Marco Asaf, Kisliouk Tatiana, Tabachnik Tzlil, Weller Aron, Meiri Noam
Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel Department of Psychology, Bar Ilan University, Ramat-Gan, Israel.
Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
Diabetes. 2016 Aug;65(8):2258-67. doi: 10.2337/db15-1608. Epub 2016 May 23.
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.
母体高脂饮食（HFD）会改变后代的进食调节，导致肥胖。这种现象部分是由下丘脑厌食神经肽阿黑皮素原（POMC）的异常表达介导的。然而，尽管一些个体后代患有病态肥胖，但其他后代却未出现编程异常。有人认为这种差异是由于表观遗传编程所致。在本研究中，我们报告在未喂食HFD的母鼠的瘦后代中，Pomc表达的必需启动子区域富含5-羟甲基胞嘧啶（5hmC），同时5-甲基胞嘧啶（5mC）水平降低。此外，在喂食HFD和对照的母鼠的后代中，5hmC与体重呈负相关，而5mC与体重呈正相关。我们进一步发现，肥胖后代中Pomc的表达由一种两步表观遗传抑制机制决定，其中CpG甲基化与组蛋白翻译后修饰相关联。Poxmc启动子处CpG甲基化的增加使得甲基结合域1（MBD1）能够与5mC结合，但不能与其衍生物5hmC结合。然后，MBD1与SET结构域分叉1甲基转移酶相互作用，促进组蛋白3赖氨酸9残基的二甲基化，从而降低Pomc mRNA的表达。这些结果表明了一种影响肥胖易感性或恢复力性状的表观遗传调控机制。
