Role of the PRC2-Six1-miR-25 signaling axis in heart failure. (April 2019)

• Record Type: Journal Article
• Authors: Oh, Jae Gyun; Jang, Seung Pil; Yoo, Jimeen; Lee, Min-Ah; Lee, Seung Hee; Lim, Taejoong; Jeong, Eden; Kho, Changwon; Kook, Hyun; Hajjar, Roger J.; Park, Woo Jin; Jeong, Dongtak
• Is Part Of: Journal of molecular and cellular cardiology. Volume 129(2019)
• Page Start: 58
• Page End: 68
• Publication Date: 2019-04
• Subjects: Heart failure -- SERCA2a -- miRNA-25 -- Six1 -- PRC2 -- Epigenetics; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.01.017
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: The reduced expression of cardiac sarco-endoplasmic reticulum Ca 2+ ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcriptional regulator of SERCA2a in the heart. However, the precise mechanism of cardiac miR-25 regulation is largely unknown. Literatures suggested that miR-25 is regulated by the transcriptional co-factor, sine oculis homeobox homolog 1 (Six1), which in turn is epigenetically regulated by polycomb repressive complex 2 (PRC 2) in cardiac progenitor cells. Therefore, we aimed to investigate whether Six1 and PRC2 are indeed involved in the regulation of the miR-25 level in the setting of heart failure. Six1 was up-regulated in the failing hearts of humans and mice. Overexpression of Six1 led to adverse cardiac remodeling, whereas knock-down of Six1 attenuated pressure overload-induced cardiac dysfunction. The adverse effects of Six1 were ameliorated by knock-down of miR-25. The epigenetic repression on the Six1 promoter by PRC2 was significantly reduced in failing hearts. Epigenetic repression of Six1 is relieved through a reduction of PRC2 activity in heart failure. Six1 up-regulates miR-25, which is followed by reduction of cardiac SERCA2a expression. Collectively, these data showed that the PRC2-Six1-miR-25 signaling axis is involved in heart failure. Our finding introduces new insight into potential treatments of heart failure. Highlights: Six1 is up-regulated in failing hearts. Overexpression of Six1 leads to cardiac abnormalities in vitro and in vivo. In cardiac stress conditions, Six1 directly binds to the MCM7 promoter, inducing an elevation of miR-25, which in turn reduces SERCA2a. In failing hearts, Six1 is epigenetically regulated through the PRC2 complex across species.