N6-Methyladenosine (m6A) is the most commonly chemical modification of messenger RNAs (mRNAs) in eukaryotes, and has been involved in various diseases. However, the role of m6A modification in heart regeneration after injury remains unclear. The study was conducted to investigate whether targeting methyltransferase-like 3 (METTL3) could replenish the loss of cardiomyocytes and improve cardiac function after myocardial infarction (MI).
METTL3 knockout mouse line was generated. A series of functional experiments were carried out and the molecular mechanism was further explored. We identified that METL3, a methyltransferase of m6A methylation, is upregulated after birth in mice, which is exactly the opposite of the changes in cardiomyocytes (CMs) proliferation. Notably, METTL3 knockout mice or administration of METTL3 shRNA adenovirus exhibited that the pre-existing CMs cell cycle re-entered, infract size decreased and cardiac function improved after MI. Mechanically, the silence of METTL3 reduced primary miR-143 (pri-miR-143) purified by m6A, thereby inhibiting the cleavage of pri-miR-143 into mature miR-143-3p. Moreover, it was found that miR-143-3p, Yap and Ctnnd1 have targeting effects to regulate CMs proliferation.
METTL3-mediated mA modification contributes to heart regeneration after MI via the METTL3-pri-miR-143-(miR-143)-Yap/Ctnnd1 axis. This study provides new insights into the significance of RNA mA modification in heart regeneration.
Copyright © 2021. Published by Elsevier Ltd.
Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury.
