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Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle

Shu-Juan Xie1,2, Hang Lei2, Bing Yang3

  • 1Vaccine Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Frontiers in Cell and Developmental Biology
|October 18, 2021
PubMed

Insights

N6-methyladenosine (m6A) RNA methylation is crucial for skeletal muscle development. METTL3/METTL14 regulate muscle cell differentiation by controlling MNK2 and ERK signaling, impacting muscle regeneration.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Skeletal Muscle Physiology

Background:

  • N6-methyladenosine (m6A) RNA methylation regulates gene expression in diverse biological processes.
  • The role of m6A in skeletal myogenesis is not well understood.

Purpose of the Study:

  • Investigate the dynamic profile, function, and molecular mechanisms of m6A modification during skeletal myogenesis.
  • Elucidate the role of m6A writers METTL3/METTL14 and reader YTHDF1 in muscle development and regeneration.

Main Methods:

  • Analysis of METTL3 and METTL14 expression during skeletal muscle development.
  • Overexpression and knockdown studies of METTL3 and METTL14 in skeletal muscle cells.
  • Genome-wide transcriptome analysis and MeRIP-seq.
  • Western blotting to assess protein levels.

Main Results:

  • METTL3 and METTL14 expression decreases during skeletal muscle development.
  • METTL3/METTL14 overexpression inhibits myogenesis, while knockdown accelerates differentiation.
  • The ERK/MAPK signaling pathway is a key downstream target regulated by METTL3/METTL14.
  • MNK2, a regulator of ERK/MAPK, is m6A modified by METTL3/METTL14 and its protein levels are regulated by YTHDF1.
  • The METTL3/14-MNK2 axis is upregulated after skeletal muscle injury.

Conclusions:

  • METTL3/METTL14 and YTHDF1 orchestrate MNK2 expression posttranscriptionally, controlling ERK signaling.
  • This m6A-mediated pathway is essential for skeletal myogenesis maintenance and contributes to muscle regeneration.
Keywords:
ERK signalingMETTL3/14MNK2m6Askeletal muscle differentiation and regeneration

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