Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology

Abstract

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.

Keywords: CHD8; autism; autism spectrum disorder (ASD); co-expression networks; de novo mutations; functional genomics; subtype; systems biology.

Figure 1

Phenotypic characteristics of patients with CHD8 Mutations. (A) Common facial features of patients with CHD8 mutations include macrocephaly, hypertelorism, down-slanted palpebral fissures, broad nose, pointed chin, and prominent supra-orbital ridge. (B) Longitudinal head circumference data for two patients (red and blue). At 2 months after birth, orbital frontal head growth is pronounced. Head growth continues to be in the 97th percentile throughout childhood. Figure originally published in Bernier et al. (2014) used with permission.

Figure 2

CHD8 functional genomics studies. (A) Flow chart describing functional genomics studies, Sugathan et al., Cotney et al., and Wilkinson et al. including CHD8 knockdown in cellular models of early neural development and ChIP-seq. Cotney et al. also incorporated primary fetal human cortical and embryonic mouse brain tissue into the ChIP-seq analysis. Integrating the gene expression and CHD8 binding profiles, networks of CHD8 regulated genes were constructed and analyzed for enrichment of candidate ASD risk genes. (B) CHD8 targeted candidate ASD risk genes found in the “Willsey set” observed between studies. Genes found in Cotney et al. specifically have CHD8 bound promoters. Human sites in Cotney et al. are shared between hNSCs and brain tissue. Though not included as part of the “Willsey set” in Cotney et al., POGZ is included here. POGZ was noted as having a CHD8 bound promoter and it is one of the high confidence “Willsey set” genes. (C) List of the shared candidate ASD risk genes from the “Willsey Set” bound by CHD8 between both studies and conserved between human and mouse.

Figure 3

Proposed mechanisms for CHD8 transcriptional activation. (A) CHD8 is most commonly found near active transcription start sites with histone modifications H3K4me3 (green circle) or H3K27ac (yellow circle). CHD8 may directly activate genes by directly binding near the transcriptional start site and promote transcription factor activity or recruitment. (B) CHD8 may indirectly activate genes through interactions between modified histone sites and other co-regulators to make chromatin more assessable.