Chromatin-regulatory genes are among the most common classes of genes mutated in autism spectrum disorder (ASD) and intellectual disability (ID). It is well established that cellular differentiation requires the precise orchestration of gene expression programs, which is mediated by dynamic changes to chromatin state and structure. However, it remains unclear why de novo mutations in a subset of chromatin regulators give rise to the specific neurobehavioral changes that underlie ASD/ID and whether mutations in different chromatin regulators converge on a common gene regulatory mechanism in ASD/ID.

In this project, Anne West plans to develop an assay system in human induced pluripotent stem cell (iPSC)-derived neurons to screen for the consequences of ASD/ID associated chromatin regulator mutations on a set of chromatin phenotypes that orchestrate synapse maturation. The screen is based on data indicating that the dynamic regulation of histone H3 lysine 27 methylation (H3K27me3) in maturing postmitotic neurons coordinates the expression of synaptic genes. The hypothesis is that deposition of H3K27me3 not only directly represses genes, but also stabilizes a subset of distal enhancer-promoter loops to poise genes for future activation.

This project will comprehensively characterize these chromatin and transcriptional relationships in iPSC-derived human neurons differentiating in culture and then phenotype the consequences of introducing ASD/ID-associated chromatin regulator mutations in a set of pilot genes. These studies are expected to establish a scalable assay in human iPSC-derived neurons that can be used to screen for convergent effects of ASD/ID-associated mutations on chromatin mechanisms that mediate maturation of synaptic gene expression programs.