Long genes linked to autism harbor intragenic super-enhancer-like chromatin domains
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413087 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6129670.fastq.gz | Fastqsanger.gz | |||
| SRR6129680_1.fastq.gz | Fastqsanger.gz | |||
| SRR6129680_2.fastq.gz | Fastqsanger.gz | |||
| SRR6129671.fastq.gz | Fastqsanger.gz | |||
| SRR6129681_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description: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 (BELDs) 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 and low Pol II pausing, and they exhibit frequent chromatin-chromatin interactions within their gene bodies. These BELD features are conserved from rodents to humans, are enriched in genes involved in synaptic function, and appear post-natally concomitant with synapse development. Importantly, we find that BELD genes are highly implicated in neurodevelopmental disorders, particularly ASDs, and that their expression is preferentially down-regulated 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 post-natal cortical development and lend support to a model by which mutations in chromatin regulators causally contribute to ASDs by preferentially impairing BELD gene transcription.
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