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

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-02-25 Epub Date: 2025-02-06 DOI:10.1016/j.celrep.2025.115279

Ting Shen, Jing Yu, Bin Xie, Cuiping Huang, Jingjie Cui, Kefu Liu, Chunyu Liu, Chao Chen

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Abstract

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.

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蛋白精氨酸甲基转移酶7通过调节神经祖细胞增殖和分化与精神分裂症有关。

全基因组关联研究（GWASs）已经确定了许多与精神分裂症（SCZ）相关的基因组位点，但其致病机制在很大程度上仍不清楚。该研究表明，蛋白精氨酸甲基转移酶7 （PRMT7）是SCZ风险snp的关键靶点，其等位基因特异性增强子活性在16q22.1。下调神经祖细胞PRMT7可降低细胞增殖，增加神经元分化，并导致神经突延长。相反，过表达PRMT7可增强鼻咽癌的增殖，降低神经元的分化。在三维（3D）脑类器官中，PRMT7缺失后出现了类似的NPC表型变化。从机制上讲，PRMT7通过启动子中组蛋白4 （H4R3me2s）精氨酸3的对称二甲基化修饰，调控CDKN2A和SYP等与细胞周期和神经元功能相关的基因的表达。值得注意的是，与其他精神障碍相比，这些基因与SCZ的关联更强。综上所述，本研究的结果表明，PRMT7是16q22.1位点的一个功能基因，作为一种表观遗传调节剂，通过调节鼻咽癌的增殖和分化，参与了SCZ的病因学。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.