Glucocorticoid signaling in pancreatic islets modulates gene regulatory programs and genetic risk of type 2 diabetes.
Glucocorticoid signaling in pancreatic islets modulates gene regulatory programs and genetic risk of type 2 diabetes.
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DOI：
10.1371/journal.pgen.1009531
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发表时间：
2021-05
期刊：
影响因子：
4.5
通讯作者：
Gaulton KJ
中科院分区：
文献类型：
--
作者：
Aylward A;Okino ML;Benaglio P;Chiou J;Beebe E;Padilla JA;Diep S;Gaulton KJ
糖皮质激素是糖稳态和胰岛功能的关键调节因子，但驱动胰岛对糖皮质激素信号反应的基因调控程序以及这些程序对糖尿病风险的贡献尚不清楚。在这项研究中，我们使用ATAC-SEQ和RNA-SEQ来定位11个原代人类胰岛样本的染色质可及性和基因表达，这些样本与糖皮质激素地塞米松在不同剂量和持续时间下体外培养。我们确定了数千个可访问的染色质位置和基因，它们的活性在糖皮质激素的反应中发生了显著变化。在糖皮质激素信号转导中上调的染色质部位显著富含糖皮质激素受体结合部位，上调的基因在离子转运和脂质代谢方面显著富含，而下调的染色质部位和基因在炎症、应激反应和增殖过程中富含。与血糖水平和T2D风险相关的遗传变异在糖皮质激素反应的染色质部位富含，包括51个已知信号的精细定位变异。在精细定位的糖皮质激素反应染色质变异中，2p21位点上的一个可能的偶然变异对β细胞增强活性具有糖皮质激素依赖的等位基因效应，并影响SIX2和Six3的表达。我们的结果提供了对糖皮质激素反应的胰岛调节程序的综合图谱，通过该图我们揭示了胰岛糖皮质激素信号在介导T2D遗传风险中的作用。糖皮质激素调节炎症和新陈代谢，被广泛用于治疗免疫疾病，尽管长期接触糖皮质激素会导致糖尿病的发展。在这项研究中，我们确定了对糖尿病发展至关重要的初级胰岛对糖皮质激素地塞米松在多个剂量和持续时间的反应。我们观察到糖皮质激素治疗后胰岛在糖皮质激素受体结合部位的广泛变化，以及涉及胰岛功能和与类固醇和脂肪代谢、离子通道活性、炎症和生长相关的过程的关键基因的变化。影响2型糖尿病和血糖水平的基因变异位于许多基因组区域受糖皮质激素影响的位置，并突出显示了受这些位置调控的基因，通过这些基因，糖皮质激素信号可能直接促进糖尿病的发展。总之，这些结果为糖皮质激素治疗如何影响胰岛功能和糖尿病风险提供了关键的见解。
Glucocorticoids are key regulators of glucose homeostasis and pancreatic islet function, but the gene regulatory programs driving responses to glucocorticoid signaling in islets and the contribution of these programs to diabetes risk are unknown. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eleven primary human islet samples cultured in vitro with the glucocorticoid dexamethasone at multiple doses and durations. We identified thousands of accessible chromatin sites and genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped variants at 51 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affected SIX2 and SIX3 expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating genetic risk of T2D. Glucocorticoids regulate inflammation and metabolism and are widely used in the treatment of immune disorders, although prolonged exposure to glucocorticoids can lead to the development of diabetes. In this study we determined the response of primary pancreatic islets, which are central to the development of diabetes, to the glucocorticoid dexamethasone at multiple doses and durations. We observed widespread changes in pancreatic islets after glucocorticoid treatment at glucocorticoid receptor binding sites, as well as at key genes involved in islet function and processes related to steroid and lipid metabolism, ion channel activity, inflammation, and growth. Genetic variants affecting type 2 diabetes and glucose levels were located in sites affected by glucocorticoids at many genomic regions, and highlighted genes regulated by these sites through which glucocorticoid signaling may contribute directly to the development of diabetes. Together these results provide key insight into how glucocorticoid treatment affects pancreatic islet function and risk of diabetes.
