OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation

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...

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Main Authors: 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
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Language:English
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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.