OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation

Abstract

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.