Downregulation of circ-ZNF609 Promotes Heart Repair by Modulating RNA N6-Methyladenosine-Modified Yap Expression

Lijun Wang; Pujiao Yu; Jiaqi Wang; Guie Xu; Tianhui Wang; Jingyi Feng; Yihua Bei; Jiahong Xu; Hongbao Wang; Saumya Das; Junjie Xiao

doi:10.34133/2022/9825916

Downregulation of circ-ZNF609 Promotes Heart Repair by Modulating RNA N⁶-Methyladenosine-Modified Yap Expression

Research (Wash D C). 2022 Apr 7:2022:9825916. doi: 10.34133/2022/9825916. eCollection 2022.

Authors

Lijun Wang^{1

2}, Pujiao Yu³, Jiaqi Wang^{1

2}, Guie Xu¹, Tianhui Wang¹, Jingyi Feng¹, Yihua Bei¹, Jiahong Xu³, Hongbao Wang⁴, Saumya Das⁵, Junjie Xiao^{1

2}

Affiliations

¹ Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.
² Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China.
³ Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
⁴ Department of Cardiology, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200065, China.
⁵ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Abstract

Circular RNAs take crucial roles in several pathophysiological processes. The regulatory role and its underlying mechanisms of circ-ZNF609 in the heart remains largely unknown. Here, we report that circ-ZNF609 is upregulated during myocardial ischemia/reperfusion (I/R) remodeling. Knockdown of circ-ZNF609 protects against acute I/R injury and attenuates left ventricle dysfunction after I/R remodeling in vivo. In vitro, circ-ZNF609 regulates cardiomyocyte survival and proliferation via modulating the crosstalk between Hippo-YAP and Akt signaling. Mechanically, N⁶-methyladenosine-modification is involved in the regulatory role of circ-ZNF609 on YAP. An in-depth study indicates that knockdown of circ-ZNF609 decreases the expression of YTHDF3 and further fine-tuned the accessibility of Yap mRNA to YTHDF1 and YTHDF2 to regulate YAP expression. circ-ZNF609 knockdown represents a promising therapeutic strategy to combat the pathological process of myocardial I/R injury.