We previously published a paper that described the discovery of many new genes contributing to autism and neurodevelopment (Talkowski et al., 2012, Cell). Among these loci was a series of genes involved in chromatin modification and transcriptional regulation, which proposed a new pathway of genes involved in autism and neurodevelopment. Most prominent among those genes was CHD8, a chromodomain helicase that was also implicated in ASD by multiple exam sequencing studies that same year. This year, we completed a long-term study to evaluate the impact of editing the genome in iPS-derived neural progenitor cells to be deficient for this gene, mimicking the effect in patients with loss-of-function mutations. We integrated mutliple functional genomic measures to determine the consequences of CHD8 deficiency in NPCs, and the results of this study were striking. Through ChIP-sequencing, we discovered that this genes binds pervasively throughout the genome, and through RNA-sequencing we uncovered a series of pathways and genes associated with neural development that are regulated by CHD8. Moreover, we discovered that CHD8 influences the expression of genes involved in transcriptional regulation that are highly expressed early in neural development, as well as genes involved in synapse formation and development that are expressed later in prenatal and early postnatal development. We also found strong connections between this locus and genes associated with cancer. Based upon these findings, many groups are actively pursuing this new avenue of research into the pleiotropic effects of strong effect chromatin modifiers.

Sugathan A*, Biagioli M*, Golzio C*, Erdin S*, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME. CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4468-77.