{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:55:52Z","timestamp":1785520552703,"version":"3.56.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T00:00:00Z","timestamp":1673222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 MH127081-01A1"],"award-info":[{"award-number":["R01 MH127081-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["4P20GM103641-06"],"award-info":[{"award-number":["4P20GM103641-06"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"South Carolina EPSCOR stimulus","award":["18-SR04"],"award-info":[{"award-number":["18-SR04"]}]},{"name":"National Institute of General Medical Sciences SC INBRE pilot","award":["5P20GM103499-17"],"award-info":[{"award-number":["5P20GM103499-17"]}]},{"name":"Brown University Legorreta Cancer Center"},{"DOI":"10.13039\/100014082","name":"Rhode Island Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014082","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Mental Health T32","award":["T32MH093315"],"award-info":[{"award-number":["T32MH093315"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.<\/jats:p>","DOI":"10.1093\/hmg\/ddad002","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T07:44:45Z","timestamp":1673250285000},"page":"1634-1646","source":"Crossref","is-referenced-by-count":16,"title":["Dysregulation of the chromatin environment leads to differential alternative splicing as a mechanism of disease in a human model of autism spectrum disorder"],"prefix":"10.1093","volume":"32","author":[{"given":"Calvin S","family":"Leung","sequence":"first","affiliation":[{"name":"Department of Molecular Biology , Cell Biology and Biochemistry, , Providence, RI 02912 , USA"},{"name":"Brown University , Cell Biology and Biochemistry, , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience , Carney 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29208 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A","family":"Marinelli","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina , Columbia, SC 29208 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan W","family":"Hollingsworth","sequence":"additional","affiliation":[{"name":"UCONN Health Comprehensive Multiple Sclerosis Center , Department of Neurology, , Farmington, CT 06030 , USA"},{"name":"University of Connecticut School of Medicine , Department of Neurology, , Farmington, CT 06030 , USA"},{"name":"Division of Multiple Sclerosis and Translational Neuroimmunology , Department of Neurology, , Farmington, CT 06030 , USA"},{"name":"University of Connecticut School of Medicine , Department of Neurology, , Farmington, CT 06030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbie M","family":"Maguire","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology , Cell Biology and Biochemistry, , Providence, RI 02912 , USA"},{"name":"Brown University , Cell Biology and Biochemistry, , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience , Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), , Providence, RI 02912 , USA"},{"name":"Brown University , Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara H","family":"Cowen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina , Columbia, SC 29208 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-033X","authenticated-orcid":false,"given":"Michael","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology , Cell Biology and Biochemistry, , Providence, RI 02912 , USA"},{"name":"Brown University , Cell Biology and Biochemistry, , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience , Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), , Providence, RI 02912 , USA"},{"name":"Brown University , Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Imitola","sequence":"additional","affiliation":[{"name":"UCONN Health Comprehensive Multiple Sclerosis Center , Department of Neurology, , Farmington, CT 06030 , USA"},{"name":"University of Connecticut School of Medicine , Department of Neurology, , Farmington, CT 06030 , USA"},{"name":"Division of Multiple Sclerosis and Translational Neuroimmunology , Department of Neurology, , Farmington, CT 06030 , USA"},{"name":"University of Connecticut School of Medicine , Department of Neurology, , Farmington, CT 06030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ece D","family":"Gamsiz Uzun","sequence":"additional","affiliation":[{"name":"Center for Computational Molecular Biology, Brown University , Providence, RI 02906 , USA"},{"name":"Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University , Providence, RI 02912 , USA"},{"name":"Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Academic Medical Center , Providence, RI 02903 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5153-1993","authenticated-orcid":false,"given":"Sofia 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