Whole-exome and whole-genome surveys have revealed multiple transcriptional regulators harboring loss of function mutations associated with risk for autism spectrum disorder (ASD). Many of these genes converge in gene co-expression networks in the developing human brain. Recent experimental studies of one prominent ASD risk gene, CHD8, indicate that CHD8 regulates other ASD risk genes during neurodevelopment and that loss of CHD8 expression may produce widespread expression changes across regulatory networks that result in altered neurodevelopment.
Given the cellular heterogeneity of the developing cortex, there is likely to be substantial cell-type specific variation in the effects of loss of function mutations in CHD8 and other regulatory factors associated with ASD. However, current experimental studies of ASD risk gene networks and the biological effects of ASD-associated loss of function mutations have not yet assessed effects at this level of cellular resolution. To identify the cell types in which ASD risk genes converge, we need robust methods for mapping the gene targets of multiple regulators associated with ASD. To date, this has not been technically feasible.
Using a CHD8 knockout mouse model as their entry point, James Noonan and colleagues will map ASD-associated regulatory networks at high cellular resolution in the developing cortex to determine the cell types in which those networks are disrupted in ASD. They will also use genetically modified human neural stem cells to identify regulatory targets of CHD8 and other ASD risk genes in a human neurodevelopmental context. By integrating these approaches, they will elucidate cell-type specific CHD8 regulatory networks and establish how those networks are disrupted due to loss of CHD8. This will reveal regulatory, cellular and developmental mechanisms contributing to ASD that are obscured by the low resolution of current analyses.