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Long genes linked to autism harbor intragenic super-enhancer-like chromatin domains

ABSTRACT: Genetic variants associated with autism spectrum disorders (ASDs) are enriched for genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is well studied, the mechanism by which disruptions of chromatin regulators promote the development of ASDs remains unclear. Here we identify 184 neuronal long genes containing super-enhancer-like chromatin modifications across their gene bodies, which we term SE long genes. We show that SE long genes exhibit reduced transcriptional RNA Polymerase II pausing, higher transcription initiation frequency, and higher expression levels. The gene body regions of SE long genes display active epigenomic status and are organized into a highly connected chromatin unit. Notably, SE long genes are enriched in known ASD-associated genes related to the synapse and signaling pathways. These characteristics present a molecular link between chromatin regulators and synaptic function, and suggest a mechanism by which disruptions in these chromatin regulators compromise the synapse. Indeed, we show that the expression of SE long genes is more sensitive to the disruptions of autism-risk chromatin regulators, including Kmt2c, Kdm5c, Kdm6b, and Mecp2, than non-SE long genes. We propose that the transcriptional impairment of SE long genes by dysfunctional chromatin regulators is a general molecular mechanism for ASD pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE104576 | GEO | 2018/05/02

REPOSITORIES: GEO

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