CHD8 haploinsufficiency results in autistic-like phenotypes in mice
CHD8 haploinsufficiency results in autistic-like phenotypes in mice
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DOI：
10.1038/nature19357
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发表时间：
2016-09-29
期刊：
影响因子：
64.8
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Katayama, Yuta;Nishiyama, Masaaki;Nakayama, Keiichi I.
自闭症谱系障碍（ASD）包括一系列神经发育障碍，其特征在于社交和沟通方面的缺陷以及限制和重复行为（1）。ASD具有很强的遗传成分，遗传力高。外显子组测序分析最近已经在ASD个体中的多种基因中鉴定出许多从头突变（2，3），其中CHD 8（编码染色质重塑剂的基因）最常受影响（4-8）。CHD 8突变是否是ASD的病因，以及它们如何建立ASD特征仍然未知。在这里，我们发现Chd 8突变杂合子小鼠表现出ASD样行为特征，包括焦虑增加，重复行为和改变的社会行为。CHD 8单倍不足并没有导致一些特定基因表达的显着变化，而是引起了小鼠大脑中基因表达的小而全面的变化，让人想起ASD患者大脑中的变化。基因集富集分析表明，神经发育延迟的突变小鼠胚胎。此外，CHD 8的表达减少与RE-1沉默转录因子（REST）的异常激活有关，该因子抑制许多神经元基因的转录。在患有ASD的人类大脑中也观察到REST激活，并且发现CHD 8与小鼠大脑中的REST发生物理相互作用。因此，我们的研究结果与以下观点一致：CHD 8单倍不足是ASD的高度外显风险因素，疾病的发病机制可能源于神经发育的延迟。
Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours(1). ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD(2,3), with CHD8, a gene encoding a chromatin remodeller, being most frequently affected(4-8). Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown. Here we show that mice heterozygous for Chd8 mutations manifest ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but instead gave rise to small but global changes in gene expression in the mouse brain, reminiscent of those in the brains of patients with ASD. Gene set enrichment analysis revealed that neurodevelopment was delayed in the mutant mouse embryos. Furthermore, reduced expression of CHD8 was associated with abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes. REST activation was also observed in the brains of humans with ASD, and CHD8 was found to interact physically with REST in the mouse brain. Our results are thus consistent with the notion that CHD8 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis probably resulting from a delay in neurodevelopment.