Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation.
Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation.
复制标题
Cnot3通过促进细胞周期抑制剂mRNA降解增强人胚胎心肌细胞增殖
DOI：
10.1038/s41598-017-01628-0
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发表时间：
2017-05-04
影响因子：
4.6
通讯作者：
Hu S
中科院分区：
文献类型：
--
作者：
Zhou B;Liu J;Ren Z;Yao F;Ma J;Song J;Bennett B;Zhen Y;Wang L;Hu G;Hu S
揭示哺乳动物心肌细胞增殖的分子基础可能最终导致更好的心脏再生方法。与广泛研究的转录调控相比，转录后调控在心肌细胞命运决定中的作用在很大程度上仍然未知。在这里，我们发现在人类ESCs的心脏分化后期，Cnot3是心肌细胞增殖的关键调节因子。Cnot3在人和小鼠具有较高增殖潜力的心肌细胞中高表达，其缺失导致细胞增殖能力显著降低。此外，Cnot3过表达大大增强了培养的人心肌细胞和梗死小鼠心脏的增殖。从机制上讲，Ccr4-Not复合物以依赖于cnot3的方式优先与抗增殖基因转录物相互作用，并促进其降解。总之，我们的研究支持了cnnot3通过促进细胞周期抑制剂mRNA降解来促进心肌细胞增殖的模型。它揭示了mRNA降解在心肌细胞生长中以前未被认识到的作用，并提出了在发育和疾病中控制心肌细胞命运的潜在策略。
Uncovering the molecular basis of mammalian cardiomyocyte proliferation may eventually lead to better approaches for heart regeneration. Compared to extensively-studied transcriptional regulation, the roles of posttranscriptional regulation in cardiac cell fate decisions remain largely unknown. Here, we identified Cnot3 as a critical regulator in cardiomyocyte proliferation at the late stage of cardiac differentiation from human ESCs. Cnot3 was highly expressed in cardiomyocytes with higher proliferation potential in both human and mouse, and its depletion resulted in significant reduction in the proliferative capacity of cells. Furthermore, Cnot3 overexpression greatly enhanced proliferation in both cultured human cardiomyocytes and infarcted murine hearts. Mechanistically, the Ccr4-Not complex preferentially interacted with anti-proliferation gene transcripts in a Cnot3-dependent manner, and promoted their degradation. Together, our study supported the model that Cnot3 enhances cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation. It revealed a previously unrecognized role of mRNA degradation in cardiomyocyte growth, and suggested a potential strategy to control cardiac cell fates in development and diseases.