Histone H4R3 symmetric di-methylation by Prmt5 protects against cardiac hypertrophy via regulation of Filip1L/β-catenin
Histone H4R3 symmetric di-methylation by Prmt5 protects against cardiac hypertrophy via regulation of Filip1L/β-catenin
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Prmt5 引起的组蛋白 H4R3 对称二甲基化通过调节 Filip1L/β-catenin 防止心脏肥大
DOI：
10.1016/j.phrs.2020.105104
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发表时间：
2020-11-01
影响因子：
9.3
通讯作者：
Liu, Peiqing
中科院分区：
文献类型：
--
作者：
Cai, Sidong;Wang, Panxia;Liu, Peiqing
背景和目的：虽然组蛋白赖氨酸甲基化在病理性心肌肥大中的作用已被广泛研究，但组蛋白精氨酸甲基化的潜在调节作用仍有待阐明。本研究主要研究蛋白质精氨酸甲基转移酶5（Prmt 5）诱导的H4 R3对称性二甲基化（H4 R3 me 2s），探讨其在心肌细胞肥大中的表观遗传调控及其机制。结论：1.在体内外心肌肥厚模型中，Prmt 5和H4 R3 me 2s的表达均受到抑制。Prmt 5沉默或其抑制剂EPZ，或敲低Prmt 5的合作者（Copr 5）以破坏H4 R3 me 2s，促进心肌细胞肥大，而野生型Prmt 5而不是失活突变体的过表达保护心肌细胞免于肥大; 3. ChIP序列分析鉴定Filip 1 L为Prmt 5诱导的H4 R3 me 2s的靶基因; 4.敲低或抑制Prmt 5受损Filip 1 L转录，随后阻止β-连环蛋白降解，从而增强心肌细胞hypertrophy.Conclusions：本研究表明，Prmt 5诱导的H4 R3 me 2s通过Filip 1 L的转录上调和随后增强β-连环蛋白降解来改善心肌细胞肥大。Prmt 5的缺乏和由此导致的H4 R3 me 2s的抑制可能促进病理性心肌肥厚的发展。prmt 5可能是病理性心肌肥厚的一个关键表观遗传调节因子。
Background and purpose: Although histone lysine methylation has been extensively studied for their participation in pathological cardiac hypertrophy, the potential regulatory role of histone arginine methylation remains to be elucidated. The present study focused on H4R3 symmetric di-methylation (H4R3me2s) induced by protein arginine methyltransferase 5 (Prmt5), and explored its epigenetic regulation and underlying mechanisms in cardiomyocyte hypertrophy.Methods and results: 1. The expressions of Prmt5 and H4R3me2s were suppressed in cardiac hypertrophy models in vivo and in vitro; 2. Prmt5 silencing or its inhibitor EPZ, or knockdown of cooperator of Prmt5 (Copr5) to disrupt H4R3me2s, facilitated cardiomyocyte hypertrophy, whereas overexpression of wild type Prmt5 rather than the inactive mutant protected cardiomyocytes against hypertrophy; 3. ChIP-sequence analysis identified Filip1L as a target gene of Prmt5-induced H4R3me2s; 4. Knockdown or inhibition of Prmt5 impaired Filip1L transcription and subsequently prevented beta-catenin degradation, thus augmenting cardiomyocyte hypertrophy.Conclusions: The present study reveals that Prmt5-induced H4R3me2s ameliorates cardiomyocyte hypertrophy by transcriptional upregulation of Filip1L and subsequent enhancement of beta-catenin degradation. Deficiency of Prmt5 and the resulting suppression of H4R3me2s might facilitate the development of pathological cardiac hypertrophy. Prmt5 might serve as a key epigenetic regulator in pathological cardiac hypertrophy.