Protein arginine methylation: a prominent modification and its demethylation

Cell Mol Life Sci. 2017 Sep;74(18):3305-3315. doi: 10.1007/s00018-017-2515-z. Epub 2017 Mar 31.


Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases.

Keywords: Histone modifications; KDM; KDM2A; KDM3A; KDM4E; KDM5C; KDM6B; KDM7B; KMT; Liquid chromatography–tandem mass spectrometry; PHF8; Post-translational modifications.

Publication types

  • Review

MeSH terms

  • Animals
  • Arginine / analogs & derivatives
  • Arginine / analysis
  • Arginine / metabolism*
  • Histone Demethylases / metabolism
  • Histones / metabolism*
  • Humans
  • Hydrolases / metabolism
  • Methylation
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases
  • Protein-Arginine N-Methyltransferases / metabolism


  • Histones
  • Arginine
  • Histone Demethylases
  • Protein-Arginine N-Methyltransferases
  • Hydrolases
  • PADI4 protein, human
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases