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

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....

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Autores principales: Zhao, Ying-Tao, Kwon, Deborah Y., Johnson, Brian S., Fasolino, Maria, Lamonica, Janine M., Kim, Yoon Jung, Zhao, Boxuan Simen, He, Chuan, Vahedi, Golnaz, Kim, Tae Hoon, Zhou, Zhaolan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028126/
https://www.ncbi.nlm.nih.gov/pubmed/29848492
http://dx.doi.org/10.1101/gr.233775.117
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author Zhao, Ying-Tao
Kwon, Deborah Y.
Johnson, Brian S.
Fasolino, Maria
Lamonica, Janine M.
Kim, Yoon Jung
Zhao, Boxuan Simen
He, Chuan
Vahedi, Golnaz
Kim, Tae Hoon
Zhou, Zhaolan
author_facet Zhao, Ying-Tao
Kwon, Deborah Y.
Johnson, Brian S.
Fasolino, Maria
Lamonica, Janine M.
Kim, Yoon Jung
Zhao, Boxuan Simen
He, Chuan
Vahedi, Golnaz
Kim, Tae Hoon
Zhou, Zhaolan
author_sort Zhao, Ying-Tao
collection PubMed
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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spelling pubmed-60281262019-01-01 Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains Zhao, Ying-Tao Kwon, Deborah Y. Johnson, Brian S. Fasolino, Maria Lamonica, Janine M. Kim, Yoon Jung Zhao, Boxuan Simen He, Chuan Vahedi, Golnaz Kim, Tae Hoon Zhou, Zhaolan Genome Res Research 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. Cold Spring Harbor Laboratory Press 2018-07 /pmc/articles/PMC6028126/ /pubmed/29848492 http://dx.doi.org/10.1101/gr.233775.117 Text en © 2018 Zhao et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Zhao, Ying-Tao
Kwon, Deborah Y.
Johnson, Brian S.
Fasolino, Maria
Lamonica, Janine M.
Kim, Yoon Jung
Zhao, Boxuan Simen
He, Chuan
Vahedi, Golnaz
Kim, Tae Hoon
Zhou, Zhaolan
Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
title Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
title_full Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
title_fullStr Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
title_full_unstemmed Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
title_short Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
title_sort long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028126/
https://www.ncbi.nlm.nih.gov/pubmed/29848492
http://dx.doi.org/10.1101/gr.233775.117
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