OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation
Yang, Mingyi; Lin, Xiaolin; Segers, Filip; Suganthan, Rajikala; Hildrestrand, Gunn Annette; Rinholm, Johanne Egge; Aas, Per Arne; Sousa, Mirta; Holm, Sverre; Bolstad, Nils; Warren, David; Berge, Rolf Kristian; Johansen, Rune Forstrøm; Yndestad, Arne; Kristiansen, Elise; Klungland, Arne; Gomez, Luisa Fernanda Luna; Eide, Lars; Halvorsen, Bente; Aukrust, Pål; Bjørås, Magnar
Peer reviewed, Journal article
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OriginalversjonCell reports. 2020, 30 (12), 4165-4178. 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.