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

Yixuan Ma; Jaroslav Bendl; Brigham J Hartley; John F Fullard; Rawan Abdelaal; Seok-Man Ho; Roman Kosoy; Peter Gochman; Judith Rapoport; Gabriel E Hoffman; Kristen J Brennand; Panos Roussos

doi:10.1016/j.biopsych.2023.07.003

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

Biol Psychiatry. 2024 Jan 15;95(2):187-198. doi: 10.1016/j.biopsych.2023.07.003. Epub 2023 Jul 14.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
⁵ 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.
⁶ 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.
⁷ 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.

PMID: 37454787
PMCID: PMC10787819 (available on 2025-01-15)
DOI: 10.1016/j.biopsych.2023.07.003

Abstract

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.

Keywords: Activity-dependent; Coexpression network; Depolarization; Epigenome; Schizophrenia; Transcriptome.

MeSH terms

Brain
Gene Expression Regulation
Humans
Induced Pluripotent Stem Cells* / metabolism
Neurons / metabolism
Schizophrenia*

Abstract

MeSH terms

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