Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation
Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation
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DOI：
10.1016/j.psyneuen.2013.10.004
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发表时间：
2014-01-01
影响因子：
3.7
通讯作者：
Wagner, Shlomo
中科院分区：
文献类型：
--
作者：
Harony-Nicolas, Hala;Mamrut, Shimrat;Wagner, Shlomo
催产素是一种含有9个氨基酸的神经肽，在胎儿排出和母乳喂养中起着至关重要的作用，最近被认为与哺乳动物的社会行为有关。中枢和外周催产素的作用都是通过由一个基因编码的催产素受体（Oxtr）来调节的。与催产素在特定下丘脑核中的高度保守表达相反，其受体在大脑中的表达在不同哺乳动物物种之间甚至在同一物种的个体内都是高度多样化的。哺乳动物大脑中Oxtr表达模式的多样性被认为有助于广泛的社会系统和组织。然而，人们对这种多样性背后的机制知之甚少。DNA甲基化是调节基因转录的主要表观遗传机制，与自闭症患者Oxtr表达水平降低有关。在这里，我们假设DNA甲基化参与了Oxtr在小鼠大脑中的表达调控。通过结合亚硫酸盐DNA转换和下一代测序，我们发现特定的CpG位点在表达不同水平Oxtr mRNA的不同脑区域之间存在差异甲基化。其中一些CpG位点位于已知调节Oxtr表达的转录因子的推定结合位点，包括雌激素受体a （ERa）和SP1。具体来说，SP1位点的甲基化被发现与Oxtr的表达呈正相关。此外，我们发现这些位点的甲基化水平在不同的大脑区域预测ERce和Oxtr mRNA水平之间的关系。总之，我们的研究结果表明，小鼠Oxtr基因的脑区域特异性表达受其启动子DNA甲基化的表观遗传调控。(C) 2013 Elsevier Ltd.版权所有。
Oxytocin is a nine amino acid neuropeptide that is known to play a critical role in fetal expulsion and breast-feeding, and has been recently implicated in mammalian social behavior. The actions of both central and peripheral oxytocin are mediated through the oxytocin receptor (Oxtr), which is encoded by a single gene. In contrast to the highly conserved expression of oxytocin in specific hypothalamic nuclei, the expression of its receptor in the brain is highly diverse among different mammalian species or even within individuals of the same species. The diversity in the pattern of brain Oxtr expression among mammals is thought to contribute to the broad range of social systems and organizations. Yet, the mechanisms underlying this diversity are poorly understood. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression levels of the Oxtr in individuals with autism. Here we hypothesize that DNA methylation is involved in the expression regulation of Oxtr in the mouse brain. By combining bisulfite DNA conversion and Next-Generation Sequencing we found that specific CpG sites are differentially methylated between distinct brain regions expressing different levels of Oxtr mRNA. Some of these CpG sites are located within putative binding sites of transcription factors known to regulate Oxtr expression, including estrogen receptor a (ERa) and SP1. Specifically, methylation of the SP1 site was found to positively correlate with Oxtr expression. Furthermore, we revealed that the methylation levels of these sites in the various brain regions predict the relationship between ERce and Oxtr mRNA levels. Collectively, our results suggest that brain region-specific expression of the mouse Oxtr gene is epigenetically regulated by DNA methylation of its promoter. (C) 2013 Elsevier Ltd. All rights reserved.