Biol Psychiatry. 2023 Jul 14:S0006-3223(23)01426-9. doi: 10.1016/j.biopsych.2023.07.003. Online ahead of print.

ABSTRACT

BACKGROUND: Converging evidence from large-scale genetic and postmortem studies highlight the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and 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 (hiPSC)-derived glutamatergic neurons (NGN2) from six schizophrenia patients and five controls.

RESULTS: Multi-omic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within one hour of KCl-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 contribute to the genetic risk for brain-related disorders. Gene co-expression 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 demonstrate that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy.

PMID:37454787 | DOI:10.1016/j.biopsych.2023.07.003