CARM1-mediated methylation of protein arginine methyltransferase 5 represses human γ-globin gene expression in erythroleukemia cells.
Min NieYadong WangChan GuoXinyu LiYing WangYexuan DengBing YaoTao GuiChi MaMing LiuPanxue WangRuoyun WangRenxiang TanMing FangBing ChenYinghong HeDavid C S HuangJunyi JuQuan ZhaoPublished in: The Journal of biological chemistry (2018)
Protein arginine methyltransferase 5 (PRMT5) is a member of the arginine methyltransferase protein family that critically mediates the symmetric dimethylation of Arg-3 at histone H4 (H4R3me2s) and is involved in many key cellular processes, including hematopoiesis. However, the post-translational modifications (PTMs) of PRMT5 that may affect its biological functions remain less well-understood. In this study, using MS analyses, we found that PRMT5 itself is methylated in human erythroleukemia Lys-562 cells. Biochemical assays revealed that coactivator-associated arginine methyltransferase 1 (CARM1) interacts directly with and methylates PRMT5 at Arg-505 both in vivo and in vitro. Substitutions at Arg-505 significantly reduced PRMT5's methyltransferase activity, decreased H4R3me2s enrichment at the γ-globin gene promoter, and increased the expression of the γ-globin gene in Lys-562 cells. Moreover, CARM1 knockdown consistently reduced PRMT5 activity and activated γ-globin gene expression. Importantly, we show that CARM1-mediated methylation of PRMT5 is essential for the intracellular homodimerization of PRMT5 to its active form. These results thus reveal a critical PTM of PRMT5 that represses human γ-globin gene expression. We conclude that CARM1-mediated asymmetric methylation of PRMT5 is critical for its dimerization and methyltransferase activity leading to the repression of γ-globin expression. Given PRMT5's crucial role in diverse cellular processes, these findings may inform strategies for manipulating its methyltransferase activity for managing hemoglobinopathy or cancer.
Keyphrases
- gene expression
- dna methylation
- induced apoptosis
- genome wide
- endothelial cells
- nitric oxide
- cell cycle arrest
- binding protein
- amino acid
- poor prognosis
- multiple sclerosis
- cell death
- squamous cell carcinoma
- copy number
- endoplasmic reticulum stress
- single cell
- oxidative stress
- signaling pathway
- mass spectrometry
- ms ms
- papillary thyroid
- pluripotent stem cells
- young adults
- reactive oxygen species
- hematopoietic stem cell