@article{f673ddca8c3d4adc990f2f3f55310560,
title = "Methylation of dual-specificity phosphatase 4 controls cell differentiation",
abstract = "Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.",
keywords = "DUSP4, HUWE1, MDS, PRMT1, leukemia, megakaryocyte, myelodysplasia syndrome, p38, platlet, trombocytopenia",
author = "Hairui Su and Ming Jiang and Chamara Senevirathne and Srinivas Aluri and Tuo Zhang and Han Guo and Juliana Xavier-Ferrucio and Shuiling Jin and Tran, {Ngoc Tung} and Liu, {Szu Mam} and Sun, {Chiao Wang} and Yongxia Zhu and Qing Zhao and Yuling Chen and Cable, {Lou Ann} and Yudao Shen and Jing Liu and Qu, {Cheng Kui} and Xiaosi Han and Klug, {Christopher A.} and Ravi Bhatia and Yabing Chen and Nimer, {Stephen D.} and Zheng, {Y. George} and Camelia Iancu-Rubin and Jian Jin and Haiteng Deng and Krause, {Diane S.} and Jenny Xiang and Amit Verma and Minkui Luo and Xinyang Zhao",
note = "Funding Information: This work was supported by grants from the NIH (1R21CA202390 and 1R01DK110574 and the Pardee Foundation to X.Z. R35GM131858 to M.L. R01GM122749 to J.J. and R01GM126154 to Y.G.Z.), the NCI (5P30 CA008748 to M.L. via MSKCC), the Tri-Institutional PhD Program in Chemical Biology (to H.G.), and the US Department of Veterans Affairs (BX0003617 and BX004426 to Y.C.). We would like to thank Dr. Iannis Aifantis at NYU for HUWE1 reagents. H.S. M.J. C.S. S.A. H.G. H.D. A.V. M.L. and X.Z. designed the study. H.S, M.J. C.S. S.A. J.X.-F. N.-T.T. S.-M.L. H.G. S.J. Y.G.Z. C.-W.S. X.H. and Y.C. performed the experiments. Q.Z. L.C. Y.S. J.L. J.J. and Y.G.Z. provided key reagents. M.J. T.Z. J.X. and M.L. performed computational analysis. C.K.Q. C.A.K. R.B. Y.C. S.D.N. H.D. D.S.K. J.X. A.V. M.L. and X.Z. supervised the project. H.S. M.J. C.S. A.V. M.L. and X.Z. prepared the manuscript with help from all coauthors. M.L. has served on the Scientific Advisory Board for Epi One. A.V. has received research funding from GlaxoSmithKline, Incyte, MedPacto, Novartis, Curis, and Eli Lilly and Company; has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene; and has equity ownership in Stelexis Therapeutics. The remaining authors declare no competing interests. Array BioPharma provided the p38 inhibitor pexmetinib (ARRY614) and participated in its phase I study (ClinicalTrials.gov: NCT01496495). We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. Funding Information: This work was supported by grants from the NIH ( 1R21CA202390 and 1R01DK110574 and the Pardee Foundation to X.Z., R35GM131858 to M.L., R01GM122749 to J.J., and R01GM126154 to Y.G.Z.), the NCI ( 5P30 CA008748 to M.L. via MSKCC), the Tri-Institutional PhD Program in Chemical Biology (to H.G.), and the US Department of Veterans Affairs ( BX0003617 and BX004426 to Y.C.). We would like to thank Dr. Iannis Aifantis at NYU for HUWE1 reagents. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = jul,
day = "27",
doi = "10.1016/j.celrep.2021.109421",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}