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

doi:10.1016/j.celrep.2020.02.063

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.

Authors

Mingyi Yang¹, Xiaolin Lin¹, Filip Segers², Rajikala Suganthan³, Gunn A Hildrestrand³, Johanne E Rinholm³, Per Arne Aas⁴, Mirta M L Sousa⁵, Sverre Holm², Nils Bolstad⁶, David Warren⁶, Rolf K Berge⁷, Rune F Johansen³, Arne Yndestad², Elise Kristiansen³, Arne Klungland³, Luisa Luna³, Lars Eide⁶, Bente Halvorsen², Pål Aukrust⁸, Magnar Bjørås⁹

Affiliations

¹ Department of Microbiology, Oslo University Hospital, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.
² Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
³ Department of Microbiology, Oslo University Hospital, Oslo, Norway.
⁴ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ 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.
⁶ Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁷ Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
⁸ 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. Electronic address: paukrust@ous-hf.no.
⁹ 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. Electronic address: magnar.bjoras@rr-research.no.

PMID: 32209476
DOI: 10.1016/j.celrep.2020.02.063

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.

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

Substances

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