美国西奈山伊坎医学院Eric J. Nestler和Catherine J. Peña研究团队合作取得最新进展。他们表明早期应激（ELS）的长期行为和细胞类型特异性分子效应是由中等棘突神经元中的H3K79me2动力学介导的。2021年3月15日出版的《自然-神经科学》杂志发表了这项成果。
在这项研究中，他们研究了接触ELS的雄性和雌性小鼠伏隔核（NAc）中组蛋白修饰的长期变化。组蛋白H3（H3K79me2）的赖氨酸79的二甲基化以及控制该修饰的酶（DOT1L和KDM2B）富含D2型中等棘突神经元，对于ELS诱导的应激敏感性的表达至关重要。
他们绘制了该组蛋白标记基因组的位点特异性调控，以揭示其调控的转录网络。最后，小分子DOT1L抑制剂的全身给药逆转了ELS诱导的行为缺陷，表明该表观遗传机制的临床意义。
研究人员表示，易患慢性社交挫败压力（CSDS）的动物表现出与抑郁相关的行为，在几个边缘脑区，尤其是NAc的转录异常。ELS促进成年后对CSDS的易感性，但尚未研究NAc中转录控制机制的相关持久变化。
附：英文原文
Title: Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
Author: Hope Kronman, Anglica Torres-Berro, Simone Sidoli, Orna Issler, Arthur Godino, Aarthi Ramakrishnan, Philipp Mews, Casey K. Lardner, Eric M. Parise, Deena M. Walker, Yentl Y. van der Zee, Caleb J. Browne, Brittany F. Boyce, Rachael Neve, Benjamin A. Garcia, Li Shen, Catherine J. Pea, Eric J. Nestler
Issue&Volume: 2021-03-15
Abstract: Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.
DOI: 10.1038/s41593-021-00814-8
Source: https://www.nature.com/articles/s41593-021-00814-8
Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex
本期文章：《自然—神经科学》：Online/在线发表
