Germline Chd8 haploinsufficiency alters brain development in mouse

We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Adult Chd8+/del5 mice exhibited cognitive impairment correlated with increased cerebral cortex, hippocampus, and amygdala volume, but displayed normal social interactions and no repetitive behaviors. Network analysis of neurodevelopmental gene expression revealed widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes, and neuroimmune signaling. Among gene co-expression networks, we identified a module with peak expression in early brain development that featured dysregulation of genes enriched for promoter binding by Chd8 and associated with RNA processing, chromatin remodeling, and cell cycle. We validated increased neuronal proliferation and splicing alterations during Chd8+/del5 brain development. Our results show that Chd8+/del5 mice exhibit neurodevelopmental changes paralleling humans with CHD8 mutations and highlight widespread pathological consequences of Chd8 haploinsufficiency. We examined RNA expression (RNA-sequencing) and Chd8 binding to the genome (ChIP-seq) from whole forebrain dissections of WT and germline heterozygous Chd8 mutant mice.本研究探究了生殖系杂合移码型CHD8 (Chd8) 突变对小鼠神经发育的影响。 成年CHD8+/del5小鼠表现出认知功能障碍，该表型与其大脑皮层、海马体及杏仁核体积增大呈相关性，但该小鼠社交行为正常，未出现重复刻板行为。 对神经发育相关基因表达的网络分析显示，CHD8+/del5小鼠体内多条参与神经发育障碍的通路存在广泛的转录组改变，涵盖神经发生、突触过程及神经免疫信号传导通路。 在基因共表达网络中，我们鉴定出一个在脑发育早期达到表达峰值的模块，该模块内的基因存在表达失调，这些基因富集于CHD8的启动子结合位点，且与RNA加工、染色质重塑及细胞周期调控相关。 我们验证了CHD8+/del5小鼠脑发育过程中神经元增殖增强及剪接异常的现象。 本研究结果表明，CHD8+/del5小鼠的神经发育改变与携带CHD8突变的人类患者高度相似，同时揭示了CHD8单倍体剂量不足所带来的广泛病理效应。 本研究对野生型（WT）及生殖系杂合CHD8突变小鼠的全前脑解剖组织，开展了RNA表达（RNA测序，RNA-sequencing）及CHD8全基因组结合分析（染色质免疫共沉淀测序，ChIP-seq）。