METTL3 drives heart failure by regulating Spp1 and Fos m6A modification in myocardial infarction
Description
METTL3 has been identified as an important RNA methyltransferase responsible for the deposition of N6-methyladenosine (m6A) in many transcripts. At present, m6A modification has been reported in the process of myocardial infarction (MI), but the detailed mechanism by which METTL3 regulates the progression of the disease has not yet been elucidated, and why m6A modification increases after myocardial infarction remains unclear. Here, we uncover that METTL3 exerts methyltransferase activity-dependent functions in gene regulation in MI, and a significant transcription factor (TF), HuR assists the METTL3 function. We first demonstrate that METTL3 is critical for promotion of the heart failure post-MI. More specifically, METTL3 directly interacts with HuR through its nuclear localization domain in the cell nucleus under normoxia condition. When hypoxia happens, METTL3 separates with HuR, and deposits m6A into 5’UTR of Spp1 and Fos mRNA to maintain mRNAs stability. By contrast, HuR binds to the ARE domain of 3’UTR of Spp1 and Fos mRNA to take them to the cytosol, maintaining their stability, too. Moreover, HIF-1α directly interacts HRE domain of Mettl3 to promote its transcription, then HuR binds to the ARE domain of 3’UTR of Mettl3 mRNA to maintain its stability to promote following translation. Collectively, our studies reveal previously unappreciated functions METTL3 with the help of HuR, and a direct target of HIF-1α under normoxia condition, which together contribute to its essential function in MI.