OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation

Cell Rep. 2020 Mar 24;30(12):4165-4178.e7. doi: 10.1016/j.celrep.2020.02.063.


Oxidation resistance gene 1 (OXR1) protects cells against oxidative stress. We find that male mice with brain-specific isoform A knockout (Oxr1A-/-) develop fatty liver. RNA sequencing of male Oxr1A-/- liver indicates decreased growth hormone (GH) signaling, which is known to affect liver metabolism. Indeed, Gh expression is reduced in male mice Oxr1A-/- pituitary gland and in rat Oxr1A-/- pituitary adenoma cell-line GH3. Oxr1A-/- male mice show reduced fasting-blood GH levels. Pull-down and proximity ligation assays reveal that OXR1A is associated with arginine methyl transferase PRMT5. OXR1A-depleted GH3 cells show reduced symmetrical dimethylation of histone H3 arginine 2 (H3R2me2s), a product of PRMT5 catalyzed methylation, and chromatin immunoprecipitation (ChIP) of H3R2me2s shows reduced Gh promoter enrichment. Finally, we demonstrate with purified proteins that OXR1A stimulates PRMT5/MEP50-catalyzed H3R2me2s. Our data suggest that OXR1A is a coactivator of PRMT5, regulating histone arginine methylation and thereby GH production within the pituitary gland.

Keywords: Arginine Methylation; Growth hormone; H3R2me2s; NAFLD; Non-alcoholic fatty liver disease; OXR1; Oxidation resistance gene 1; PRMT1; PRMT5; brain-liver axis; epigenetic regulation; neuroendocrine regulation; pituitary gland; protein arginine methyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / metabolism*
  • Brain / metabolism
  • Cell Line
  • Fatty Liver / genetics
  • Fatty Liver / pathology
  • Female
  • Gene Expression Regulation
  • Growth Hormone / blood
  • Growth Hormone / metabolism
  • Histones / metabolism*
  • Hormones / metabolism
  • Immunity / genetics
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / metabolism*
  • Organ Specificity
  • Pituitary Gland / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Domains
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Rats
  • Receptors, Somatotropin / metabolism
  • STAT5 Transcription Factor / metabolism
  • Structure-Activity Relationship
  • Transcriptome / genetics


  • Histones
  • Hormones
  • Mitochondrial Proteins
  • Oxr1 protein, mouse
  • Receptors, Somatotropin
  • STAT5 Transcription Factor
  • Growth Hormone
  • Arginine
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases