Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes
Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes
Abstract Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). ChIP-seq was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000bp upstream of transcription start site, was highly predictive of brain expressed genes. This signature was observed at 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After eight days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.
Liang Lindsay、State Matthew W.、Rubenstein John L. R.、Page Nicholas F.、Fazel Darbandi Siavash、Markenscoff-Papadimitriou Eirene、Sanders Stephan J.、Lim Kenneth、An Joon-Yong、Nord Alex S.、Ypsilanti Athena R.
Department of Psychiatry and Weill Institute for Neurosciences, University of California San FranciscoDepartment of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco||Institute for Human Genetics, University of California San FranciscoNina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco||Department of Psychiatry and Weill Institute for Neurosciences, University of California San FranciscoDepartment of Psychiatry and Weill Institute for Neurosciences, University of California San FranciscoNina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco||Department of Psychiatry and Weill Institute for Neurosciences, University of California San FranciscoNina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco||Department of Psychiatry and Weill Institute for Neurosciences, University of California San FranciscoDepartment of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco||Bakar Computational Health Sciences Institute, University of California San Francisco||Institute for Human Genetics, University of California San Francisco||Institute for Developmental and Regenerative Medicine, Old Road CampusNina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco||Department of Psychiatry and Weill Institute for Neurosciences, University of California San FranciscoSchool of Biosystem and Biomedical Science, College of Health Science, Korea University||BK21FOUR R&E Center for Learning Health Systems, Korea UniversityDepartment of Neurobiology, Physiology, and Behavior and Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, University of California DavisNina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco||Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco
基础医学神经病学、精神病学遗传学
Liang Lindsay,State Matthew W.,Rubenstein John L. R.,Page Nicholas F.,Fazel Darbandi Siavash,Markenscoff-Papadimitriou Eirene,Sanders Stephan J.,Lim Kenneth,An Joon-Yong,Nord Alex S.,Ypsilanti Athena R..Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes[EB/OL].(2025-03-28)[2025-05-29].https://www.biorxiv.org/content/10.1101/2022.10.17.512583.点此复制
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