Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.
Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.
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Stard10基因座的染色质3D相互作用分析揭示了FCHSD2作为胰岛素分泌的调节剂。
DOI：
10.1016/j.celrep.2021.108703
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发表时间：
2021-02-02
期刊：
影响因子：
8.8
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
Hu M;Cebola I;Carrat G;Jiang S;Nawaz S;Khamis A;Canouil M;Froguel P;Schulte A;Solimena M;Ibberson M;Marchetti P;Cardenas-Diaz FL;Gadue PJ;Hastoy B;Almeida-Souza L;McMahon H;Rutter GA
利用染色质构象捕获，我们发现STARD10 2型糖尿病（T2D）基因座中的增强子簇形成了一个明确的三维（3D）染色质结构域。该基因座内有一个4.1 kb的区域，携带5个t2d相关变异，与ctcf结合区域和具有强转录活性的增强子相互作用。对人类胰岛三维染色质相互作用图谱的分析表明，FCHSD2基因是增强子簇的另一个靶标。crispr - cas9介导的人胰腺源性内皮细胞（EndoC-βH1）突变区或相关增强子的缺失会损害葡萄糖刺激的胰岛素分泌。在含有CRISPR缺失的细胞中，STARD10和FCHSD2的表达均降低，而在人类胰岛中，STARD10和FCHSD2的低表达与拥有风险变异等位基因有关，后者在名义上是相关的。最后，crispr - cas9介导的STARD10或FCHSD2缺失，而不是ARAP1缺失，会损害受调节的胰岛素分泌。因此，STARD10位点上的多个基因影响β细胞功能。STARD10的2型风险变异位于ctcf -侧翼的增强子簇中风险变异携带区域的缺失抑制了受调节的胰岛素分泌3D染色质相互作用图显示FCHSD2是增强子簇的靶标。在这篇文章中，Hu等人展示了在STARD10位点上含有影响2型糖尿病风险的GWAS变异的基因组区域对基因调控的重要性。他们还确定FCHSD2可能是这些变异对胰岛素分泌影响的中介。
Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function. Type 2 risk variants at STARD10 reside in CTCF-flanked enhancer clusters Loss of the risk variant-bearing region inhibits regulated insulin secretion 3D chromatin interaction maps reveal FCHSD2 as target of the enhancer cluster Deletion of STARD10 or FCHSD2 from EndoC-βH1 β cells inhibits insulin secretion In this article, Hu et al. show the importance, for gene regulation, of a genomic region harboring GWAS variants that affect type 2 diabetes risk at the STARD10 locus. They also identify FCHSD2 as a likely mediator of the effects of these variants on insulin secretion.
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影响因子：
30.8
作者：
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 muylti-Ethnic Samples (T2D-GENES) Consortium;Mahajan A;Go MJ;Zhang W;Below JE;Gaulton KJ;Ferreira T;Horikoshi M;Johnson AD;Ng MC;Prokopenko I;Saleheen D;Wang X;Zeggini E;Abecasis GR;Adair LS;Almgren P;Atalay M;Aung T;Baldassarre D;Balkau B;Bao Y;Barnett AH;Barroso I;Basit A;Been LF;Beilby J;Bell GI;Benediktsson R;Bergman RN;Boehm BO;Boerwinkle E;Bonnycastle LL;Burtt N;Cai Q;Campbell H;Carey J;Cauchi S;Caulfield M;Chan JC;Chang LC;Chang TJ;Chang YC;Charpentier G;Chen CH;Chen H;Chen YT;Chia KS;Chidambaram M;Chines PS;Cho NH;Cho YM;Chuang LM;Collins FS;Cornelis MC;Couper DJ;Crenshaw AT;van Dam RM;Danesh J;Das D;de Faire U;Dedoussis G;Deloukas P;Dimas AS;Dina C;Doney AS;Donnelly PJ;Dorkhan M;van Duijn C;Dupuis J;Edkins S;Elliott P;Emilsson V;Erbel R;Eriksson JG;Escobedo J;Esko T;Eury E;Florez JC;Fontanillas P;Forouhi NG;Forsen T;Fox C;Fraser RM;Frayling TM;Froguel P;Frossard P;Gao Y;Gertow K;Gieger C;Gigante B;Grallert H;Grant GB;Grrop LC;Groves CJ;Grundberg E;Guiducci C;Hamsten A;Han BG;Hara K;Hassanali N;Hattersley AT;Hayward C;Hedman AK;Herder C;Hofman A;Holmen OL;Hovingh K;Hreidarsson AB;Hu C;Hu FB;Hui J;Humphries SE;Hunt SE;Hunter DJ;Hveem K;Hydrie ZI;Ikegami H;Illig T;Ingelsson E;Islam M;Isomaa B;Jackson AU;Jafar T;James A;Jia W;Jöckel KH;Jonsson A;Jowett JB;Kadowaki T;Kang HM;Kanoni S;Kao WH;Kathiresan S;Kato N;Katulanda P;Keinanen-Kiukaanniemi KM;Kelly AM;Khan H;Khaw KT;Khor CC;Kim HL;Kim S;Kim YJ;Kinnunen L;Klopp N;Kong A;Korpi-Hyövälti E;Kowlessur S;Kraft P;Kravic J;Kristensen MM;Krithika S;Kumar A;Kumate J;Kuusisto J;Kwak SH;Laakso M;Lagou V;Lakka TA;Langenberg C;Langford C;Lawrence R;Leander K;Lee JM;Lee NR;Li M;Li X;Li Y;Liang J;Liju S;Lim WY;Lind L;Lindgren CM;Lindholm E;Liu CT;Liu JJ;Lobbens S;Long J;Loos RJ;Lu W;Luan J;Lyssenko V;Ma RC;Maeda S;Mägi R;Männisto S;Matthews DR;Meigs JB;Melander O;Metspalu A;Meyer J;Mirza G;Mihailov E;Moebus S;Mohan V;Mohlke KL;Morris AD;Mühleisen TW;Müller-Nurasyid M;Musk B;Nakamura J;Nakashima E;Navarro P;Ng PK;Nica AC;Nilsson PM;Njølstad I;Nöthen MM;Ohnaka K;Ong TH;Owen KR;Palmer CN;Pankow JS;Park KS;Parkin M;Pechlivanis S;Pedersen NL;Peltonen L;Perry JR;Peters A;Pinidiyapathirage JM;Platou CG;Potter S;Price JF;Qi L;Radha V;Rallidis L;Rasheed A;Rathman W;Rauramaa R;Raychaudhuri S;Rayner NW;Rees SD;Rehnberg E;Ripatti S;Robertson N;Roden M;Rossin EJ;Rudan I;Rybin D;Saaristo TE;Salomaa V;Saltevo J;Samuel M;Sanghera DK;Saramies J;Scott J;Scott LJ;Scott RA;Segrè AV;Sehmi J;Sennblad B;Shah N;Shah S;Shera AS;Shu XO;Shuldiner AR;Sigurđsson G;Sijbrands E;Silveira A;Sim X;Sivapalaratnam S;Small KS;So WY;Stančáková A;Stefansson K;Steinbach G;Steinthorsdottir V;Stirrups K;Strawbridge RJ;Stringham HM;Sun Q;Suo C;Syvänen AC;Takayanagi R;Takeuchi F;Tay WT;Teslovich TM;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tikkanen E;Trakalo J;Tremoli E;Trip MD;Tsai FJ;Tuomi T;Tuomilehto J;Uitterlinden AG;Valladares-Salgado A;Vedantam S;Veglia F;Voight BF;Wang C;Wareham NJ;Wennauer R;Wickremasinghe AR;Wilsgaard T;Wilson JF;Wiltshire S;Winckler W;Wong TY;Wood AR;Wu JY;Wu Y;Yamamoto K;Yamauchi T;Yang M;Yengo L;Yokota M;Young R;Zabaneh D;Zhang F;Zhang R;Zheng W;Zimmet PZ;Altshuler D;Bowden DW;Cho YS;Cox NJ;Cruz M;Hanis CL;Kooner J;Lee JY;Seielstad M;Teo YY;Boehnke M;Parra EJ;Chambers JC;Tai ES;McCarthy MI;Morris AP
通讯作者：
Morris AP
影响因子：
30.8
作者：
Mahajan A;Taliun D;Thurner M;Robertson NR;Torres JM;Rayner NW;Payne AJ;Steinthorsdottir V;Scott RA;Grarup N;Cook JP;Schmidt EM;Wuttke M;Sarnowski C;Mägi R;Nano J;Gieger C;Trompet S;Lecoeur C;Preuss MH;Prins BP;Guo X;Bielak LF;Below JE;Bowden DW;Chambers JC;Kim YJ;Ng MCY;Petty LE;Sim X;Zhang W;Bennett AJ;Bork-Jensen J;Brummett CM;Canouil M;Ec Kardt KU;Fischer K;Kardia SLR;Kronenberg F;Läll K;Liu CT;Locke AE;Luan J;Ntalla I;Nylander V;Schönherr S;Schurmann C;Yengo L;Bottinger EP;Brandslund I;Christensen C;Dedoussis G;Florez JC;Ford I;Franco OH;Frayling TM;Giedraitis V;Hackinger S;Hattersley AT;Herder C;Ikram MA;Ingelsson M;Jørgensen ME;Jørgensen T;Kriebel J;Kuusisto J;Ligthart S;Lindgren CM;Linneberg A;Lyssenko V;Mamakou V;Meitinger T;Mohlke KL;Morris AD;Nadkarni G;Pankow JS;Peters A;Sattar N;Stančáková A;Strauch K;Taylor KD;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tuomilehto J;Witte DR;Dupuis J;Peyser PA;Zeggini E;Loos RJF;Froguel P;Ingelsson E;Lind L;Groop L;Laakso M;Collins FS;Jukema JW;Palmer CNA;Grallert H;Metspalu A;Dehghan A;Köttgen A;Abecasis GR;Meigs JB;Rotter JI;Marchini J;Pedersen O;Hansen T;Langenberg C;Wareham NJ;Stefansson K;Gloyn AL;Morris AP;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
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：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
8.1
作者：
Khamis, Amna;Canouil, Mickael;Froguel, Philippe
通讯作者：
Froguel, Philippe