Objectives: We are investigating the role of multiple chromatin regulators in ASD using an unbiased experimental strategy that includes: a) Chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) to map binding sites of ASD-associated chromatin regulators; and b) cross-referencing these binding data with genome-wide histone modification maps to identify target genes activated or repressed by specific chromatin regulators.
Methods: To validate our approach, we have used ChIP-seq to map binding sites for multiple genes carrying one or more de novo mutations based on four recently published whole exome sequencing studies. We simultaneously generated maps of histone modifications associated with active promoters and enhancers. Combining these data we will identify regulatory elements and their target genes under the control of ASD related chromatin modifying genes, thus revealing specific gene regulation mechanisms potentially affected by ASD-associated mutations.
Results: We show that histone modification maps and chromatin regulator binding data can be combined to identify regulatory elements and associated genes putatively under the control of ASD-associated chromatin regulators. We will present specific data on genes implicated in ASD via recent whole exome sequencing data.
Conclusions: Our results demonstrate the feasibility of directly identifying the gene targets of ASD-associated chromatin regulators during brain development using ChIP-seq. Integrating these target datasets with maps of chromatin state and gene expression will allow us to define regulatory networks perturbed in ASD. This will provide insight into the developmental etiology of ASD and serve as a foundation for future experimental studies.
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