ABSTRACT: Converging evidence from large-scale genetic and post-mortem studies highlight the role of aberrant neurotransmission and genetic regulation in schizophrenia. To better understand how the activity-dependent regulome contributes to risk for psychiatric disorders, we profile the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons from individuals with schizophrenia and controls. Multi-omic data integration associates global patterns of chromatin accessibility with gene expression and identifies enhancer-promoter interactions in glutamatergic neurons. Within one hour of KCl-induced depolarization, independent of diagnosis, glutamatergic neurons display substantial activity-dependent changes in the expression of genes regulating synaptic function and are linked to schizophrenia and autism spectrum disorder. Depolarization-induced changes in chromatin accessibility likewise reveal significant heritability enrichment for schizophrenia, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for schizophrenia. Moreover, we identify key drivers within co-expressed modules of both schizophrenia- and activity-associated genes. Overall, we demonstrate that deciphering the activity-dependent regulome in glutamatergic neurons could reveal novel targets for advanced diagnosis and therapy.
Data access
Raw and processed data are available at GEO:GSE203082. Additionally, you can view the open chromatin tracks in the UCSC genome browser.