Current Diabetes Reports

, 15:66 | Cite as

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

  • Michael L. Stitzel
  • Ina Kycia
  • Romy Kursawe
  • Duygu Ucar
Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Abstract

Islets of Langerhans contain multiple hormone-producing endocrine cells controlling glucose homeostasis. Transcription establishes and maintains islet cellular fates and identities. Genetic and environmental disruption of islet transcription triggers cellular dysfunction and disease. Early transcriptional regulation studies of specific islet genes, including insulin (INS) and the transcription factor PDX1, identified the first cis-regulatory DNA sequences and trans-acting factors governing islet function. Here, we review how human islet “omics” studies are reshaping our understanding of transcriptional regulation in islet (dys)function and diabetes. First, we highlight the expansion of islet transcript number, form, and function and of DNA transcriptional regulatory elements controlling their production. Next, we cover islet transcriptional effects of genetic and environmental perturbation. Finally, we discuss how these studies’ emerging insights should empower our diabetes research community to build mechanistic understanding of diabetes pathophysiology and to equip clinicians with tailored, precision medicine options to prevent and treat islet dysfunction and diabetes.

Keywords

Genome-wide association study (GWAS) Promoter Broad H3K4me3 domain (BD) Enhancer Stretch/super enhancer (SE) Chromatin interaction analysis by paired end tag sequencing (ChIA-PET) Chromatin immunoprecipitation (ChIP)-seq RNA-seq Islet Type 1/2 diabetes (T1D/T2D) Chromatin Expression quantitative trait locus (eQTL) Splicing quantitative trait locus (sQTL) Allele-specific expression (ASE) Allele-specific expression quantitative trait locus (aseQTL) Single nucleotide polymorphism (SNP) Inflammation Oxidative stress Endoplasmic reticulum (ER) stress 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem Off J Histochem Soc. 2005;53(9):1087–97.CrossRefGoogle Scholar
  2. 2.
    Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren P-O, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A. 2006;103(7):2334–9.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, et al. Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia. 2012;55(3):707–18.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Rosengren AH, Braun M, Mahdi T, Andersson SA, Travers ME, Shigeto M, et al. Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes. Diabetes. 2012;61(7):1726–33.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Dimas AS, Lagou V, Barker A, Knowles JW, Mägi R, Hivert M-F, et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes. 2014;63(6):2158–71.Google Scholar
  6. 6.••
    DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in multi-Ethnic Samples (T2D-GENES) Consortium, A. Mahajan, M. J. Go, W. Zhang, J. E. Below, K. J. Gaulton, T. Ferreira, M. Horikoshi, A. D. Johnson, M. C. Y. Ng, I. Prokopenko, D. Saleheen, X. Wang, E. Zeggini, G. R. Abecasis, L. S. Adair, P. Almgren, M. Atalay, T. Aung, D. Baldassarre, B. Balkau, Y. Bao, A. H. Barnett, I. Barroso, A. Basit, L. F. Been, J. Beilby, G. I. Bell, R. Benediktsson, R. N. Bergman, B. O. Boehm, E. Boerwinkle, L. L. Bonnycastle, N. Burtt, Q. Cai, H. Campbell, J. Carey, S. Cauchi, M. Caulfield, J. C. N. Chan, L.-C. Chang, T.-J. Chang, Y.-C. Chang, G. Charpentier, C.-H. Chen, H. Chen, Y.-T. Chen, K.