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影响因子：
64.8
作者：
Fuchsberger, Christian;Flannick, Jason;Teslovich, Tanya M.;Mahajan, Anubha;Agarwala, Vineeta;Gaulton, Kyle J.;Ma, Clement;Fontanillas, Pierre;Moutsianas, Loukas;McCarthy, Davis J.;Rivas, Manuel A.;Perry, John R. B.;Sim, Xueling;Blackwell, Thomas W.;Robertson, Neil R.;Rayner, N. William;Cingolani, Pablo;Locke, Adam E.;Tajes, Juan Fernandez;Highland, Heather M.;Dupuis, Josee;Chines, Peter S.;Lindgren, Cecilia M.;Hartl, Christopher;Jackson, Anne U.;Chen, Han;Huyghe, Jeroen R.;van de Bunt, Martijn;Pearson, Richard D.;Kumar, Ashish;Mueller-Nurasyid, Martina;Grarup, Niels;Stringham, Heather M.;Gamazon, Eric R.;Lee, Jaehoon;Chen, Yuhui;Scott, Robert A.;Below, Jennifer E.;Chen, Peng;Huang, Jinyan;Go, Min Jin;Stitzel, Michael L.;Pasko, Dorota;Parker, Stephen C. J.;Varga, Tibor V.;Green, Todd;Beer, Nicola L.;Day-Williams, Aaron G.;Ferreira, Teresa;Fingerlin, Tasha;Horikoshi, Momoko;Hu, Cheng;Huh, Iksoo;Ikram, Mohammad Kamran;Kim, Bong-Jo;Kim, Yongkang;Kim, Young Jin;Kwon, Min-Seok;Lee, Juyoung;Lee, Selyeong;Lin, Keng-Han;Maxwell, Taylor J.;Nagai, Yoshihiko;Wang, Xu;Welch, Ryan P.;Yoon, Joon;Zhang, Weihua;Barzilai, Nir;Voight, Benjamin F.;Han, Bok-Ghee;Jenkinson, Christopher P.;Kuulasmaa, Teemu;Kuusisto, Johanna;Manning, Alisa;Ng, Maggie C. Y.;Palmer, Nicholette D.;Balkau, Beverley;Stancakova, Alena;Abboud, Hanna E.;Boeing, Heiner;Giedraitis, Vilmantas;Prabhakaran, Dorairaj;Gottesman, Omri;Scott, James;Carey, Jason;Kwan, Phoenix;Grant, George;Smith, Joshua D.;Neale, Benjamin M.;Purcell, Shaun;Butterworth, Adam S.;Howson, Joanna M. M.;Lee, Heung Man;Lu, Yingchang;Kwak, Soo-Heon;Zhao, Wei;Danesh, John;Lam, Vincent K. L.;Park, Kyong Soo;Saleheen, Danish;So, Wing Yee;Tam, Claudia H. T.;Afzal, Uzma;Aguilar, David;Arya, Rector;Aung, Tin;Chan, Edmund;Navarro, Carmen;Cheng, Ching-Yu;Palli, Domenico;Correa, Adolfo;Curran, Joanne E.;Rybin, Denis;Farook, Vidya S.;Fowler, Sharon P.;Freedman, Barry I.;Griswold, Michael;Hale, Daniel Esten;Hicks, Pamela J.;Khor, Chiea-Chuen;Kumar, Satish;Lehne, Benjamin;Thuillier, Dorothee;Lim, Wei Yen;Liu, Jianjun;van der Schouw, Yvonne T.;Loh, Marie;Musani, Solomon K.;Puppala, Sobha;Scott, William R.;Yengo, Loic;Tan, Sian-Tsung;Taylor, Herman A., Jr.;Thameem, Farook;Wilson, Gregory, Sr.;Wong, Tien Yin;Njolstad, Pal Rasmus;Levy, Jonathan C.;Mangino, Massimo;Bonnycastle, Lori L.;Schwarzmayr, Thomas;Fadista, Joao;Surdulescu, Gabriela L.;Herder, Christian;Groves, Christopher J.;Wieland, Thomas;Bork-Jensen, Jette;Brandslund, Ivan;Christensen, Cramer;Koistinen, Heikki A.;Doney, Alex S. F.;Kinnunen, Leena;Esko, Tonu;Farmer, Andrew J.;Hakaste, Liisa;Hodgkiss, Dylan;Kravic, Jasmina;Lyssenko, Valeriya;Hollensted, Mette;Jorgensen, Marit E.;Jorgensen, Torben;Ladenvall, Claes;Justesen, Johanne