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.

抗氧化基因1（OXR1）保护细胞免受氧化应激。我们发现具有脑特异性同工型A基因敲除（Oxr1A ^-/-）的雄性小鼠会发展出脂肪肝。雄性Oxr1A ^-/-肝脏的RNA测序表明生长激素（GH）信号降低，这已知会影响肝脏代谢。实际上，在雄性小鼠Oxr1A ^-/-垂体腺和大鼠Oxr1A ^-/-垂体腺瘤细胞系GH3中，Gh表达降低。Oxr1A ^-/-雄性小鼠的空腹GH水平降低。下拉和邻近连接测定表明OXR1A与精氨酸甲基转移酶PRMT5相关。OXR1A耗尽的GH3细胞显示组蛋白H3精氨酸2（H3R2me2s）（PRMT5催化的甲基化产物）的对称二甲基化降低，H3R2me2s的染色质免疫沉淀（ChIP）显示Gh启动子富集降低。最后，我们用纯化的蛋白质证明OXR1A刺激PRMT5 / MEP50催化的H3R2me2s。我们的数据表明OXR1A是PRMT5的共激活因子，可调节组蛋白精氨酸甲基化，从而调节垂体内GH的产生。