Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains

Abstract

Genetic variants associated with autism spectrum disorders (ASDs) are enriched in genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is widely studied, the mechanism by which chromatin regulators contribute to ASD risk remains poorly understood. Upon profiling and analyzing the transcriptional and epigenomic features of genes expressed in the cortex, we uncovered a unique set of long genes that contain broad enhancer-like chromatin domains (BELD) spanning across their entire gene bodies. Analyses of these BELD genes show that they are highly transcribed with frequent RNA polymerase II (Pol II) initiation, low Pol II pausing, and exhibit frequent chromatin-chromatin interactions within their gene bodies. These BELD features are conserved from rodents to humans, enriched in genes involved in synaptic function, and appear postnatally concomitant with synapse development. Importantly, we find that BELD genes are highly implicated in neurodevelopmental disorders, particularly ASDs, and that their expression is preferentially downregulated in individuals with idiopathic autism. Finally, we find that the transcription of BELD genes is particularly sensitive to alternations in ASD-associated chromatin regulators. These findings suggest that the epigenomic regulation of BELD genes is important for postnatal cortical development and lends support to a model by which mutations in chromatin regulators causally contribute to ASDs by preferentially impairing BELD gene transcription.