Chronic social stress induces DNA methylation changes at an evolutionary conserved intergenic region in chromosome X
Chronic social stress induces DNA methylation changes at an evolutionary conserved intergenic region in chromosome X
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DOI：
10.1080/15592294.2018.1486654
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发表时间：
2018-01-01
期刊：
影响因子：
3.7
通讯作者：
Potash, James B.
中科院分区：
文献类型：
--
作者：
Hing, Benjamin;Braun, Patricia;Potash, James B.
长期暴露于负面生活事件导致的慢性压力增加了情绪和焦虑障碍的风险。虽然慢性应激可以改变与行为相关的基因表达，但这种变化的分子调节因子尚未完全确定。其中一个可能起作用的过程是DNA甲基化，这是一种表观遗传过程，其中甲基被添加到核苷酸上，主要是CpG背景下的胞嘧啶，并且可以由慢性应激诱导。目前尚不清楚慢性社会失败（人类社会压力的一种模式）在多大程度上影响整个基因组的DNA甲基化模式。我们的研究通过使用一种称为甲基序列的靶向捕获方法来研究暴露于14天社会失败的小鼠基因组中假定的调节区域齿状回的DNA甲基化模式来解决这个问题。研究结果在亚硫酸氢盐焦磷酸测序的独立队列中得到了重复。鉴定出两个差异甲基化区（DMRs）。一个DMR位于Drosha的第9内含子，在应激小鼠中显示甲基化降低。这一观察结果在两个独立队列中的一个中得到了重复。在X染色体的基因间区发现了第二个DMR，应激小鼠在该区域的甲基化增加。这种甲基化差异在两个独立的队列和重度抑郁症（MDD）死后的大脑中得到了重复。这些结果突出了一个以前不知道的区域，即慢性社会失败压力的甲基化差异，这可能与重度抑郁症有关。
Chronic stress resulting from prolonged exposure to negative life events increases the risk of mood and anxiety disorders. Although chronic stress can change gene expression relevant for behavior, molecular regulators of this change have not been fully determined. One process that could play a role is DNA methylation, an epigenetic process whereby a methyl group is added onto nucleotides, predominantly cytosine in the CpG context, and which can be induced by chronic stress. It is unknown to what extent chronic social defeat, a model of human social stress, influences DNA methylation patterns across the genome. Our study addressed this question by using a targeted-capture approach called Methyl-Seq to investigate DNA methylation patterns of the dentate gyrus at putative regulatory regions across the mouse genome from mice exposed to 14days of social defeat. Findings were replicated in independent cohorts by bisulfite-pyrosequencing. Two differentially methylated regions (DMRs) were identified. One DMR was located at intron 9 of Drosha, and it showed reduced methylation in stressed mice. This observation replicated in one of two independent cohorts. A second DMR was identified at an intergenic region of chromosome X, and methylation in this region was increased in stressed mice. This methylation difference replicated in two independent cohorts and in Major Depressive Disorder (MDD) postmortem brains. These results highlight a region not previously known to be differentially methylated by chronic social defeat stress and which may be involved in MDD.