Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes

Siavash Fazel Darbandi; Joon-Yong An; Kenneth Lim; Nicholas F. Page; Lindsay Liang; David M. Young; Athena R. Ypsilanti; Matthew W. State; Alex S. Nord; Stephan J. Sanders; John L.R. Rubenstein

Cell Reports (Jun 2024)

Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes

Siavash Fazel Darbandi,
Joon-Yong An,
Kenneth Lim,
Nicholas F. Page,
Lindsay Liang,
David M. Young,
Athena R. Ypsilanti,
Matthew W. State,
Alex S. Nord,
Stephan J. Sanders,
John L.R. Rubenstein

Affiliations

Siavash Fazel Darbandi: Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Joon-Yong An: School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, South Korea; BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, South Korea
Kenneth Lim: Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Nicholas F. Page: Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Lindsay Liang: Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
David M. Young: Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Athena R. Ypsilanti: Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Matthew W. State: Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
Alex S. Nord: Department of Neurobiology, Physiology, and Behavior and Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA
Stephan J. Sanders: Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA; Institute for Developmental and Regenerative Medicine, Old Road Campus, Roosevelt Dr., Headington, Oxford OX3 7TY, UK; Corresponding author
John L.R. Rubenstein: Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 6
p. 114329

Abstract

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Summary: Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (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, 1–2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 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 that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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