RT Journal Article
SR Electronic
T1 Methylation of Dual Specificity Phosphatase 4 Controls Cell Differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.16.422727
DO 10.1101/2020.12.16.422727
A1 Hairui Su
A1 Ming Jiang
A1 Chamara Senevirathne
A1 Srinivas Aluri
A1 Tuo Zhang
A1 Han Guo
A1 Juliana Xavier-Ferrucio
A1 Shuiling Jin
A1 Ngoc-Tung Tran
A1 Szu-Mam Liu
A1 Chiao-Wang Sun
A1 Yongxia Zhu
A1 Qing Zhao
A1 Yuling Chen
A1 LouAnn Cable
A1 Yudao Shen
A1 Jing Liu
A1 Cheng-Kui Qu
A1 Xiaosi Han
A1 Christopher A. Klug
A1 Ravi Bhatia
A1 Yabing Chen
A1 Stephen D. Nimer
A1 Y. George Zheng
A1 Camelia Iancu-Rubin
A1 Jian Jin
A1 Haiteng Deng
A1 Diane S. Krause
A1 Jenny Xiang
A1 Amit Verma
A1 Minkui Luo
A1 Xinyang Zhao
YR 2020
UL http://biorxiv.org/content/early/2020/12/16/2020.12.16.422727.abstract
AB A collection of signaling and epigenetic events needs to be orchestrated for normal development of hematopoietic lineages. While mitogen-activated protein (MAP) kinases (MAPKs) and multiple epigenetic modulators have been implicated in the megakaryocytic (Mk) cell differentiation, the underlying molecular mechanisms of signaling-epigenetic crosstalk remain unclear. MAPKs are in general inactivated by dual specificity phosphatases (DUSPs), whose activities are tightly regulated by various posttranslational modifications. Using knockdown screening and single-cell transcriptional analysis, we determined that DUSP4 is the phosphatase that inactivates p38 MAPK in hematopoietic cells and serves as a key regulator to promote Mk differentiation. With the nextgeneration Bioorthogonal Profiling of Protein Methylation technology for live cells, we identified DUSP4 as a PRMT1 substrate. Mechanistically, PRMT1-mediated Arg351 methylation of DUSP4 triggers its ubiquitinylation by HUWE1 (an E3 ligase) and then degradation, which results in p38 MAPK activation and inhibition of Mk differentiation in vitro and in vivo. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation and thus argues immunological roles of Mk cells. Collectively, these results demonstrate a critical role of PRMT1-mediated posttranslational modification of DUSP4 in regulation of Mk differentiation and maturation. In the context of thrombocytopenia observed in myelodysplastic syndromes (MDS), we demonstrated 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 in MDS samples. These findings provide novel mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a targeting strategy for treatment of thrombocytopenia associated with myeloid malignancies such as MDS.Competing Interest StatementM.L. has served as a member of the Scientific Advisory Board for Epi One Inc.. 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. Other authors have no conflicts of interest relevant to this work. Array BioPharma provided the p38 inhibitor Pexmetinib (ARRY614) and participated in its Phase I study (ClinicalTrials.gov Identifier: NCT01496495).