Epigenome signatures landscaped by histone H3K9me3 are associated with the synaptic dysfunction in Alzheimer's disease
Epigenome signatures landscaped by histone H3K9me3 are associated with the synaptic dysfunction in Alzheimer's disease
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DOI：
10.1111/acel.13153
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发表时间：
2020-05-17
期刊：
影响因子：
7.8
通讯作者：
Ryu，Hoon
中科院分区：
文献类型：
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作者：
Lee，Min Young;Lee，Junghee;Ryu，Hoon
阿尔茨海默病（AD）是老年人痴呆的最常见病因，其发病机制至今仍不完全清楚。最近，表观遗传修饰已被证明在神经退行性变中起着潜在的作用，但在AD中，由异染色质标记的表观遗传标记的具体参与尚未研究。在此，我们发现H3K9me3介导的异染色质凝聚在散发性AD死后脑的皮质中升高。为了确定哪些表观基因组受到异染色质的调节，我们对正常受试者和AD患者的死后大脑进行了H3K9me3染色质免疫沉淀（ChIP）测序和mRNA测序。全基因组ChIP和mRNA测序数据的综合分析确定了H3K9me3高度占据的表观基因组，并与AD中的mRNA表达水平呈负相关。生物网络分析进一步揭示了H3K9me3标记的表观基因组主要参与突触传递、神经元分化和细胞运动。总之，我们的数据表明，H3K9me3的异常异染色质重塑导致突触功能相关基因的下调，表明H3K9me3的表观遗传改变与散发性AD的突触病理学相关。
The pathogenesis of Alzheimer's disease (AD) and the commonest cause of dementia in the elderly remain incompletely understood. Recently, epigenetic modifications have been shown to play a potential role in neurodegeneration, but the specific involvement of epigenetic signatures landscaped by heterochromatin has not been studied in AD. Herein, we discovered that H3K9me3‐mediated heterochromatin condensation is elevated in the cortex of sporadic AD postmortem brains. In order to identify which epigenomes are modulated by heterochromatin, we performed H3K9me3‐chromatin immunoprecipitation (ChIP)‐sequencing and mRNA‐sequencing on postmortem brains from normal subjects and AD patients. The integrated analyses of genome‐wide ChIP‐ and mRNA‐sequencing data identified epigenomes that were highly occupied by H3K9me3 and inversely correlated with their mRNA expression levels in AD. Biological network analysis further revealed H3K9me3‐landscaped epigenomes to be mainly involved in synaptic transmission, neuronal differentiation, and cell motility. Together, our data show that the abnormal heterochromatin remodeling by H3K9me3 leads to down‐regulation of synaptic function‐related genes, suggesting that the epigenetic alteration by H3K9me3 is associated with the synaptic pathology of sporadic AD.