Role of the PRC2-Six1-miR-25 signaling axis in heart failure

• Published in: Journal of molecular and cellular cardiology 2019-04, Vol.129, p.58-68
• Main 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
• Format: Article
• Language: English
• Subjects: Epigenetics; Heart failure; miRNA-25; PRC2; SERCA2a; Six1
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.01.017

The reduced expression of cardiac sarco-endoplasmic reticulum Ca2+ 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. •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.