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KDM6A mediates the removal of repressive trimethylation from H3K27me3 to activate target gene expression. It is not known, however, whether KDM6A plays a role in the regulation of cardiac aging. We hypothesized that cardiac-specific KDM6A knockout accelerates cardiac aging. Aging decreased histone demethylase KDM6A expression and activity in human cardiomyocytes. Downregulation of KDM6A expression was also found in cardiomyocytes of aged mice. The cardiomyocytes-specific KDM6A knockout (Myh6-KDM6A cKO) mouse model was created by using Cre-LoxP system. KDM6A deletion didn't cause overt cardiac remodeling and dysfunction in normal condition. However, cardiomyocytes-specific conditional knockout of KDM6A exaggerated ISO-induced cardiac dysfunction and cardiac remodeling. Moreover, Myh6-KDM6A cKO mice showed early cardiac aging at 23-month-old, while control mice didn't display cardiac aging until 27-month-old. Therefore, KDM6A deletion accelerated cardiac aging. ChiP-Seq analysis revealed candidate transcription factors participating in KDM6A cKO-induced cardiac aging. In particular, HoxC4 was down-regulated in the cardiomyocytes of Myh6-KDM6A cKO mice. Knockdown of HoxC4 gene in H9c2 cardiomyoblast cell line caused ER stress. The ER stress further resulted in oxidative stress and cardiomyocytes apoptosis in cardiomyocytes-specific conditional knockout of KDM6A mice. Cardiomyocytes-specific conditional knockout of KDM6A causes cardiac aging through induction of HoxC4-mediated ER stress. These observations suggest KDM6A a potential therapeutic target for cardiac aging. © FASEB.


Kai Chen, Bo Zhang, Zhongjie Sun. Histone H3K27 Demethylase KDM6A Regulates Cardiac Aging viaInduction of HoxC4 mediated ER Stress. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35554159

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