Methylation of dual-specificity phosphatase 4 controls cell differentiation

Hairui Su; Ming Jiang; Chamara Senevirathne; Srinivas Aluri; Tuo Zhang; Han Guo; Juliana Xavier-Ferrucio; Shuiling Jin; Ngoc Tung Tran; Szu Mam Liu; Chiao Wang Sun; Yongxia Zhu; Qing Zhao; Yuling Chen; Lou Ann Cable; Yudao Shen; Jing Liu; Cheng Kui Qu; Xiaosi Han; Christopher A. Klug; Ravi Bhatia; Yabing Chen; Stephen D. Nimer; Y. George Zheng; Camelia Iancu-Rubin; Jian Jin; Haiteng Deng; Diane S. Krause; Jenny Xiang; Amit Verma; Minkui Luo; Xinyang Zhao

doi:10.1016/j.celrep.2021.109421

Methylation of dual-specificity phosphatase 4 controls cell differentiation

Hairui Su, Ming Jiang, Chamara Senevirathne, Srinivas Aluri, Tuo Zhang, Han Guo, Juliana Xavier-Ferrucio, Shuiling Jin, Ngoc Tung Tran, Szu Mam Liu, Chiao Wang Sun, Yongxia Zhu, Qing Zhao, Yuling Chen, Lou Ann Cable, Yudao Shen, Jing Liu, Cheng Kui Qu, Xiaosi Han, Christopher A. KlugRavi Bhatia, Yabing Chen, Stephen D. Nimer, Y. George Zheng, Camelia Iancu-Rubin, Jian Jin, Haiteng Deng, Diane S. Krause, Jenny Xiang, Amit Verma, Minkui Luo, Xinyang Zhao

Oncology

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Article number	109421
Journal	Cell Reports
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2021.109421
State	Published - Jul 27 2021

Keywords

DUSP4
HUWE1
MDS
PRMT1
leukemia
megakaryocyte
myelodysplasia syndrome
p38
platlet
trombocytopenia

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.109421

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Su, H., Jiang, M., Senevirathne, C., Aluri, S., Zhang, T., Guo, H., Xavier-Ferrucio, J., Jin, S., Tran, N. T., Liu, S. M., Sun, C. W., Zhu, Y., Zhao, Q., Chen, Y., Cable, L. A., Shen, Y., Liu, J., Qu, C. K., Han, X., ... Zhao, X. (2021). Methylation of dual-specificity phosphatase 4 controls cell differentiation. Cell Reports, 36(4), Article 109421. https://doi.org/10.1016/j.celrep.2021.109421

Su, H, Jiang, M, Senevirathne, C, Aluri, S, Zhang, T, Guo, H, Xavier-Ferrucio, J, Jin, S, Tran, NT, Liu, SM, Sun, CW, Zhu, Y, Zhao, Q, Chen, Y, Cable, LA, Shen, Y, Liu, J, Qu, CK, Han, X, Klug, CA, Bhatia, R, Chen, Y, Nimer, SD, Zheng, YG, Iancu-Rubin, C, Jin, J, Deng, H, Krause, DS, Xiang, J, Verma, A, Luo, M & Zhao, X 2021, 'Methylation of dual-specificity phosphatase 4 controls cell differentiation', Cell Reports, vol. 36, no. 4, 109421. https://doi.org/10.1016/j.celrep.2021.109421

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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 = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jul,

day = "27",

doi = "10.1016/j.celrep.2021.109421",

language = "English (US)",

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T1 - Methylation of dual-specificity phosphatase 4 controls cell differentiation

AU - Su, Hairui

AU - Jiang, Ming

AU - Senevirathne, Chamara

AU - Aluri, Srinivas

AU - Zhang, Tuo

AU - Guo, Han

AU - Xavier-Ferrucio, Juliana

AU - Jin, Shuiling

AU - Tran, Ngoc Tung

AU - Liu, Szu Mam

AU - Sun, Chiao Wang

AU - Zhu, Yongxia

AU - Zhao, Qing

AU - Chen, Yuling

AU - Cable, Lou Ann

AU - Shen, Yudao

AU - Liu, Jing

AU - Qu, Cheng Kui

AU - Han, Xiaosi

AU - Klug, Christopher A.

AU - Bhatia, Ravi

AU - Chen, Yabing

AU - Nimer, Stephen D.

AU - Zheng, Y. George

AU - Iancu-Rubin, Camelia

AU - Jin, Jian

AU - Deng, Haiteng

AU - Krause, Diane S.

AU - Xiang, Jenny

AU - Verma, Amit

AU - Luo, Minkui

AU - Zhao, Xinyang

PY - 2021/7/27

Y1 - 2021/7/27

N2 - 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.

AB - 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.

KW - DUSP4

KW - HUWE1

KW - MDS

KW - PRMT1

KW - leukemia

KW - megakaryocyte

KW - myelodysplasia syndrome

KW - p38

KW - platlet

KW - trombocytopenia

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DO - 10.1016/j.celrep.2021.109421

M3 - Article

C2 - 34320342

AN - SCOPUS:85111217156

SN - 2211-1247

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 109421

ER -

Methylation of dual-specificity phosphatase 4 controls cell differentiation

Abstract

Keywords

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