTCAGGAAACAGC CTCGAG GCTGTTTCCTGAGTTTGGTTC TTTTT

shRNA672-r AATT AAAAA GAACCAAACTCAGGAAACAGC CTCGAG GCTGTTTCCTGAGTTTGGTTC

qRT-PCR primers: GAPDH TGCACCACCAACTGCTTAGC GGCATGGACTGTGGTCATGAG

NELFB CGTGCCACAAGTTCACCTG TTGATGGCGAAGGGGTCAC

MSI1

42

ACTCAGTTGGCAGACTACGC AGTCACCATCTTGGGCTGTG

TRIM56 GGTCTGACCCAACAAGTAGCA AAACCATGCTGAATGGCCAGG

H19 GAACCAGACCTCATCAGCCC ACAGAGTCGTGGAGGCTTTG

VGF CGCTGACCCGAGTGAATCTG CATACGCGCCTGGAATTGA

SSTR5-AS1 CCCTTTGGAGGAAGGACGTG TCCTTTTGGACCACGCTGAT

SRCAP AACTGGCGCTATCTCATTCTGG CTGTTCTGCAAGGGAGTTCCT

INS GCAGCCTTTGTGAACCAACAC CCCCGCACACTAGGTAGAGA

MKNK2 CCAGCCGAACTTCAGGGTTT CGTCCGGGATGTCAATGGG

GPX4 GCCATCAAGTGGAACTTCACC CTTCTCTATCACCAGGGGCTC

SDF4 GAGGAGCTGGAGAGCTACAT ACTCGCTGTACTTGAGCACC

VEGFB GAGATGTCCCTGGAAGAACACA

43

GAGTGGGATGGGTGATGTCAG

SNX4 AGCAGAAAAACGAACTGGAAGA CTCTGACCATCGGTATGTTCAAC

ABCC8 GCTGTCTTCTGGAGCAGCCTT GCTGTCTTCTGGAGCAGCCTT

RCN2 CAGGTGGGATCCAACTGCAA ACAGCTCTTGGGGATCAAGC

TRIAP1 GTGCTTCAATCGCTGGTTCG TTGCTTTCTGAACACACTGCTG

EIF5 GCTCCGTATCCAGCAGTGAG CATTCGACGCCTTTGAGCTT

DLK1 AGGGTCCCCTTTGTGACCA GCAGGCCCGAACATCTCTATC

TVP23B CGCCATGTTGCAGCAGGATA CACTGCCCAAAAGTCACACG

SLC39A13 TCAGCGGCTACCTCAACCT AGGAGCCCGATCTTCTTGCT

CDIPT GCCCAACCTCATCGGTTATG AGCAGCGTGTCCATCGAAAG

SSTR5 TGTTTGCGGGATGTTGGCT CTGTTGGCGTAGGAGAGGA

44

References 1. Kent WJ, et al. (2002) The human genome browser at UCSC. Genome Res

12(6):996-1006. 2. Casper J, et al. (2018) The UCSC Genome Browser database: 2018 update.

Nucleic Acids Res 46(D1):D762-D769. 3. Rosenbloom KR, et al. (2013) ENCODE data in the UCSC Genome Browser:

year 5 update. Nucleic Acids Res 41(Database issue):D56-63. 4. Mularoni L, Ramos-Rodriguez M, & Pasquali L (2017) The Pancreatic Islet

Regulome Browser. Front Genet 8:13. 5. Zhang T, et al. (2016) FoxO1 Plays an Important Role in Regulating beta-Cell

Compensation for Insulin Resistance in Male Mice. Endocrinology 157(3):1055-1070.

6. Villafuerte BC, et al. (2017) Over-expression of insulin-response element binding protein-1 (IRE-BP1) in mouse pancreatic islets increases expression of RACK1 and TCTP: Beta cell markers of high glucose sensitivity. Biochim Biophys Acta 1865(2):186-194.