Protein arginine methyltransferase 7 is linked to schizophrenia by regulating the function of neural progenitor cell. Protein arginine methyltransferase 7 is linked to schizophrenia by regulating the function of neural progenitor cell

Schizophrenia (SCZ) is a severe mental disorder with strong heritability and complex inheritance, which affects about 1% of populations worldwide. In this study, we prioritized protein arginine methyltransferase 7 (PRMT7) for SCZ susceptibility. Next, we explored the cellular and molecular infrastructures conferring PRMT7 to SCZ risk. Down-regulation of PRMT7 in neural progenitor cells (NPCs) caused decreased proliferation and increased neuronal differentiation. Additionally, the differentiated neurons derived from these NPCs displayed longer neurites compared to controls. Conversely, Over-expression of PRMT7 led to enhanced NPC proliferation and reduced neuronal differentiation. Moreover, in 3D cerebral organoids, the similar NPC phenotypic changes were observed following PRMT7 depletion. Mechanistically, the expression of genes related to cell cycle and neuronal functions were under regulation of PRMT7 via depositing H4R3me2s on their promoter regions. Disease enrichment analysis revealed that these PRMT7-regulated genes were more strongly associated with SCZ compared to other mental disorders. In summary, this study uncovers that PRMT7 is a functional gene at 16q22.1 contributing to the etiology of SCZ by impacting the proliferation and differentiation of NPCs as an epigenetic regulator. Overall design: To uncover the mechanism of PRMT7 contributing to SCZ risk, we establisded NPC models with PRMT7 downregulation via two different shRNAs.

精神分裂症（Schizophrenia, SCZ）是一种遗传力较强且遗传机制复杂的重度精神障碍，全球人群患病率约为1%。本研究将蛋白质精氨酸甲基转移酶7（Protein Arginine Methyltransferase 7, PRMT7）鉴定为精神分裂症易感基因。随后，我们解析了介导PRMT7参与精神分裂症风险调控的细胞与分子基础。在神经前体细胞（Neural Progenitor Cells, NPCs）中下调PRMT7的表达，会导致细胞增殖能力下降，同时促进神经元分化。此外，由此类神经前体细胞分化得到的神经元，其神经突长度较对照组更长。反之，过表达PRMT7则可增强神经前体细胞的增殖能力，并抑制神经元分化。此外，在三维大脑类器官（cerebral organoids）中，PRMT7敲低后同样观察到了类似的神经前体细胞表型变化。机制层面，PRMT7可通过在靶基因启动子区域沉积H4R3me2s修饰，调控细胞周期与神经元功能相关基因的表达。疾病富集分析显示，相较于其他精神障碍，这些受PRMT7调控的基因与精神分裂症的关联更为显著。综上，本研究揭示位于16q22.1区域的PRMT7是一款功能性基因，其作为表观遗传调控因子，通过影响神经前体细胞的增殖与分化过程参与精神分裂症的发病机制。整体实验设计：为解析PRMT7介导精神分裂症风险的分子机制，我们通过两种不同的短发夹RNA（short hairpin RNA, shRNA）构建了PRMT7下调表达的神经前体细胞模型。