Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity

被引：85

作者：

Kuehnen, Peter ^{[1
]}

Handke, Daniela ^{[1
]}

Waterland, Robert A. ^{[2
,3
]}

Hennig, Branwen J. ^{[4
]}

Silver, Matt ^{[4
]}

Fulford, Anthony J. ^{[4
]}

Dominguez-Salas, Paula ^{[5
,6
]}

Moore, Sophie E. ^{[4
,7
]}

Prentice, Andrew M. ^{[4
]}

Spranger, Joachim ^{[8
,9
,10
,11
]}

Hinney, Anke ^{[12
]}

Hebebrand, Johannes ^{[12
]}

Heppner, Frank L. ^{[13
,14
]}

Walzer, Lena ^{[1
]}

Groetzinger, Carsten ^{[15
]}

Gromoll, Joerg ^{[16
]}

Wiegand, Susanna ^{[17
]}

Grueters, Annette ^{[17
]}

Krude, Heiko ^{[1
]}

机构：

[1] Charite Univ Med Berlin, Inst Expt Pediat Endocrinol, D-13353 Berlin, Germany

[2] Baylor Coll Med, ARS, USDA, Childrens Nutr Res Ctr,Dept Pediat, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[4] London Sch Hyg & Trop Med, MRC Unit, Gambia & MRC Int Nutr Grp, London WC1E 7HT, England

[5] Univ London, Royal Vet Coll, Vet Epidemiol Econ & Publ Hlth Grp, London AL10 9EU, Herts, England

[6] Int Livestock Res Inst, Nairobi 00100, Kenya

[7] MRC Human Nutr Res, Elsie Widdowson Lab, Cambridge CB1 9NL, England

[8] Charite Univ Med Berlin, Dept Endocrinol Diabet & Nutr, D-10117 Berlin, Germany

[9] Charite Univ Med Berlin, Charite Ctr Cardiovasc Res CCR, D-10117 Berlin, Germany

[10] Charite Univ Med Berlin, Expt & Clin Res Ctr ECRC, D-10117 Berlin, Germany

[11] Max Delbruck Ctr, D-10117 Berlin, Germany

[12] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, Univ Hosp Essen AoR, D-45141 Essen, Germany

[13] Charite Univ Med Berlin, Dept Neuropathol, D-10117 Berlin, Germany

[14] NeuroCure, Cluster Excellence, Charitepl 1, D-10117 Berlin, Germany

[15] Charite Univ Med Berlin, Dept Hepatol & Gastroenterol, Mol Canc Res Ctr MKFZ, D-13353 Berlin, Germany

[16] Univ Munster, Ctr Reprod Med & Androl, D-48149 Munster, Germany

[17] Charite, Dept Pediat Endocrinol & Diabet, D-13353 Berlin, Germany

来源：

CELL METABOLISM | 2016年 / 24卷 / 03期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

BODY-MASS INDEX; MISSING HERITABILITY; TRANSGENERATIONAL INHERITANCE; MICE; DISEASE; HUMANS; MOUSE;

D O I：

10.1016/j.cmet.2016.08.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritability." We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation.

引用

页码：502 / 509

页数：8

共 32 条

[1] Fibroblast Growth Factor 21 Predicts the Metabolic Syndrome and Type 2 Diabetes in Caucasians [J].

Bobbert, Thomas ;

Schwarz, Franziska ;

Fischer-Rosinsky, Antje ;

Pfeiffer, Andreas F. H. ;

Moehlig, Matthias ;

Mai, Knut ;

Spranger, Joachim .

DIABETES CARE, 2013, 36 (01) :145-149

[2] Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity [J].

Dalgaard, Kevin ;

Landgraf, Kathrin ;

Heyne, Steffen ;

Lempradl, Adelheid ;

Longinotto, John ;

Gossens, Klaus ;

Ruf, Marius ;

Orthofer, Michael ;

Strogantsev, Ruslan ;

Selvaraj, Madhan ;

Lu, Tess Tsai-Hsiu ;

Casas, Eduard ;

Teperino, Raffaele ;

Surani, M. Azim ;

Zvetkova, Ilona ;

Rimmington, Debra ;

Tung, Y. C. Loraine ;

Lam, Brian ;

Larder, Rachel ;

Yeo, Giles S. H. ;

O'Rahilly, Stephen ;

Vavouri, Tanya ;

Whitelaw, Emma ;

Penninger, Josef M. ;

Jenuwein, Thomas ;

Cheung, Ching-Lung ;

Ferguson-Smith, Anne C. ;

Coll, Anthony P. ;

Koerner, Antje ;

Pospisilik, J. Andrew .

