N6-Methyladenosine RNA Methylation in Myogenesis

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PROJECT SUMMARY/ABSTRACT The key myogenic processes at the molecular level are incompletely understood, hindering the development of therapeutic interventions for numerous muscle degenerative diseases. To fill this knowledge gap, we have been investigating how an emerging mode of post-transcriptional gene regulation known as epitranscriptomics, plays a role in skeletal myogenesis (myoblast differentiation and muscle regeneration). Epitranscriptomics is a dynamic process that regulates mRNA stability, splicing, and translation by reversible chemical modifications on mRNAs. N6-methyladenosine (m6A) is the most abundant epitranscriptomic mark. The m6A epitranscriptomic mark is installed by methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), and erased by alkylation repair homolog 5 (ALKBH5) and fat mass- and obesity-associated (FTO). A group of reader proteins selectively recognize m6A-modified mRNAs and control their fates. Our recent studies show that m6A mRNA methylation regulates myoblast differentiation and skeletal muscle regeneration and that the levels of epitranscriptomic writers and erasers are tightly regulated during these processes. We also observed changes in m6A epitranscriptomic marks at the transcriptome-wide level. These studies collectively suggest that m6A mRNA methylation plays a central role in normal myogenic processes by regulating critical molecular pathways. Here, we propose to identify molecular players involved in this process and thus gain deeper mechanistic insights. We will perform an innovative transcriptome-wide analysis to identify direct mRNA targets of m6A methylation in myogenic processes. Additionally, we will mechanistically characterize a select subset of prioritized m6A target mRNAs, both previously associated with myogenesis, as well as novel, to examine their involvement in myogenesis. Our proposed research will make a significant impact by elucidating a fundamental molecular mechanism of m6A mRNA methylation in the key myogenic processes.