CHD8 haploinsufficiency results in delayed neurodevelopment and autistic-like phenotypes in mice. Mus musculus

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 behaviours1. 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, with CHD8, a gene encoding a chromatin remodeler, being most frequently affected2-6. Whether CHD8 mutation is causative for ASD and how it might establish ASD traits have remained unknown, however. Here we show that mice heterozygous for Chd8 mutation manifest macrocephaly and ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. Unexpectedly, CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but rather gave rise to small but global changes in that of a large number of ASD-related genes in the brain. Gene set enrichment analysis (GSEA) revealed that neurodevelopment is delayed in the mutant embryos. Furthermore, reduced expression of CHD8 resulted in abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes, likely accounting for the delay in neurodevelopment in the mutant mice. Our results thus indicate that CHD8 haploinsufficiency is a cause of ASD, with disease pathogenesis likely resulting from abnormal REST activation and a consequent delay in neurodevelopment.

自闭症谱系障碍（Autism Spectrum Disorder, ASD）是一类以社交互动与沟通缺陷、受限及重复行为为核心特征的神经发育障碍[1]。ASD具有较强的遗传基础且遗传力极高。近期的外显子组测序（Exome sequencing）分析已在众多自闭症患者的多个基因中鉴定出大量新发突变，其中编码染色质重塑因子的CHD8基因是受影响最为频繁的靶点[2-6]。然而，CHD8突变是否为自闭症的致病诱因，以及其如何介导自闭症表型的形成，迄今仍未明确。本研究显示，携带Chd8突变的杂合子小鼠可表现出头围增大及类自闭症行为特征，包括焦虑水平升高、重复行为与社交行为异常。出乎意料的是，CHD8单倍体剂量不足（haploinsufficiency）并未引发少数特定基因的表达出现显著变化，反而导致大脑内大量自闭症相关基因的表达产生小幅但全局性的改变。基因集富集分析（Gene Set Enrichment Analysis, GSEA）结果显示，突变胚胎的神经发育存在延迟。此外，CHD8表达水平下调会导致RE-1沉默转录因子（RE-1 Silencing Transcription Factor, REST）异常激活，该因子可抑制众多神经元基因的转录，这或可解释突变小鼠神经发育延迟的表型。综上，本研究结果证实CHD8单倍体剂量不足是自闭症的致病原因之一，其疾病发病机制可能源于REST异常激活及由此引发的神经发育延迟。