CELL, 2016, 164 (03) :353-364

[3] DNA methylation and body-mass index: a genome-wide analysis [J].

Dick, Katherine J. ;

Nelson, Christopher P. ;

Tsaprouni, Loukia ;

Sandling, Johanna K. ;

Aissi, Dylan ;

Wahl, Simone ;

Meduri, Eshwar ;

Morange, Pierre-Emmanuel ;

Gagnon, France ;

Grallert, Harald ;

Waldenberger, Melanie ;

Peters, Annette ;

Erdmann, Jeanette ;

Hengstenberg, Christian ;

Cambien, Francois ;

Goodall, Alison H. ;

Ouwehand, Willem H. ;

Schunkert, Heribert ;

Thompson, John R. ;

Spector, Tim D. ;

Gieger, Christian ;

Tregout, David-Alexandre ;

Deloukas, Panos ;

Samani, Nilesh J. .

LANCET, 2014, 383 (9933) :1990-1998

[4] Maternal nutrition at conception modulates DNA methylation of human metastable epialleles [J].

Dominguez-Salas, Paula ;

Moore, Sophie E. ;

Baker, Maria S. ;

Bergen, Andrew W. ;

Cox, Sharon E. ;

Dyer, Roger A. ;

Fulford, Anthony J. ;

Guan, Yongtao ;

Laritsky, Eleonora ;

Silver, Matt J. ;

Swan, Gary E. ;

Zeisel, Steven H. ;

Innis, Sheila M. ;

Waterland, Robert A. ;

Prentice, Andrew M. ;

Hennig, Branwen J. .

NATURE COMMUNICATIONS, 2014, 5

[5] VIEWPOINT Missing heritability and strategies for finding the underlying causes of complex disease [J].

Eichler, Evan E. ;

Flint, Jonathan ;

Gibson, Greg ;

Kong, Augustine ;

Leal, Suzanne M. ;

Moore, Jason H. ;

Nadeau, Joseph H. .

NATURE REVIEWS GENETICS, 2010, 11 (06) :446-450

[6]

Elks Cathy E, 2012, Front Endocrinol (Lausanne), V3, P29, DOI 10.3389/fendo.2012.00029

[7] Heterozygosity for a POMC-Null mutation and increased obesity risk in humans [J].

Farooqi, I. Sadaf ;

Drop, Stenvert ;

Clements, Agnes ;

Keogh, Julia M. ;

Biernacka, Joanna ;

Lowenbein, Sarah ;

Challis, Benjamin G. ;

O'Rahilly, Stephen .

DIABETES, 2006, 55 (09) :2549-2553

[8] Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice [J].

Gapp, Katharina ;

Jawaid, Ali ;

Sarkies, Peter ;

Bohacek, Johannes ;

Pelczar, Pawel ;

Prados, Julien ;

Farinelli, Laurent ;

Miska, Eric ;

Mansuy, Isabelle M. .

NATURE NEUROSCIENCE, 2014, 17 (05) :667-+

[9] Changes in gene expression foreshadow diet-induced obesity in genetically identical mice [J].

Koza, Robert A. ;

Nikonova, Larissa ;

Hogan, Jessica ;

Rim, Jong-Seop ;

Mendoza, Tamra ;

Faulk, Christopher ;

Skaf, Jihad ;

Kozak, Leslie P. .

PLOS GENETICS, 2006, 2 (05) :769-780

[10] Obesity due to proopiomelanocortin deficiency:: Three new cases and treatment trials with thyroid hormone and ACTH4-10 [J].

Krude, H ;

Biebermann, H ;

Schnabel, D ;

Tansek, MZ ;

Theunissen, P ;

Mullis, PE ;

Grüters, A .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (10) :4633-4640

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