-S. Chia, M. Chidambaram, P. S. Chines, N. H. Cho, Y. M. Cho, L.-M. Chuang, F. S. Collins, M. C. Cornelis, D. J. Couper, A. T. Crenshaw, R. M. van Dam, J. Danesh, D. Das, U. de Faire, G. Dedoussis, P. Deloukas, A. S. Dimas, C. Dina, A. S. Doney, P. J. Donnelly, M. Dorkhan, C. van Duijn, J. Dupuis, S. Edkins, P. Elliott, V. Emilsson, R. Erbel, J. G. Eriksson, J. Escobedo, T. Esko, E. Eury, J. C. Florez, P. Fontanillas, N. G. Forouhi, T. Forsen, C. Fox, R. M. Fraser, T. M. Frayling, P. Froguel, P. Frossard, Y. Gao, K. Gertow, C. Gieger, B. Gigante, H. Grallert, G. B. Grant, L. C. Grrop, C. J. Groves, E. Grundberg, C. Guiducci, A. Hamsten, B.-G. Han, K. Hara, N. Hassanali, A. T. Hattersley, C. Hayward, A. K. Hedman, C. Herder, A. Hofman, O. L. Holmen, K. Hovingh, A. B. Hreidarsson, C. Hu, F. B. Hu, J. Hui, S. E. Humphries, S. E. Hunt, D. J. Hunter, K. Hveem, Z. I. Hydrie, H. Ikegami, T. Illig, E. Ingelsson, M. Islam, B. Isomaa, A. U. Jackson, T. Jafar, A. James, W. Jia, K.-H. Jöckel, A. Jonsson, J. B. M. Jowett, T. Kadowaki, H. M. Kang, S. Kanoni, W. H. L. Kao, S. Kathiresan, N. Kato, P. Katulanda, K. M. Keinanen-Kiukaanniemi, A. M. Kelly, H. Khan, K.-T. Khaw, C.-C. Khor, H.-L. Kim, S. Kim, Y. J. Kim, L. Kinnunen, N. Klopp, A. Kong, E. Korpi-Hyövälti, S. Kowlessur, P. Kraft, J. Kravic, M. M. Kristensen, S. Krithika, A. Kumar, J. Kumate, J. Kuusisto, S. H. Kwak, M. Laakso, V. Lagou, T. A. Lakka, C. Langenberg, C. Langford, R. Lawrence, K. Leander, J.-M. Lee, N. R. Lee, M. Li, X. Li, Y. Li, J. Liang, S. Liju, W.-Y. Lim, L. Lind, C. M. Lindgren, E. Lindholm, C.-T. Liu, J. J. Liu, S. Lobbens, J. Long, R. J. F. Loos, W. Lu, J. Luan, V. Lyssenko, R. C. W. Ma, S. Maeda, R. Mägi, S. Männisto, D. R. Matthews, J. B. Meigs, O. Melander, A. Metspalu, J. Meyer, G. Mirza, E. Mihailov, S. Moebus, V. Mohan, K. L. Mohlke, A. D. Morris, T. W. Mühleisen, M. Müller-Nurasyid, B. Musk, J. Nakamura, E. Nakashima, P. Navarro, P.-K. Ng, A. C. Nica, P. M. Nilsson, I. Njølstad, M. M. Nöthen, K. Ohnaka, T. H. Ong, K. R. Owen, C. N. A. Palmer, J. S. Pankow, K. S. Park, M. Parkin, S. Pechlivanis, N. L. Pedersen, L. Peltonen, J. R. B. Perry, A. Peters, J. M. Pinidiyapathirage, C. G. Platou, S. Potter, J. F. Price, L. Qi, V. Radha, L. Rallidis, A. Rasheed, W. Rathman, R. Rauramaa, S. Raychaudhuri, N. W. Rayner, S. D. Rees, E. Rehnberg, S. Ripatti, N. Robertson, M. Roden, E. J. Rossin, I. Rudan, D. Rybin, T. E. Saaristo, V. Salomaa, J. Saltevo, M. Samuel, D. K. Sanghera, J. Saramies, J. Scott, L. J. Scott, R. A. Scott, A. V. Segrè, J. Sehmi, B. Sennblad, N. Shah, S. Shah, A. S. Shera, X. O. Shu, A. R. Shuldiner, G. Sigurđsson, E. Sijbrands, A. Silveira, X. Sim, S. Sivapalaratnam, K. S. Small, W. Y. So, A. Stančáková, K. Stefansson, G. Steinbach, V. Steinthorsdottir, K. Stirrups, R. J. Strawbridge, H. M. Stringham, Q. Sun, C. Suo, A.-C. Syvänen, R. Takayanagi, F. Takeuchi, W. T. Tay, T. M. Teslovich, B. Thorand, G. Thorleifsson, U. Thorsteinsdottir, E. Tikkanen, J. Trakalo, E. Tremoli, M. D. Trip, F. J. Tsai, T. Tuomi, J. Tuomilehto, A. G. Uitterlinden, A. Valladares-Salgado, S. Vedantam, F. Veglia, B. F. Voight, C. Wang, N. J. Wareham, R. Wennauer, A. R. Wickremasinghe, T. Wilsgaard, J. F. Wilson, S. Wiltshire, W. Winckler, T. Y. Wong, A. R. Wood, J.-Y. Wu, Y. Wu, K. Yamamoto, T. Yamauchi, M. Yang, L. Yengo, M. Yokota, R. Young, D. Zabaneh, F. Zhang, R. Zhang, W. Zheng, P. Z. Zimmet, D. Altshuler, D. W. Bowden, Y. S. Cho, N. J. Cox, M. Cruz, C. L. Hanis, J. Kooner, J.-Y. Lee, M. Seielstad, Y. Y. Teo, M. Boehnke, E. J. Parra, J. C. Chambers, E. S. Tai, M. I. McCarthy, and A. P. Morris, Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat. Genet., vol. 46, no. 3, pp. 234–244, Mar. 2014. This large genetic meta-analysis study and references therein highlight the current knowledge about sequence variants contributing genetic risk for type 2 diabetes in multiple ethnic groups. Google Scholar
