M7G Methyltransferase METTL1 Promotes Post-ischemic Angiogenesis via Promoting VEGFA mRNA Translation.

Yongchao Zhao,Zhiqiang Pei,Chaofu Li,Bei Shi,Junbo Ge,Fuhai Li,Xiaolei Sun,Lingqiu Kong

doi:10.3389/fcell.2021.642080

Abstract

Post-transcriptional modifications play pivotal roles in various pathological processes and ischemic disorders. However, the role of N7-methylguanosine (m7G), particularly m7G in mRNA, on post-ischemic angiogenesis remains largely unknown. Here, we identified that methyltransferase like 1 (METTL1) was a critical candidate responsible for a global decrease of m7G within mRNA from the ischemic tissues. The in vivo gene transfer of METTL1 improved blood flow recovery and increased angiogenesis with enhanced mRNA m7G upon post-ischemic injury. Increased METTL1 expression using plasmid transfection in vitro promoted HUVECs proliferation, migration, and tube formation with a global increase of m7G in mRNA. Mechanistically, METTL1 promoted VEGFA mRNA translation in an m7G methylation-dependent manner. Our findings emphasize a critical link between mRNA m7G and ischemia and provide a novel insight of targeting METTL1 in the therapeutic angiogenesis for ischemic disorders, including peripheral arterial disease.

Highlights

Ischemic cardiovascular disease, including myocardial infarction and peripheral arterial disease (PAD), is the leading cause of mobility and mortality worldwide (Murabito et al, 2002)
Utilizing gains of function strategies, we identified that methyltransferase like 1 (METTL1) improved blood flow recovery and increased angiogenesis with enhanced m7G upon post-ischemic injury in vivo and increased Human umbilical vein endothelial cells (HUVECs) angiogenesis in vitro via promoting the VEGFA mRNA translation in an m7G methylation-dependent manner
Our results reveal a critical role of m7G in promoting post-ischemic angiogenesis

Summary

INTRODUCTION

Ischemic cardiovascular disease, including myocardial infarction and peripheral arterial disease (PAD), is the leading cause of mobility and mortality worldwide (Murabito et al, 2002). Function roles of m7G methylation within mRNA are associated with translation efficiency alteration of transcripts that contain METTL1 and WDR4 affected m7G sites (Guy and Phizicky, 2014; Malbec et al, 2019; Zhang et al, 2019). These internal m7G methylation impact RNA function and have been suggested associated with human diseases (Lin et al, 2018). Our study uncovered a novel direct link between m7G methylation and post-ischemic angiogenesis, providing insight into targeting METTL1 in the treatment of ischemic disorders, including PAD

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT

Findings

LIMITATIONS