Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology.
Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology.
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DOI：
10.3389/fnins.2015.00477
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发表时间：
2015
影响因子：
4.3
通讯作者：
O'Roak BJ
中科院分区：
文献类型：
--
作者：
Barnard RA;Pomaville MB;O'Roak BJ
自闭症谱系障碍（ASD）是一种常见的神经发育障碍，具有强大但复杂的遗传成分。最近基于家族的外显子组测序策略已经发现了特定基因的复发性从头突变，为ASD风险提供了强有力的证据，但也凸显了该疾病的极端遗传异质性。然而，这些基因的破坏在发育早期的关键分子通路上聚集。特别是，功能富集分析发现，有一个偏向基因参与转录调控，如染色质修饰。在这里，我们回顾了最近的遗传，动物模型，共表达网络和功能基因组学研究有关的高置信度ASD风险基因，CHD8。CHD 8是一种染色质重塑因子，可能是常见ASD病因的“主调节因子”。具有CHD8突变的个体显示出ASD亚型，其包括类似的身体特征，例如大头畸形和长期GI问题，包括复发性便秘。类似地，CHD8破坏的动物模型表现出增大的头围和降低的肠道运动表型。系统生物学方法表明CHD8和其他候选ASD风险基因在胎儿中期发育期间富集，这可能代表ASD病因学的关键时间窗。来自早期发育的细胞和初级组织模型的转录和CHD8结合位点谱表明CHD8也可以通过直接和间接手段正向调节其他候选ASD风险基因。然而，需要继续研究以阐明调控机制，并确定哪些CHD8靶点与ASD风险最相关。总的来说，这些初步研究表明了常见ASD病因的潜力和未来个性化治疗的发展。
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a “master regulator” of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future.