  7. 7.
    Soleimanpour SA, Stoffers DA. The pancreatic β cell and type 1 diabetes: innocent bystander or active participant? Trends Endocrinol Metab TEM. 2013;24(7):324–31.CrossRefPubMedGoogle Scholar
  8. 8.••
    Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, et al. β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37(6):1751–8. This article summarizes progress in and recommendations for further understanding islet/beta cell failure in type 2 diabetes based on proceedings at the October 2013 Global Partnership to Accelerate Diabetes Research Conference.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5(7):621–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Kutlu B, Burdick D, Baxter D, Rasschaert J, Flamez D, Eizirik DL, et al. Detailed transcriptome atlas of the pancreatic beta cell. BMC Med Genet. 2009;2:3.Google Scholar
  11. 11.
    Nica AC, Ongen H, Irminger J-C, Bosco D, Berney T, Antonarakis SE, et al. Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome. Genome Res. 2013;23(9):1554–62.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.•
    Parker SCJ, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A. 2013;110(44):17921–6. This study identified long enhancer states as regulators of cell type-specific functions in islets and other cell types. Moreover, sequence variants associated with genetic risk for diseases (such as type 2 diabetes) were specifically enriched in stretch enhancers of disease-relevant cell types (such as islets).PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.••
    Morán I, Akerman I, van de Bunt M, Xie R, Benazra M, Nammo T, et al. Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. 2012;16(4):435–48. This was the first study to systematically identify human islet lncRNAs.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, et al. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab. 2012;16(1):122–34.CrossRefPubMedGoogle Scholar
  15. 15.
    Cnop M, Abdulkarim B, Bottu G, Cunha DA, Igoillo-Esteve M, Masini M, et al. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes. 2014;63(6):1978–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Eizirik DL, Sammeth M, Bouckenooghe T, Bottu G, Sisino G, Igoillo-Esteve M, et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 2012;8(3):e1002552.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.•
    Fadista J, Vikman P, Laakso EO, Mollet IG, Esguerra JL, Taneera J, et al. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci U S A. 2014;111(38):13924–9. This study identified hundreds of genetic variants that alter islet transcription by RNA-seq of pancreatic islets from ∼90 individuals.Google Scholar
  18. 18.•
    Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, et al. Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest. 2013;123(3):1275–84. This study performed RNA-seq and ChIP-seq on dissociated, sorted islet cells to identify alpha and beta cell enriched transcripts and epigenetic promoter modifications.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148(6):1160–71.CrossRefPubMedGoogle Scholar
  20. 20.
