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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)187-198
Number of pages12
JournalBiological Psychiatry
Volume95
Issue number2
DOIs
StatePublished - 15 Jan 2024

Keywords

  • Activity-dependent
  • Coexpression network
  • Depolarization
  • Epigenome
  • Schizophrenia
  • Transcriptome

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