表观遗传学
帕金森病
Mef2
生物
表观遗传学
多巴胺能
线粒体
发病机制
遗传学
增强子
神经科学
疾病
转录因子
生物信息学
细胞生物学
医学
免疫学
多巴胺
基因表达
基因
病理
DNA甲基化
作者
Minhong Huang,Dan Lou,Adhithiya Charli,Dehui Kong,Huajun Jin,Gary Zenitsky,Vellareddy Anantharam,Anumantha G. Kanthasamy,Zhibin Wang
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2021-09-08
卷期号:6 (17)
被引量:14
标识
DOI:10.1172/jci.insight.138088
摘要
Mitochondrial dysfunction is a major pathophysiological contributor to the progression of Parkinson's disease (PD); however, whether it contributes to epigenetic dysregulation remains unknown. Here, we show that both chemically and genetically driven mitochondrial dysfunctions share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.3 (H3.3K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27ac. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed that mitochondrial dysfunction induces H3K27ac in ex vivo and in vivo (MitoPark) neurodegenerative models of PD. Notably, the significantly increased H3K27ac in postmortem PD brains highlights the clinical relevance to the human PD population. Our results reveal an exciting mitochondrial dysfunction-metabolism-H3K27ac-transcriptome axis for PD pathogenesis. Collectively, the mechanistic insights link mitochondrial dysfunction to epigenetic dysregulation in dopaminergic degeneration and offer potential new epigenetic intervention strategies for PD.
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