    Soleimanpour SA, Gupta A, Bakay M, Ferrari AM, Groff DN, Fadista J, et al. The diabetes susceptibility gene Clec16a regulates mitophagy. Cell. 2014;157(7):1577–90.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Klein D, Misawa R, Bravo-Egana V, Vargas N, Rosero S, Piroso J, et al. MicroRNA expression in alpha and beta cells of human pancreatic islets. PLoS One. 2013;8(1):e55064.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    van de Bunt M, Gaulton KJ, Parts L, Moran I, Johnson PR, Lindgren CM, et al. The miRNA profile of human pancreatic islets and beta-cells and relationship to type 2 diabetes pathogenesis. PLoS One. 2013;8(1):e55272.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Guay C, Jacovetti C, Nesca V, Motterle A, Tugay K, Regazzi R. Emerging roles of non-coding RNAs in pancreatic β-cell function and dysfunction. Diabetes Obes Metab. 2012;14 Suppl 3:12–21.CrossRefPubMedGoogle Scholar
  24. 24.
    O’Brien RM. Moving on from GWAS: functional studies on the G6PC2 gene implicated in the regulation of fasting blood glucose. Curr Diab Rep. 2013;13(6):768–77.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Guttman M, Rinn JL. Modular regulatory principles of large non-coding RNAs. Nature. 2012;482(7385):339–46.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Washietl S, Kellis M, Garber M. Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals. Genome Res. 2014;24(4):616–28.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458(7235):223–7.Google Scholar
  28. 28.
    Hay CW, Docherty K. Comparative analysis of insulin gene promoters: implications for diabetes research. Diabetes. 2006;55(12):3201–13.CrossRefPubMedGoogle Scholar
  29. 29.
    Gerrish K, Van Velkinburgh JC, Stein R. Conserved transcriptional regulatory domains of the pdx-1 gene. Mol Endocrinol Baltim Md. 2004;18(3):533–48.CrossRefGoogle Scholar
  30. 30.
    Gerrish K, Gannon M, Shih D, Henderson E, Stoffel M, Wright CV, et al. Pancreatic beta cell-specific transcription of the pdx-1 gene. The role of conserved upstream control regions and their hepatic nuclear factor 3beta sites. J Biol Chem. 2000;275(5):3485–92.CrossRefPubMedGoogle Scholar
  31. 31.
    Chakrabarti SK, James JC, Mirmira RG. Quantitative assessment of gene targeting in vitro and in vivo by the pancreatic transcription factor, Pdx1. Importance of chromatin structure in directing promoter binding. J Biol Chem. 2002;277(15):13286–93.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12(1):7–18.CrossRefPubMedGoogle Scholar
  33. 33.
    Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, et al. High-resolution mapping and characterization of open chromatin across the genome. Cell. 2008;132(2):311–22.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007;39(3):311–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 2009;459(7243):108–12.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011;470(7333):279–83.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010;107(50):21931–6.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Barski A, Cuddapah S, Cui K, Roh T-Y, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–37.CrossRefPubMedGoogle Scholar
  39. 39.
    Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, et al. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab. 2010;12(5):443–55.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, et al. A map of open chromatin in human pancreatic islets. Nat Genet. 2010;42(3):255–9.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.•
    Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K, Wong ED, et al. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell. 2014;158(3):673–88. Similar to stretch/super enhancers (SEs), this study identified long stretches of H3K4me3 as an important feature of cell type-specific promoters, termed Broad Domains (BDS).Google Scholar
  42. 42.•
    Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I, et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet. 2014;46(2):136–43. Using ChIP-seq of islet TFs, this study found that islet-specific enhancer clusters are bound by multiple islet TFs. Consistent with earlier stretch/super enhancer studies [12, 54], GWAS SNPs for T2D and related traits are enriched in these islet enhancer clusters.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res. 2010;20(4):428–33.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Lee EK, Kim W, Tominaga K, Martindale JL, Yang X, Subaran SS, et al. RNA-binding protein HuD controls insulin translation. Mol Cell. 2012;45(6):826–35.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Stergachis AB, Neph S, Reynolds A, Humbert R, Miller B, Paige SL, et al. Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell. 2013;154(4):888–903.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Project Consortium ENCODE, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.CrossRefGoogle Scholar
  47. 47.
    Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28(10):1045–8.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Mutskov V, Felsenfeld G. The human insulin gene is part of a large open chromatin domain specific for human islets. Proc Natl Acad Sci U S A. 2009;106(41):17419–24.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Smith E, Shilatifard A. Enhancer biology and enhanceropathies. Nat Struct Mol Biol. 2014;21(3):210–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337(6099):1190–5.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Roadmap Epigenomics Consortium A, Kundaje W, Meuleman J, Ernst M, Bilenky A, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–30.CrossRefGoogle Scholar
  52. 52.
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–19.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320–34.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.•
    Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934–47. This study extended earlier super enhancer (SE) studies into human cells, identifying SEs in 86 cell/tissue types and showing that sequence variants contributing to diseases overlap SEs of disease-relevant cell types.CrossRefPubMedGoogle Scholar
  55. 55.
    Li G, Ruan X, Auerbach RK, Sandhu KS, Zheng M, Wang P, et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell. 2012;148(1–2):84–98.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Kieffer-Kwon K-R, Tang Z, Mathe E, Qian J, Sung M-H, Li G, et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell. 2013;155(7):1507–20.CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang Y, Wong C-H, Birnbaum RY, Li G, Favaro R, Ngan CY, et al. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature. 2013;504(7479):306–10.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326(5950):289–93.PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Smemo S, Tena JJ, Kim K-H, Gamazon ER, Sakabe NJ, Gómez-Marín C, et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014;507(7492):371–5.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Dekker J, Marti-Renom MA, Mirny LA. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet. 2013;14(6):390–403.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Xu Z, Wei G, Chepelev I, Zhao K, Felsenfeld G. Mapping of INS promoter interactions reveals its role in long-range regulation of SYT8 transcription. Nat Struct Mol Biol. 2011;18(3):372–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Xu Z, Lefevre GM, Gavrilova O, Foster St Claire MB, Riddick G, Felsenfeld G. Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion. Proc Natl Acad Sci U S A. 2014;111(47):16760–5.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Cook PR. The organization of replication and transcription. Science. 1999;284(5421):1790–5.CrossRefPubMedGoogle Scholar
  64. 64.
    Zhang J, Poh HM, Peh SQ, Sia YY, Li G, Mulawadi FH, et al. ChIA-PET analysis of transcriptional chromatin interactions. Methods San Diego Calif. 2012;58(3):289–99.CrossRefGoogle Scholar
  65. 65.
    Hughes JR, Roberts N, McGowan S, Hay D, Giannoulatou E, Lynch M, et al. Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat Genet. 2014;46(2):205–12.CrossRefPubMedGoogle Scholar
  66. 66.
    Shaw-Smith C, De Franco E, Lango Allen H, Batlle M, Flanagan SE, Borowiec M, et al. GATA4 mutations are a cause of neonatal and childhood-onset diabetes. Diabetes. 2014;63(8):2888–94.CrossRefPubMedGoogle Scholar
  67. 67.
    De Franco E, Shaw-Smith C, Flanagan SE, Shepherd MH, International NDM C, Hattersley AT, et al. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. Diabetes. 2013;62(3):993–7.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Tornovsky S, Crane A, Cosgrove KE, Hussain K, Lavie J, Heyman M, et al. Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. J Clin Endocrinol Metab. 2004;89(12):6224–34.CrossRefPubMedGoogle Scholar
  69. 69.
    Ek J, Hansen SP, Lajer M, Nicot C, Boesgaard TW, Pruhova S, et al. A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes. Diabetes. 2006;55(6):1869–73.CrossRefPubMedGoogle Scholar
  70. 70.
    Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, Roosen S, et al. A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet. 2001;10(19):2089–97.CrossRefPubMedGoogle Scholar
  71. 71.
    Wirsing A, Johnstone KA, Harries LW, Ellard S, Ryffel GU, Stanik J, et al. Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro. Diabet Med J Br Diabet Assoc. 2010;27(6):631–5.CrossRefGoogle Scholar
  72. 72.
