Cell Reports (Jul 2021)
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,
- LouAnn 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
Affiliations
- Hairui Su
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Ming Jiang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
- Chamara Senevirathne
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
- Srinivas Aluri
- Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA
- Tuo Zhang
- Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
- Han Guo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
- Juliana Xavier-Ferrucio
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Shuiling Jin
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Ngoc-Tung Tran
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Szu-Mam Liu
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Chiao-Wang Sun
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Yongxia Zhu
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
- Qing Zhao
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Yuling Chen
- Department of School of Life Sciences, Tsinghua University, Beijing 100084, China
- LouAnn Cable
- Array BioPharma, Boulder, CO 80301 USA
- Yudao Shen
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Jing Liu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Cheng-Kui Qu
- Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Xiaosi Han
- Department of Neurology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Christopher A. Klug
- Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Ravi Bhatia
- Division of Hematology and Oncology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Yabing Chen
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Veterans Affairs Birmingham Medical Center, Research Department, Birmingham, AL 35294, USA
- Stephen D. Nimer
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33146 USA
- Y. George Zheng
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
- Camelia Iancu-Rubin
- Department of Medicine, Hematology and Oncology Division, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Haiteng Deng
- Department of School of Life Sciences, Tsinghua University, Beijing 100084, China
- Diane S. Krause
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Jenny Xiang
- Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
- Amit Verma
- Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA; Corresponding author
- Minkui Luo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA; Corresponding author
- Xinyang Zhao
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Corresponding author
- Journal volume & issue
-
Vol. 36,
no. 4
p. 109421
Abstract
Summary: 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.
