Locus-specific DNA methylation of Mecp2 promoter leads to autism-like phenotypes in mice
Locus-specific DNA methylation of Mecp2 promoter leads to autism-like phenotypes in mice
复制标题
Mecp2启动子的位点特异性DNA甲基化导致小鼠出现自闭症样表型
DOI：
10.1038/s41419-020-2290-x
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发表时间：
2020-02-03
影响因子：
9
通讯作者：
Li, Jia-Da
中科院分区：
文献类型：
--
作者：
Lu, Zongyang;Liu, Zhen;Li, Jia-Da
Autism spectrum disorder (ASD) is a neurodevelopmental disease with a strong heritability, but recent evidence suggests that epigenetic dysregulation may also contribute to the pathogenesis of ASD. Especially, increased methylation at the MECP2 promoter and decreased MECP2 expression were observed in the brains of ASD patients. However, the causative relationship of MECP2 promoter methylation and ASD has not been established. In this study, we achieved locus-specific methylation at the transcription start site (TSS) of Mecp2 in Neuro-2a cells and in mice, using nuclease-deactivated Cas9 (dCas9) fused with DNA methyltransferase catalytic domains, together with five locus-targeting sgRNAs. This locus-specific epigenetic modification led to a reduced Mecp2 expression and a series of behavioral alterations in mice, including reduced social interaction, increased grooming, enhanced anxiety/depression, and poor performance in memory tasks. We further found that specifically increasing the Mecp2 promoter methylation in the hippocampus was sufficient to induce most of the behavioral changes. Our finding therefore demonstrated for the first time the casual relationship between locus-specific DNA methylation and diseases symptoms in vivo, warranting potential therapeutic application of epigenetic editing.
