Department of Microbiology, Oslo University Hospital, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.
Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
Cell Rep. 2020 Mar 24;30(12):4165-4178.e7. doi: 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.
氧化还原酶 1（OXR1）基因可保护细胞免受氧化应激。我们发现，大脑特异性同工型 A 敲除（Oxr1A）的雄性小鼠会发生脂肪肝。雄性 Oxr1A 肝脏的 RNA 测序表明生长激素（GH）信号降低，已知其会影响肝脏代谢。事实上，雄性小鼠 Oxr1A 垂体和大鼠 Oxr1A 垂体腺瘤细胞系 GH3 中的 Gh 表达减少。Oxr1A 雄性小鼠表现出空腹血 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 细胞中组蛋白 H3 精氨酸 2（H3R2me2s）的对称二甲基化减少，这是 PRMT5 催化甲基化的产物，并且 H3R2me2s 的染色质免疫沉淀（ChIP）显示 Gh 启动子富集减少。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 的共激活剂，调节组蛋白精氨酸甲基化，从而调节垂体中的 GH 产生。
