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Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders.
Ma, Yixuan; Bendl, Jaroslav; Hartley, Brigham J; Fullard, John F; Abdelaal, Rawan; Ho, Seok-Man; Kosoy, Roman; Gochman, Peter; Rapoport, Judith; Hoffman, Gabriel E; Brennand, Kristen J; Roussos, Panos.
Affiliation
  • 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;
  • 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;
  • 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
  • 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;
  • 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
  • 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
  • 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;
  • 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, Ne
  • 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, Ica
  • 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;
Biol Psychiatry ; 95(2): 187-198, 2024 Jan 15.
Article in En | MEDLINE | ID: mdl-37454787
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Induced Pluripotent Stem Cells Type of study: Etiology_studies / Guideline / Risk_factors_studies Limits: Humans Language: En Journal: Biol Psychiatry Year: 2024 Document type: Article
Fulltext
Add to My VHL
Print
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Induced Pluripotent Stem Cells Type of study: Etiology_studies / Guideline / Risk_factors_studies Limits: Humans Language: En Journal: Biol Psychiatry Year: 2024 Document type: Article