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. 2015 May 19;5(5):e568.
doi: 10.1038/tp.2015.62.

The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes

B Wilkinson  1 , N Grepo  2 , B L Thompson  3 , J Kim  4 , K Wang  4 , O V Evgrafov  4 , W Lu  5 , J A Knowles  4 , D B Campbell  4
Affiliations

The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes

B Wilkinson et al. Transl Psychiatry. .

Abstract

Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715 genes, including both protein-coding and noncoding RNAs. Among the 10 most changed transcripts, 4 (40%) were noncoding RNAs. The transcriptional changes among protein-coding genes involved a highly interconnected network of genes that are enriched in neuronal development and in previously identified ASD candidate genes. These results suggest that CHD8 insufficiency may be a central hub in neuronal development and ASD risk.

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Figures

Figure 1
Figure 1
Quantitative modeling of disruptive mutations in CHD8. (a) Quantitative PCR showed that a 20 nM concentration of CHD8 siRNA resulted in an ~50% reduction of CHD8 transcript. (b) Representative western blot indicated decreased CHD8 protein following CHD8 siRNA-mediated knockdown. (c) Quantitative analysis of western blot data shows a significant reduction in CHD8 protein following CHD8 siRNA treatment. Error bars are s.e.m., **P<0.01, *P<0.05. CHD8, chromodomain helicase DNA-binding protein 8; siRNA, small interfering RNA.
Figure 2
Figure 2
qPCR validation of differentially expressed genes identified by RNA-Seq. Fifteen genes excluding CHD8 were assayed via qPCR to establish the validity of the differential expression analysis based on the obtained RNA-seq data. qPCR and RNA-seq values showed a statistically significant correlation with both Pearson and Spearman methods. qPCR, quantitative PCR.
Figure 3
Figure 3
Representative enrichment of gene ontology among differentially expressed genes. (a) Gene ontology (GO) enrichment analysis on all differentially expressed genes due to knockdown of CHD8. (b) GO enrichment analysis on genes downregulated in response to knockdown of CHD8. Upregulated genes subjected to GO analysis indicated enrichment of mitochondrial membrane genes only (not shown). P-value represents Benjamini–Hotchberg correction for multiple tests. CHD8, chromodomain helicase DNA-binding protein 8.
Figure 4
Figure 4
Protein–protein interaction analysis of differentially expressed genes—Disease Association Protein–Protein Link Evaluator (DAPPLE) was used to determine direct relationships among the protein products of the genes that were differentially expressed due to knockdown of CHD8. A subnetwork of genes with associated corrected P-values <0.05, indicating seed proteins that are more likely to be connected to other seed proteins within the network than by chance, was generated and visualized using Cytoscape software. Increasing significance corresponds to increasing node size. Differential expression of the associated gene product is shown with increasing densities of blue and red indicating the degree of down- and upregulation conferred by knockdown of CHD8, respectively. CHD8, chromodomain helicase DNA-binding protein 8.
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