Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders.

Autor:	Ma Y; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York., Bendl J; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York., Hartley BJ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Black Family Stem Cell Institute, New York, New York., Fullard JF; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York., Abdelaal R; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Black Family Stem Cell Institute, New York, New York., Ho SM; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Black Family Stem Cell Institute, New York, New York., Kosoy R; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York., Gochman P; Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland., Rapoport J; Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland., Hoffman GE; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York., Brennand KJ; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Black Family Stem Cell Institute, New York, New York. Electronic address: kristen.brennand@yale.edu., Roussos P; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York; Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, New York. Electronic address: panagiotis.roussos@mssm.edu.
Jazyk:	angličtina
Zdroj:	Biological psychiatry [Biol Psychiatry] 2024 Jan 15; Vol. 95 (2), pp. 187-198. Date of Electronic Publication: 2023 Jul 14.
DOI:	10.1016/j.biopsych.2023.07.003
Abstrakt:	Background: Converging evidence from large-scale genetic and postmortem studies highlights the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and understanding how changes contribute to disease remain challenging. Methods: To better understand how the activity-dependent regulome contributes to risk for brain-related disorders, we profiled the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell-derived glutamatergic neurons (NGN2) from 6 patients with schizophrenia and 5 control participants. Results: Multiomic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within 1 hour of potassium chloride-induced depolarization, independent of diagnosis, glutamatergic neurons displayed substantial activity-dependent changes in the expression of genes regulating synaptic function. Depolarization-induced changes in the regulome revealed significant heritability enrichment for schizophrenia and Parkinson's disease, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for brain-related disorders. Gene coexpression network analysis elucidated interactions among activity-dependent and disease-associated genes and pointed to a key driver (NAV3) that interacted with multiple genes involved in axon guidance. Conclusions: Overall, we demonstrated that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy. (Copyright © 2023 Society of Biological Psychiatry. All rights reserved.)
Databáze:	MEDLINE
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