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

Zhao, Y.-T., Kwon, D. Y., Johnson, B. S., Fasolino, M., Lamonica, J. M., Kim, Y. J., Zhao, B. S., He, C., Vahedi, G., Kim, T. H., & Zhou, Z.

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

2018

Cold Spring Harbor Laboratory

Animals
Autism Spectrum Disorder genetics
Autistic Disorder genetics
Chromatin genetics
Humans
Index Medicus
Male
Mice
Mice, Inbred C57BL
Mutation genetics
Neurogenesis genetics
RNA Polymerase II genetics
Regulatory Sequences, Nucleic Acid genetics
Transcription, Genetic genetics

English

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.

Genome Research, Volume 28, Issue 7, May 2018, pages 933-942

© 2018 Zhao et al.; Published by Cold Spring Harbor Laboratory Press

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