Dataset Information

Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation.

ABSTRACT: 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.

SUBMITTER: Zhou B

PROVIDER: S-EPMC5431451 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation.

Zhou Bingying B Liu Junwei J Ren Zongna Z Yao Fang F Ma Jingwei J Song Jiangping J Bennett Brian B Zhen Yisong Y Wang Li L Hu Guang G Hu Shengshou S

Scientific reports 20170504 1

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 prol ...[more]

PMID: 28473716

Similar Datasets

Project description:RATIONALE:Understanding and manipulating the cardiomyocyte cell cycle has been the focus of decades of research, however the ultimate goal of activating mitotic activity in adult mammalian cardiomyocytes remains elusive and controversial. The relentless pursuit of controlling cardiomyocyte mitosis has been complicated and obfuscated by a multitude of indices used as evidence of cardiomyocyte cell cycle activity that lack clear identification of cardiomyocyte "proliferation" versus cell cycle progression, endoreplication, endomitosis, and even DNA damage. Unambiguous appreciation of the complexity of cardiomyocyte replication that avoids oversimplification and misinterpretation is desperately needed. OBJECTIVE:Track cardiomyocyte cell cycle activity and authenticate fidelity of proliferation markers as indicators of de novo cardiomyogenesis in post-mitotic cardiomyocytes. METHODS AND RESULTS:Cardiomyocytes expressing the FUCCI construct driven by the α-myosin heavy chain promoter were readily and uniformly detected through the myocardium of transgenic mice. Cardiomyocyte cell cycle activity peaks at postnatal day 2 and rapidly declines thereafter with almost all cardiomyocytes arrested at the G1/S cell cycle transition. Myocardial infarction injury in adult hearts prompts transient small increases in myocytes progressing through cell cycle without concurrent mitotic activity, indicating lack of cardiomyogenesis. In comparison, cardiomyogenic activity during early postnatal development correlated with coincidence of FUCCI and cKit+ cells that were undetectable in the adult myocardium. CONCLUSIONS:Cardiomyocyte-specific expression of Fluorescence Ubiquitination-based Cell Cycle Indicators (FUCCI) reveals previously unappreciated aspects of cardiomyocyte cell cycle arrest and biological activity in postnatal development and in response to pathologic damage. Compared to many other methods and model systems, the FUCCI transgenic (FUCCI-Tg) mouse represents a valuable tool to unambiguously track cell cycle and proliferation of the entire cardiomyocyte population in the adult murine heart. FUCCI-Tg provides a desperately needed novel approach in the armamentarium of tools to validate cardiomyocyte proliferative activity that will reveal cell cycle progression, discriminate between cycle progression, DNA replication, and proliferation, and provide important insight for enhancing cardiomyocyte proliferation in the context of adult myocardial tissue.

Dataset Information

Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation.

Publications

Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets