MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

• Published in: Advanced science 2022-05, Vol.9 (14), p.e2105539-n/a
• Main Authors: Zhang, Lan, Wang, Ling, Hu, Xue‐Bin, Hou, Min, Xiao, Yuan, Xiang, Jia‐Wen, Xie, Jie, Chen, Zhi‐Gang, Yang, Tian‐Heng, Nie, Qian, Fu, Jia‐Ling, Wang, Yan, Zheng, Shu‐Yu, Liu, Yun‐Fei, Gan, Yu‐Wen, Gao, Qian, Bai, Yue‐Yue, Wang, Jing‐Miao, Qi, Rui‐Li, Zou, Ming, Ke, Qin, Zhu, Xing‐Fei, Gong, Lili, Liu, Yizhi, Li, David Wan‐Cheng
• Format: Article
• Language: English
• Subjects: Animals; anterior subcapsular cataract (ASC); cataract; Cataract - genetics; Cataract - metabolism; Cataracts; Cell cycle; dephosphorylation; enhancer of zeste homolog 2 (EZH2); Enhancer of Zeste Homolog 2 Protein - metabolism; Epithelial-Mesenchymal Transition - genetics; epithelial‐mesenchymal transition (EMT); Fibrosis; Gene expression; Humans; Kinases; lens; Lens, Crystalline - metabolism; Lens, Crystalline - pathology; Mice; Myosin-Light-Chain Phosphatase - metabolism; MYPT1; Pathogenesis; Phosphatase; Phosphorylation; Physiology; posterior subcapsular cataract (PCO); POSTN; Protein expression; protein phosphotase‐1; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Statistical analysis; Transcription factors
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202105539

The methyltransferase EZH2 plays an important role in regulating chromatin conformation and gene transcription. Phosphorylation of EZH2 at S21 by AKT kinase suppresses its function. However, protein phosphatases responsible for the dephosphorylation of EZH2‐S21 remain elusive. Here, it is demonstrated that EZH2 is highly expressed in the ocular lens, and AKT‐EZH2 axis is important in TGFβ‐induced epithelial‐mesenchymal transition (EMT). More importantly, it is identified that MYPT1/PP1 dephosphorylates EZH2‐S21 and thus modulates its functions. MYPT1 knockout accelerates EMT, but expression of the EZH2‐S21A mutant suppresses EMT through control of multiple families of genes. Furthermore, the phosphorylation status and gene expression modulation of EZH2 are implicated in control of anterior subcapsular cataracts (ASC) in human and mouse eyes. Together, the results identify the specific phosphatase for EZH2‐S21 and reveal EZH2 dephosphorylation control of several families of genes implicated in lens EMT and ASC pathogenesis. These results provide important novel information in EZH2 function and regulation. MYPT1/PP1 is identified as the specific protein phosphatase for dephosphorylating histone methyltransferase enhancer of zeste homolog 2 (EZH2) at S21 residue, demonstrating that EZH2 dephosphorylation/EZH2‐S21A expression causes global changes in multiple families of genes implicated in epithelial‐mesenchymal transition (EMT), contributing to fibrotic diseases, and revealing that AKT‐EZH2‐H3K27Me3 signal axis plays an important role in lens EMT induced by TGFβ and mediates pathogenesis of anterior subcapsular cataract (ASC).