OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation
Mingyi Yang,
Xiaolin Lin,
Filip Segers,
Rajikala Suganthan,
Gunn A. Hildrestrand,
Johanne E. Rinholm,
Per Arne Aas,
Mirta M.L. Sousa,
Sverre Holm,
Nils Bolstad,
David Warren,
Rolf K. Berge,
Rune F. Johansen,
Arne Yndestad,
Elise Kristiansen,
Arne Klungland,
Luisa Luna,
Lars Eide,
Bente Halvorsen,
Pål Aukrust,
Magnar Bjørås
Affiliations
Mingyi Yang
Department of Microbiology, Oslo University Hospital, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
Xiaolin Lin
Department of Microbiology, Oslo University Hospital, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
Filip Segers
Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
Rajikala Suganthan
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Gunn A. Hildrestrand
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Johanne E. Rinholm
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Per Arne Aas
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Mirta M.L. Sousa
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Laboratory Medicine, St. Olavs Hospital, Trondheim, Norway; Proteomics and Metabolomics Core Facility-PROMEC, Norwegian University of Science and Technology, the Central Norway Regional Health Authority, Trondheim, Norway
Sverre Holm
Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
Nils Bolstad
Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
David Warren
Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
Rolf K. Berge
Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
Rune F. Johansen
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Arne Yndestad
Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
Elise Kristiansen
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Arne Klungland
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Luisa Luna
Department of Microbiology, Oslo University Hospital, Oslo, Norway
Lars Eide
Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway
Bente Halvorsen
Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
Pål Aukrust
Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway; Corresponding author
Magnar Bjørås
Department of Microbiology, Oslo University Hospital, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Laboratory Medicine, St. Olavs Hospital, Trondheim, Norway; Corresponding author
Summary: 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. : Yang et al. show that OXR1A interacts with methyltransferase PRMT5 to promote arginine methylation of histone H3R2 and to regulate transcription of growth hormone in the pituitary gland. Male mice with OXR1A knockout display growth-hormone deficiency and develop fatty liver. Keywords: Oxidation resistance gene 1, OXR1, protein arginine methyltransferase, PRMT1, PRMT5, Arginine Methylation, H3R2me2s, pituitary gland, brain-liver axis, Growth hormone, Non-alcoholic fatty liver disease, NAFLD, neuroendocrine regulation, epigenetic regulation