    Gasperíková D, Tribble ND, Staník J, Hucková M, Misovicová N, van de Bunt M, et al. Identification of a novel beta-cell glucokinase (GCK) promoter mutation (-71G > C) that modulates GCK gene expression through loss of allele-specific Sp1 binding causing mild fasting hyperglycemia in humans. Diabetes. 2009;58(8):1929–35.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Borowiec M, Liew CW, Thompson R, Boonyasrisawat W, Hu J, Mlynarski WM, et al. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc Natl Acad Sci U S A. 2009;106(34):14460–5.PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.•
    Weedon MN, Cebola I, Patch A-M, Flanagan SE, De Franco E, Caswell R, et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014;46(1):61–4. This very elegant study combined genetic analysis of patient samples with functional genomics to demonstrate that rare mutations likely cause pancreatic agenesis by disrupting a developmental enhancer.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    S. Onengut-Gumuscu, W.-M. Chen, O. Burren, N. J. Cooper, A. R. Quinlan, J. C. Mychaleckyj, E. Farber, J. K. Bonnie, M. Szpak, E. Schofield, P. Achuthan, H. Guo, M. D. Fortune, H. Stevens, N. M. Walker, L. D. Ward, A. Kundaje, M. Kellis, M. J. Daly, J. C. Barrett, J. D. Cooper, P. Deloukas, Type 1 Diabetes Genetics Consortium, J. A. Todd, C. Wallace, P. Concannon, and S. S. Rich, Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet., Mar. 2015.Google Scholar
  76. 76.
    Fløyel T, Brorsson C, Nielsen LB, Miani M, Bang-Berthelsen CH, Friedrichsen M, et al. CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proc Natl Acad Sci U S A. 2014;111(28):10305–10.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007;117(8):2155–63.PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li D-Q, et al. Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science. 2010;327(5962):217–20.CrossRefPubMedGoogle Scholar
  79. 79.
    Kulzer JR, Stitzel ML, Morken MA, Huyghe JR, Fuchsberger C, Kuusisto J, et al. A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Am J Hum Genet. 2014;94(2):186–97.PubMedCentralCrossRefPubMedGoogle Scholar
  80. 80.
    Fogarty MP, Cannon ME, Vadlamudi S, Gaulton KJ, Mohlke KL. Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus. PLoS Genet. 2014;10(9):e1004633.PubMedCentralCrossRefPubMedGoogle Scholar
  81. 81.
    Lyssenko V, Nagorny CLF, Erdos MR, Wierup N, Jonsson A, Spégel P, et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet. 2009;41(1):82–8.PubMedCentralCrossRefPubMedGoogle Scholar
  82. 82.••
    Tang Y, Axelsson AS, Spégel P, Andersson LE, Mulder H, Groop LC, et al. Genotype-based treatment of type 2 diabetes with an α2A-adrenergic receptor antagonist. Sci Transl Med. 2014;6(257):257ra–139. This study, together with [4] and [78], is a compelling example translating a common genetic variant associated with diabetes risk into molecular function, pathophysiologic consequences, and a genotype-based, precision medicine approach to correcting these effects.CrossRefGoogle Scholar
  83. 83.
    Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng Y-H, et al. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell. 2005;122(3):337–49.CrossRefPubMedGoogle Scholar
  84. 84.
    Marselli L, Thorne J, Dahiya S, Sgroi DC, Sharma A, Bonner-Weir S, et al. Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One. 2010;5(7):e11499.PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    Kameswaran V, Bramswig NC, McKenna LB, Penn M, Schug J, Hand NJ, et al. Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab. 2014;19(1):135–45.PubMedCentralCrossRefPubMedGoogle Scholar
  86. 86.•
    Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, et al. Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123(8):3305–16. This very thorough study demonstrates that oxidative stress alters islet transcription factor localization and activity. This phenomenon is also observed in islets from type 2 diabetics, implicating environmental perturbation of transcriptional elements/programs as an important pathophysiologic event in diabetes.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Michael L. Stitzel
    • 1
  • Ina Kycia
    • 1
  • Romy Kursawe
    • 1
  • Duygu Ucar
    • 1
  1. 1.The Jackson Laboratory for Genomic Medicine (JAX-GM)FarmingtonUSA

Personalised recommendations