Protein arginine methyltransferase 7 linked to schizophrenia through regulation of neural progenitor cell proliferation and differentiation

Genome-wide association studies (GWASs) have identified numerous genomic loci linked to schizophrenia (SCZ), while their pathogenic mechanisms largely remain unclear. This study demonstrated protein arginine methyltransferase 7 (PRMT7) as a key target of SCZ risk SNPs with allele-specific enhancer activity at 16q22.1. Downregulating PRMT7 in neural progenitor cells (NPCs) decreased proliferation, increased neuronal differentiation, and also led to longer neurites in these neurons. Conversely, overexpressing PRMT7 enhanced NPC proliferation and reduced neuronal differentiation. In three-dimensional (3D) cerebral organoids, similar NPC phenotypic changes were noted following PRMT7 depletion. Mechanistically, PRMT7 regulates the expression of genes related to the cell cycle and neuronal functions, such as CDKN2A and SYP, via symmetrical di-methylation at arginine 3 of histone 4 (H4R3me2s) modification in their promoters. Notably, these genes have a stronger association with SCZ compared to other mental disorders. Together, the results of this study reveal that PRMT7 is a functional gene at 16q22.1, contributing to the etiology of SCZ by modulating NPC proliferation and differentiation as an epigenetic regulator.