不对称甲基转移酶 PRMT3 通过 miR-3648 调节人骨髓间充质干细胞成骨。

Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648.

机构信息

Department of Prosthodontics, Peking University School and Hospital of Stomatology, 100081, Beijing, China.

National Engineering Lab for Digital and Material Technology of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, 100081, Beijing, China.

出版信息

Cell Death Dis. 2019 Aug 5;10(8):581. doi: 10.1038/s41419-019-1815-7.

Histone arginine methylation, which is catalyzed by protein arginine methyltransferases (PRMTs), plays a key regulatory role in various biological processes. Several PRMTs are involved in skeletal development; however, their role in the osteogenic differentiation of mesenchymal stem cells (MSCs) is not completely clear. In this study, we aimed to elucidate the function of PRMT3, a type-I PRMT that catalyzes the formation of ω-mono- or asymmetric dimethyl arginine, in MSCs osteogenesis. We found that PRMT3 promoted MSCs osteogenic commitment and bone remodeling. PRMT3 activated the expression of miR-3648 by enhancing histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) levels at promoter region of the gene. Overexpression of miR-3648 rescued impaired osteogenesis in PRMT3-deficient cells. Moreover, administration of Prmt3 shRNA or a chemical inhibitor of PRMT3 (SGC707) caused an osteopenia phenotype in mice. These results indicate that PRMT3 is a potential therapeutic target for the treatment of bone regeneration and osteopenia disorders.

组蛋白精氨酸甲基化由蛋白质精氨酸甲基转移酶（PRMTs）催化，在各种生物过程中发挥关键的调节作用。几种 PRMTs 参与骨骼发育；然而，它们在间充质干细胞（MSCs）成骨分化中的作用尚不完全清楚。在这项研究中，我们旨在阐明 PRMT3 的功能，PRMT3 是一种 I 型 PRMT，催化 ω-单甲基或非对称二甲基精氨酸的形成，在 MSCs 成骨中。我们发现 PRMT3 促进 MSCs 成骨细胞的分化和骨重塑。PRMT3 通过增强基因启动子区域的组蛋白 H4 精氨酸 3 位不对称二甲基化（H4R3me2a）水平来激活 miR-3648 的表达。miR-3648 的过表达挽救了 PRMT3 缺陷细胞中受损的成骨作用。此外，Prmt3 shRNA 的给药或 PRMT3 的化学抑制剂（SGC707）在小鼠中引起了骨质疏松表型。这些结果表明 PRMT3 是治疗骨再生和骨质疏松症的潜在治疗靶点。