The BAF complex works with FOS to regulate human neuronal activity-dependent ASD-associated gene programs

Abstract

The BAF chromatin remodeling complex is critical to normal brain development, and rare variants within genes encoding BAF subunits are a common genetic cause of neurodevelopmental disorders, including autism spectrum disorder (ASD). Yet the factors that direct BAF binding across the neuronal genome, the human neuronal gene programs that are regulated by BAF, and the mechanisms whereby BAF subunit perturbation leads to ASD are not known. We find that BAF binds with the activity-dependent transcription factor FOS to distal regulatory regions that, in response to neuronal activity, undergo chromatin opening and show evidence of enhancer activation. Knock-out of ARID1A, a BAF subunit implicated in ASD, leads to decreased chromatin accessibility at FOS/BAF binding sites concomitant with decreased expression of nearby activity-regulated ASD-associated genes. Additionally, we find that the FOS binding motif in FOS/BAF-bound regions is highly constrained in the human population, and that rare variants in this motif in ASD-affected individuals disrupt stimulus-dependent enhancer activation. This suggests that genetic variation in FOS/BAF-bound regions contributes to ASD pathogenesis, due to an inability to recruit FOS and BAF to enhancers to promote gene expression. Together, our findings highlight a role for BAF in mediating neuronal transcriptional programs downstream of FOS and reveal a mechanism by which non-coding variants may impact BAF function and contribute to risk for ASD.