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

Abstract

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.

• Authors: Jae Gyun Oh, Seung Pil Jang, Jimeen Yoo, Min-Ah Lee, Seung Hee Lee, Taejoong Lim, Eden Jeong, Changwon Kho, Hyun Kook, Roger J Hajjar, Woo Jin Park, Dongtak Jeong
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 129 Pg. 58-68 (04 2019) ISSN: 1095-8584 [Electronic] England
• PMID: 30771307 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Homeodomain Proteins
• MIRN25 microRNA, mouse
• MicroRNAs
• SIX1 protein, human
• Six1 protein, mouse
• Polycomb Repressive Complex 2

Topics

• Animals
• Epigenesis, Genetic
• Gene Knockdown Techniques
• Heart Failure (genetics, physiopathology)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Mice, Inbred C57BL
• MicroRNAs (genetics, metabolism)
• Polycomb Repressive Complex 2 (metabolism)
• Pressure
• Promoter Regions, Genetic
• Signal Transduction
• Up-Regulation (genetics)
• Ventricular Remodeling (genetics)