Long Genes Linked to Autism Spectrum Disorders Harbor Broad Enhancer-Like Chromatin Domains

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dc.contributor.authorZhao, Y. -T
dc.contributor.authorKwon, D. Y.
dc.contributor.authorJohnson, B. S.
dc.contributor.authorFasolino, M.
dc.contributor.authorLamonica, J. M.
dc.contributor.authorKim, Yoon Jung
dc.contributor.authorZhao, B. S.
dc.contributor.authorHe, C.
dc.contributor.authorVahedi, G.
dc.contributor.authorKim, Tae Hoon
dc.contributor.authorZhou, Z.
dc.contributor.utdAuthorKim, Yoon Jung
dc.contributor.utdAuthorKim, Tae Hoon
dc.date.accessioned2019-08-30T20:43:40Z
dc.date.available2019-08-30T20:43:40Z
dc.date.created2018-05-18
dc.descriptionIncludes supplementary material
dc.description.abstractGenetic 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.
dc.description.departmentSchool of Natural Sciences and Mathematics
dc.description.sponsorshipThis work was supported by NIH R01MH091850 and R01NS081054; T32 Training Program in Neurodevelopmental Disabilities (T32NS007413); Cell and Molecular Biology Training Grant (TG32-GM072290).
dc.identifier.bibliographicCitationZhao, Y. -T, D. Y. Kwon, B. S. Johnson, M. Fasolino, et al. 2018. "Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains." Genome Research 29(8): 933-942, doi:10.1101/gr.233775.117
dc.identifier.issn1088-9051
dc.identifier.issue8
dc.identifier.urihttps://hdl.handle.net/10735.1/6848
dc.identifier.volume29
dc.language.isoen
dc.publisherCold Spring Harbor Laboratory Press
dc.relation.urihttp://dx.doi.org/10.1101/gr.233775.117
dc.rightsCC BY-NC 4.0 (Attribution-NonCommercial)
dc.rights©2018 The Authors
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.source.journalGenome Research
dc.subjectAutism spectrum disorders
dc.subjectChromatin
dc.subjectRNA polymerases
dc.subjectSynapses
dc.titleLong Genes Linked to Autism Spectrum Disorders Harbor Broad Enhancer-Like Chromatin Domains
dc.type.genrearticle

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