The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes

被引：105

作者：

Ramos-Rodriguez, Mireia ^{[1
]}

Raurell-Vila, Helena ^{[1
]}

Colli, Maikel L. ^{[2
]}

Alvelos, Maria Ines ^{[2
]}

Subirana-Granes, Marc ^{[1
]}

Juan-Mateu, Jonas ^{[2
]}

Norris, Richard ^{[1
]}

Turatsinze, Jean-Valery ^{[2
]}

Nakayasu, Ernesto S. ^{[3
]}

Webb-Robertson, Bobbie-Jo M. ^{[3
]}

Inshaw, Jamie R. J. ^{[4
]}

Marchetti, Piero ^{[5
]}

Piemonti, Lorenzo ^{[6
]}

Esteller, Manel ^{[7
,8
,9
,10
]}

Todd, John A. ^{[4
]}

Metz, Thomas O. ^{[3
]}

Eizirik, Decio L. ^{[2
]}

Pasquali, Lorenzo ^{[1
,7
,11
]}

机构：

[1] Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain

[2] Univ Libre Bruxelles, Ctr Diabet Res & Welbio, Med Fac, Brussels, Belgium

[3] Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA

[4] Univ Oxford, Wellcome Ctr Human Genet, NIHR Oxford Biomed Res Ctr, Nuffield Dept Med,JDRF Wellcome Diabet & Inflamma, Oxford, England

[5] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy

[6] Ist Sci San Raffaele, Diabet Res Inst, Milan, Italy

[7] Josep Carreras Leukaemia Res Inst, Barcelona, Spain

[8] Ctr Invest Biomed Red Canc, Madrid, Spain

[9] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain

[10] Univ Barcelona, Sch Med & Hlth Sci, Physiol Sci Dept, Barcelona, Spain

[11] CIBER Diabet & Enfermedades Metabol Asociadas, Barcelona, Spain

来源：

NATURE GENETICS | 2019年 / 51卷 / 11期

基金：

欧盟地平线“2020”; 美国国家卫生研究院;

关键词：

3-DIMENSIONAL ORGANIZATION; TRANSCRIPTION FACTORS; TOPOLOGICAL DOMAINS; READ ALIGNMENT; OPEN CHROMATIN; SOFTWARE TOOL; MACROPHAGE; EXPRESSION; NETWORK; COLOCALIZATION;

D O I：

10.1038/s41588-019-0524-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic beta cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the beta-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the beta-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the beta-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human beta cells. Our study illustrates how beta cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.

引用

页码：1588 / +

页数：20

共 83 条

[1] Variant Set Enrichment: an R package to identify disease-associated functional genomic regions [J].

Ahmed, Musaddeque ;

Sallari, Richard C. ;

Guo, Haiyang ;

Moore, Jason H. ;

He, Housheng Hansen ;

Lupien, Mathieu .

BIODATA MINING, 2017, 10

[2] Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response [J].

Alasoo, Kaur ;

Rodrigues, Julia ;

Mukhopadhyay, Subhankar ;

Knights, Andrew J. ;

Mann, Alice L. ;

Kundu, Kousik ;

Hale, Christine ;

Dougan, Gordon ;

Gaffney, Daniel J. .

NATURE GENETICS, 2018, 50 (03) :424-+

[3] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[4] HTSeq-a Python']Python framework to work with high-throughput sequencing data [J].

Anders, Simon ;

Pyl, Paul Theodor ;

Huber, Wolfgang .

BIOINFORMATICS, 2015, 31 (02) :166-169

[5]

Aronesty E., 2013, The Open Bioinformatics Journal, V7, P1, DOI [DOI 10.2174/1875036201307010001, 10.2174/1875036201307010001]

[6]

Assenov Y, 2014, NAT METHODS, V11, P1138, DOI [10.1038/NMETH.3115, 10.1038/nmeth.3115]

[7] Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells [J].

Barutcu, A. Rasim ;

Lajoie, Bryan R. ;

McCord, Rachel P. ;

Tye, Coralee E. ;

Hong, Deli ;

Messier, Terri L. ;

Browne, Gillian ;

van Wijnen, Andre J. ;

Lian, Jane B. ;

Stein, Janet L. ;

Dekker, Job ;

Imbalzano, Anthony N. ;

Stein, Gary S. .

GENOME BIOLOGY, 2015, 16

[8] DNA methylation patterns and epigenetic memory [J].

Bird, A .

GENES & DEVELOPMENT, 2002, 16 (01) :6-21

[9] Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms [J].

Brozzi, Flora ;

Nardelli, Tarlliza R. ;

Lopes, Miguel ;

Millard, Isabelle ;

Barthson, Jenny ;

Igoillo-Esteve, Mariana ;

Grieco, Fabio A. ;

Villate, Olatz ;

Oliveira, Joana M. ;

Casimir, Marina ;

Bugliani, Marco ;

Engin, Feyza ;

Hotamisligil, Gokhan S. ;

Marchetti, Piero ;

Eizirik, Decio L. .

DIABETOLOGIA, 2015, 58 (10) :2307-2316

[10] Assessment of a novel two-component enzyme preparation for human islet isolation and transplantation [J].

Bucher, P ;

Mathe, Z ;

Morel, P ;

Bosco, D ;

Andres, A ;

Kurfuest, M ;

Friedrich, O ;

Raemsch-Guenther, N ;

Buhler, LH ;

Berney, T .

TRANSPLANTATION, 2005, 79 (01) :91-97

← 1 2 3 4 5 6 7 8 9 →