DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients

被引：302

作者：

Volkmar, Michael ^{[1
]}

Dedeurwaerder, Sarah ^{[1
]}

Cunha, Daniel A. ^{[2
]}

Ndlovu, Matladi N. ^{[1
]}

Defrance, Matthieu ^{[1
]}

Deplus, Rachel ^{[1
]}

Calonne, Emilie ^{[1
]}

Volkmar, Ute ^{[3
]}

Igoillo-Esteve, Mariana ^{[2
]}

Naamane, Najib ^{[2
]}

Del Guerra, Silvia ^{[4
]}

Masini, Matilde ^{[4
]}

Bugliani, Marco ^{[4
]}

Marchetti, Piero ^{[4
]}

Cnop, Miriam ^{[2
,5
]}

Eizirik, Decio L. ^{[2
]}

Fuks, Francois ^{[1
]}

机构：

[1] Univ Libre Bruxelles, Fac Med, Lab Canc Epigenet, B-1070 Brussels, Belgium

[2] Univ Libre Bruxelles, Fac Med, Expt Med Lab, B-1070 Brussels, Belgium

[3] Univ Bonn, Inst Cellular & Mol Biol IZMB, Dept Mol Evolut, Bonn, Germany

[4] Univ Pisa, Dept Endocrinol & Metab, Metab Unit, Pisa, Italy

[5] Erasmus Hosp, Div Endocrinol, Brussels, Belgium

来源：

EMBO JOURNAL | 2012年 / 31卷 / 06期

关键词：

DNA methylation; pancreatic islets; type; 2; diabetes; GENOME-WIDE ASSOCIATION; ENDOPLASMIC-RETICULUM STRESS; EPIDERMAL-GROWTH-FACTOR; BETA-CELL DYSFUNCTION; NF-KAPPA-B; INSULIN-SECRETION; GENE-EXPRESSION; GLUCOSE-TOLERANCE; ER STRESS; COMBINATION THERAPY;

D O I：

10.1038/emboj.2011.503

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In addition to genetic predisposition, environmental and lifestyle factors contribute to the pathogenesis of type 2 diabetes (T2D). Epigenetic changes may provide the link for translating environmental exposures into pathological mechanisms. In this study, we performed the first comprehensive DNA methylation profiling in pancreatic islets from T2D and non-diabetic donors. We uncovered 276 CpG loci affiliated to promoters of 254 genes displaying significant differential DNA methylation in diabetic islets. These methylation changes were not present in blood cells from T2D individuals nor were they experimentally induced in non-diabetic islets by exposure to high glucose. For a subgroup of the differentially methylated genes, concordant transcriptional changes were present. Functional annotation of the aberrantly methylated genes and RNAi experiments highlighted pathways implicated in beta-cell survival and function; some are implicated in cellular dysfunction while others facilitate adaptation to stressors. Together, our findings offer new insights into the intricate mechanisms of T2D pathogenesis, underscore the important involvement of epigenetic dysregulation in diabetic islets and may advance our understanding of T2D aetiology. The EMBO Journal (2012) 31, 1405-1426. doi:10.1038/emboj.2011.503; Published online 31 January 2012

引用

页码：1405 / 1426

页数：22

共 147 条

[1] Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase [J].

Ahuja, Nidhi ;

Schwer, Bjoern ;

Carobbio, Stefania ;

Waltregny, David ;

North, Brian J. ;

Castronovo, Vincenzo ;

Maechler, Pierre ;

Verdin, Eric .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (46) :33583-33592

[2]

[Anonymous], 1995, Diabetes, V44, P1249

[3]

[Anonymous], MICROARRAY ANAL V1 0

[4]

[Anonymous], 1973, NUMERICAL TAXONOMY P

[5]

[Anonymous], POINT BISERIAL CORRE

[6]

[Anonymous], IDF DIAB ATL

[7] Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, an animal model of insulin resistance [J].

Anuradha, CV ;

Balakrishnan, SD .

CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 1999, 77 (10) :749-754

[8] ESTABLISHMENT OF 2-MERCAPTOETHANOL-DEPENDENT DIFFERENTIATED INSULIN-SECRETING CELL-LINES [J].

ASFARI, M ;

JANJIC, D ;

MEDA, P ;

LI, GD ;

HALBAN, PA ;

WOLLHEIM, CB .

ENDOCRINOLOGY, 1992, 130 (01) :167-178

[9] Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene [J].

Bell, AC ;

Felsenfeld, G .

NATURE, 2000, 405 (6785) :482-485

[10] Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus [J].

Bell, Christopher G. ;

Teschendorff, Andrew E. ;

Rakyan, Vardhman K. ;

Maxwell, Alexander P. ;

Beck, Stephan ;

Savage, David A. .

BMC MEDICAL GENOMICS, 2010, 3

← 1 2 3 4 5 6 7 8 9 10 →