Mapping cis-regulatory elements in human excitatory and inhibitory neurons links psychiatric disease heritability and activity-regulated transcriptional programs

Genome-wide association studies (GWAS) have identified hundreds of loci associated with psychiatric diseases, yet there is a lack of understanding of disease pathophysiology. Common risk variants can shed light on the molecular mechanisms underlying these diseases; however, identifying specific causal variants remains challenging. An added complication is that most common risk variants are in non-coding regions. Their impact is likely to be restricted to particular cell types, developmental stages, or cell states. Here, we comprehensively mapped cis-regulatory elements in two defined populations of human excitatory and inhibitory neurons derived from pluripotent stem cells. Overall design: We performed CUT&RUN (cleavage under targets and release using nuclease) to measure H3K27ac profiles in human induced glutamatergic (Glu) and GABAergic (GABA) neurons derived from human pluripotent stem cells (ES and iPSCs). We exposed neurons to an elevated level of potassium chloride (KCl) to study activity-induced responses, and profiled H3K27ac at various time points after depolarization.