Marie;Karajamaki, Annemari;Kriebel, Jennifer;Rathmann, Wolfgang;Lannfelt, Lars;Lauritzen, Torsten;Narisu, Narisu;Linneberg, Allan;Melander, Olle;Milani, Lili;Neville, Matt;Orho-Melander, Marju;Qi, Lu;Qi, Qibin;Roden, Michael;Rolandsson, Olov;Swift, Amy;Rosengren, Anders H.;Stirrups, Kathleen;Wood, Andrew R.;Mihailov, Evelin;Blancher, Christine;Carneiro, Mauricio O.;Maguire, Jared;Poplin, Ryan;Shakir, Khalid;Fennell, Timothy;DePristo, Mark;de Angelis, Martin Hrabe;Deloukas, Panos;Gjesing, Anette P.;Jun, Goo;Nilsson, Peter;Murphy, Jacquelyn;Onofrio, Robert;Thorand, Barbara;Hansen, Torben;Meisinger, Christa;Hu, Frank B.;Isomaa, Bo;Karpe, Fredrik;Liang, Liming;Peters, Annette;Huth, Cornelia;O'Rahilly, Stephen P.;Palmer, Colin N. A.;Pedersen, Oluf;Rauramaa, Rainer;Tuomilehto, Jaakko;Salomaa, Veikko;Watanabe, Richard M.;Syvanen, Ann-Christine;Bergman, Richard N.;Bharadwaj, Dwaipayan;Bottinger, Erwin P.;Cho, Yoon Shin;Chandak, Giriraj R.;Chan, Juliana C. N.;Chia, Kee Seng;Daly, Mark J.;Ebrahim, Shah B.;Langenberg, Claudia;Elliott, Paul;Jablonski, Kathleen A.;Lehman, Donna M.;Jia, Weiping;Ma, Ronald C. W.;Pollin, Toni I.;Sandhu, Manjinder;Tandon, Nikhil;Froguel, Philippe;Barroso, Ines;Teo, Yik Ying;Zeggini, Eleftheria;Loos, Ruth J. F.;Small, Kerrin S.;Ried, Janina S.;DeFronzo, Ralph A.;Grallert, Harald;Glaser, Benjamin;Metspalu, Andres;Wareham, Nicholas J.;Walker, Mark;Banks, Eric;Gieger, Christian;Ingelsson, Erik;Im, Hae Kyung;Illig, Thomas;Franks, Paul W.;Buck, Gemma;Trakalo, Joseph;Buck, David;Prokopenko, Inga;Magi, Reedik;Lind, Lars;Farjoun, Yossi;Owen, Katharine R.;Gloyn, Anna L.;Strauch, Konstantin;Tuomi, Tiinamaija;Kooner, Jaspal Singh;Lee, Jong-Young;Park, Taesung;Donnelly, Peter;Morris, Andrew D.;Hattersley, Andrew T.;Bowden, Donald W.;Collins, Francis S.;Atzmon, Gil;Chambers, John C.;Spector, Timothy D.;Laakso, Markku;Strom, Tim M.;Bell, Graeme I.;Blangero, John;Duggirala, Ravindranath;Tai, E. Shyong;McVean, Gilean;Hanis, Craig L.;Wilson, James G.;Seielstad, Mark;Frayling, Timothy M.;Meigs, James B.;Cox, Nancy J.;Sladek, Rob;Lander, Eric S.;Gabriel, Stacey;Burtt, Noel P.;Mohlke, Karen L.;Meitinger, Thomas;Groop, Leif;Abecasis, Goncalo;Florez, Jose C.;Scott, Laura J.;Morris, Andrew P.;Kang, Hyun Min;Boehnke, Michael;Altshuler, David;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
4.1
作者：
Coutinho, Agnes E.;Chapman, Karen E.
通讯作者：
Chapman, Karen E.
影响因子：
16.6
作者：
Greenwald, William W.;Chiou, Joshua;Gaulton, Kyle J.
通讯作者：
Gaulton, Kyle J.
人类胰岛中的开放染色质图。
影响因子：
30.8
作者：
Gaulton, Kyle J.;Nammo, Takao;Pasquali, Lorenzo;Simon, Jeremy M.;Giresi, Paul G.;Fogarty, Marie P.;Panhuis, Tami M.;Mieczkowski, Piotr;Secchi, Antonio;Bosco, Domenico;Berney, Thierry;Montanya, Eduard;Mohlke, Karen L.;Lieb, Jason D.;Ferrer, Jorge
通讯作者：
Ferrer, Jorge