Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

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Zurück zum Zitat 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. 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.

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Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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).PubMedCentralCrossRefPubMed 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).PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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. 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.

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148(6):1160–71.CrossRefPubMed Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148(6):1160–71.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

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Zurück zum Zitat Hay CW, Docherty K. Comparative analysis of insulin gene promoters: implications for diabetes research. Diabetes. 2006;55(12):3201–13.CrossRefPubMed Hay CW, Docherty K. Comparative analysis of insulin gene promoters: implications for diabetes research. Diabetes. 2006;55(12):3201–13.CrossRefPubMed

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Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12(1):7–18.CrossRefPubMed Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12(1):7–18.CrossRefPubMed

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Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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). 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).

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRef 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.CrossRef

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat Smith E, Shilatifard A. Enhancer biology and enhanceropathies. Nat Struct Mol Biol. 2014;21(3):210–9.CrossRefPubMed Smith E, Shilatifard A. Enhancer biology and enhanceropathies. Nat Struct Mol Biol. 2014;21(3):210–9.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRef 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.CrossRef

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat Cook PR. The organization of replication and transcription. Science. 1999;284(5421):1790–5.CrossRefPubMed Cook PR. The organization of replication and transcription. Science. 1999;284(5421):1790–5.CrossRefPubMed

Zurück zum Zitat 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.CrossRef 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.CrossRef

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.CrossRef 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.CrossRef

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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. 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.

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.CrossRef 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.CrossRef

Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed

Zurück zum Zitat 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed