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Title: Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity

Author
item KUHNEN, PETER - Charite' University Hospital Berlin
item HANDKE, DANIELA - Charite' University Hospital Berlin
item WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)
item HENNIG, BRANWEN - London School Of Hygiene & Tropical Medicine
item SILBER, MATT - London School Of Hygiene & Tropical Medicine
item FULFORD, ANTHONY - London School Of Hygiene & Tropical Medicine
item DOMINGUEZ-SALAS, PAULA - Royal Veterinary College
item MOORE, SOPHIE - London School Of Hygiene & Tropical Medicine
item PRENTICE, ANDREW - London School Of Hygiene & Tropical Medicine
item SPRANGER, JOACHIM - Charite' University Hospital Berlin
item HINNEY, ANKE - University Of Duisburg-Essen

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/28/2016
Publication Date: 9/13/2016
Citation: Kuhnen, P., Handke, D., Waterland, R.A., Hennig, B.J., Silber, M., Fulford, A.J., Doninguez-Salas, P., Moore, S.E., Prentice, A.M., Spranger, J., Hinney, A. 2016. Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity. Cell Metabolism. 24:1-8.

Interpretive Summary: "Epigenetics" describes the study of the molecular mechanisms that stabilize gene expression potential in different tissues and cell types; one of these mechanisms, DNA methylation, is recognized as the most stable. Over ten years ago it was shown in the agouti viable yellow (Avy) mouse model that a mother's nutrition before and during pregnancy can affect establishment of DNA methylation in her offspring, and this affects body weight regulation (risk of obesity) throughout life. But, it was not known if similar phenomena occur in humans. In this study, we have identified a region in the human genome that appears to be a "metastable epiallele" (very similar to the mouse Avy locus). This locus is in the POMC gene, which plays an important role in energy balance. We showed that interindividual variation in this region is affected by maternal nutrition around the time of conception, is stable for many years, and is correlated with body weight. This provides the first evidence in humans that maternal nutrition around the time of conception can cause epigenetic changes in the offspring that persist to affect lifelong risk of obesity.

Technical Abstract: 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 lasermicrodissected 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. Togegher, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation.