YTHDF2 alleviates cardiac hypertrophy via regulating Myh7 mRNA decoy

Abstract

Background Pathological cardiac hypertrophy is a major contributor of heart failure (HF), which seriously threatens human’s health world widely. Deregulation of m6A RNA methylation, and m6A methyltransferases and de-methyltransferases have been demonstrated to act essential roles in cardiac hypertrophy and HF. Here, we studied the potential roles and its underlying mechanisms of m6A Reader YTHDF proteins in HF. In this study, we constructed HF mouse model by transverse aortic constriction surgery. Primary cardiomyocytes were isolated and stimulated with isoproterenol (ISO) or phenylephrine (PHE) to induce myocardial hypertrophy. Results Through single-cell RNA-seq analysis, immunofluorescent staining, HE staining, Western blotting, and real time-PCR detections, we found that YTHDF2 mRNA and protein level, but not YTHDF1 or YTHDF3, was significantly increased during HF development. YTHDF2 overexpression could efficiently alleviate cardiac hypertrophy. Furthermore, through immunoprecipitation accompanied with mass spectrometry analysis, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that ISO stimulation did not evidently affect YTHDF2-interacting proteins. However, ISO or PHE stimulation significantly increased YTHDF2 protein interacting with Myh7 (beta-myosin heavy chain) mRNA, an important cardiac hypertrophy marker, in an m6A-dependent manner. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2 on cardiac hypertrophy. Finally, we found that ISO or PHE stimulation promoted YTHDF2 protein expression through enhancing Ythdf2 mRNA stability in an m6A-dependent manner in cardiomyocytes. Conclusions Overall, our results indicate that the m6A Reader YTHDF2 suppresses cardiac hypertrophy via Myh7 mRNA decoy in an m6A-dependent manner. This study highlights the functional importance of YTHDF2-dependent cardiac m6A mRNA regulation during cardiac hypertrophy, and provides a novel mechanistic insight into the therapeutic mechanisms of YTHDF2.

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

“…However, the mechanism by which METTL14 exerts its inhibitory effects remains unknown. At present, a large number of studies have shown that m 6 A modifications caused by the abnormal expression of m 6 A core modification and reading proteins are involved in various physiological and pathological processes, such as biological growth and development, sperm development and maturation, DNA damage repair, biological rhythms, and various types of tumors [ 33 , 46 ]. Chai et al showed that YTHDF2 could promote the malignant progression of gliomas by accelerating UBX domain protein 1 (UBXN1) mRNA degradation via METTL3-mediated m 6 A modification [ 1 ]; Pan et al verified that YTHDF2 could lead to the reduction of Tet1 mRNA decay by binding to m 6 A in Tet1 mRNA [ 47 ]; Hou et al confirmed that the small ubiquitin-related modifier (SUMO)ylation of YTHDF2 could significantly increase the binding affinity of m 6 A-modified mRNAs and subsequently result in deregulated gene expression responsible for cancer progression [ 48 ].…”

Circular RNA circ‐TNPO3 inhibits clear cell renal cell carcinoma metastasis by binding to IGF2BP2 and destabilizing SERPINH1 mRNA

“…As another member of the IGF2BP family, IGF2BP3 reportedly promotes eIF4E‐mediated translational activation by decreasing the stability of EIF4E‐BP2 mRNA, which in turn enhances the proliferation of tumour cells. 52 In addition, YTHDF2, a common RNA binding protein, has been reported to inhibit the mRNA stability of several target genes, including MYH7, 53 EGFR, 54 UBXN1, 55 LXRA and HIVEP2. 56 As a famous m6A reader, IGF2BP2 can enhance mRNA stability through its recognition of RNA N6‐methyladenosine.…”

Emerging role of m6A modification in cardiovascular diseases

“…Consistent with the above report, T. Y. Liu et al (2017) generated hnRNP A1 knockout mice, which showing severe muscle development defects, thus resulting in embryonic lethality. Recently, Xu et al (2021) reported the functional importance of YTHD2 in regulating m 6 A methylation during cardiac hypertrophy. First, an increased level of YTHD2 was detected in tissues of mice with cardiac hypertrophy and the protective role of YTHD2 was suggested by less fibrosis, lower ratio of heart weight to body weight, and fewer enlarged cardiomyocytes after TAC‐induced cardiac hypertrophy in mice model that delivering with AAV‐YTHDF2.…”

“…First, an increased level of YTHD2 was detected in tissues of mice with cardiac hypertrophy and the protective role of YTHD2 was suggested by less fibrosis, lower ratio of heart weight to body weight, and fewer enlarged cardiomyocytes after TAC‐induced cardiac hypertrophy in mice model that delivering with AAV‐YTHDF2. The further investigation reported that YTHDF2 interacting with Myh7 mRNA via recognizing its m 6 A site promoted its degradation, thus alleviating myocardial hypertrophy (Xu et al, 2021).…”