title: DNA CpG Methylation (5-Methylcytosine) and Its Derivative (5-Hydroxymethylcytosine) Alter Histone Posttranslational Modifications at the Pomc Promoter, Affecting the Impact of Perinatal Diet on Leanness and Obesity of the Offspring.
abstract: A maternal high-fat diet (HFD) alters the offspring's feeding regulation, leading to obesity. This phenomenon is partially mediated by aberrant expression of the hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC). Nevertheless, although some individual offspring suffer from morbid obesity, others escape the malprogramming. It is suggested that this difference is due to epigenetic programming. In this study, we report that in lean offspring of non-HFD-fed dams, essential promoter regions for Pomc expression were enriched with 5-hydroxymethylcytosine (5hmC) together with a reduction in the level of 5-methylcytosine (5mC). Moreover, 5hmC was negatively correlated whereas 5mC was positively correlated with body weight in offspring from both HFD- and control-fed dams. We further found that Pomc expression in obese offspring is determined by a two-step epigenetic inhibitory mechanism in which CpG methylation is linked with histone posttranslational modifications. An increase in CpG methylation at the Poxmc promoter enables binding of methyl-binding domain 1 (MBD1) to 5mC, but not to its derivative 5hmC. MBD1 then interacts with SET domain bifurcated 1 methyltransferase to promote bimethylation on the histone 3 lysine 9 residue, reducing Pomc mRNA expression. These results suggest an epigenetic regulatory mechanism that affects obesity-prone or resilient traits.
authors.affiliation: Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel Department of Psychology, Bar Ilan University, Ramat-Gan, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Marco
authors.affiliation: Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kisliouk
authors.affiliation: Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel Department of Psychology, Bar Ilan University, Ramat-Gan, Israel.
authors.forename: Tzlil
authors.initials: T
authors.lastname: Tabachnik
authors.affiliation: Department of Psychology, Bar Ilan University, Ramat-Gan, Israel Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel.
authors.forename: Aron
authors.initials: A
authors.lastname: Weller
authors.affiliation: Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel meiri@agri.huji.ac.il.
authors.forename: Noam
authors.initials: N
authors.lastname: Meiri
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D006657:Histones / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D013447:Sulfites / Q000494:pharmacology; D013851:Thinness / Q000378:metabolism
chemical_list: D006657:Histones; D013447:Sulfites; C011865:5-hydroxymethylcytosine; D011333:Pro-Opiomelanocortin; D044503:5-Methylcytosine; C042345:hydrogen sulfite