Lysine Methyltransferase SMYD1 Regulates Myogenesis via skNAC Methylation

Cells. 2023 Jun 22;12(13):1695. doi: 10.3390/cells12131695.

Abstract

The SMYD family is a unique class of lysine methyltransferases (KMTases) whose catalytic SET domain is split by a MYND domain. Among these, Smyd1 was identified as a heart- and skeletal muscle-specific KMTase and is essential for cardiogenesis and skeletal muscle development. SMYD1 has been characterized as a histone methyltransferase (HMTase). Here we demonstrated that SMYD1 methylates is the Skeletal muscle-specific splice variant of the Nascent polypeptide-Associated Complex (skNAC) transcription factor. SMYD1-mediated methylation of skNAC targets K1975 within the carboxy-terminus region of skNAC. Catalysis requires physical interaction of SMYD1 and skNAC via the conserved MYND domain of SMYD1 and the PXLXP motif of skNAC. Our data indicated that skNAC methylation is required for the direct transcriptional activation of myoglobin (Mb), a heart- and skeletal muscle-specific hemoprotein that facilitates oxygen transport. Our study revealed that the skNAC, as a methylation target of SMYD1, illuminates the molecular mechanism by which SMYD1 cooperates with skNAC to regulate transcriptional activation of genes crucial for muscle functions and implicates the MYND domain of the SMYD-family KMTases as an adaptor to target substrates for methylation.

Keywords: heart and skeletal muscle; methyltransferase; transcriptional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • DNA-Binding Proteins* / chemistry
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Gene Expression Regulation, Developmental*
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase* / chemistry
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Methylation
  • Molecular Chaperones* / metabolism
  • Muscle Development* / genetics
  • Muscle Proteins* / chemistry
  • Muscle Proteins* / genetics
  • Muscle Proteins* / metabolism
  • Mutation
  • Protein Domains
  • Protein Isoforms / metabolism
  • Transcription Factors* / chemistry
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcriptional Activation*

Substances

  • DNA-Binding Proteins
  • Histone-Lysine N-Methyltransferase
  • Molecular Chaperones
  • Muscle Proteins
  • nascent-polypeptide-associated complex
  • Protein Isoforms
  • SMYD1 protein, human
  • Transcription Factors