Browsing by Author "Zhao, Xinyang"

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    Methylation of dual-specificity phosphatase 4 controls cell differentiation
    (Cell Press, 2021) Su, Hairui; Jiang, Ming; Senevirathne, Chamara; Aluri, Srinivas; Zhang, Tuo; Guo, Han; Xavier-Ferrucio, Juliana; Jin, Shuiling; Tran, Ngoc-Tung; Liu, Szu-Mam; Sun, Chiao-Wang; Zhu, Yongxia; Zhao, Qing; Chen, Yuling; Cable, LouAnn; Shen, Yudao; Liu, Jing; Qu, Cheng-Kui; Han, Xiaosi; Klug, Christopher A.; Bhatia, Ravi; Chen, Yabing; Nimer, Stephen D.; Zheng, Y. George; Iancu-Rubin, Camelia; Jin, Jian; Deng, Haiteng; Krause, Diane S.; Xiang, Jenny; Verma, Amit; Luo, Minkui; Zhao, Xinyang; Pediatrics, School of Medicine
    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.
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    PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex
    (Elsevier B.V., 2013-12-26) Vu, Ly P.; Perna, Fabiana; Wang, Lan; Voza, Francesca; Figueroa, Maria E.; Tempst, Paul; Erdjument-Bromage, Hediye; Gao, Rui; Chen, Sisi; Paietta, Elisabeth; Deblasio, Tony; Melnick, Ari; Liu, Yan; Zhao, Xinyang; Nimer, Stephen D.; Department of Pediatrics, IU School of Medicine
    Defining the role of epigenetic regulators in hematopoiesis has become critically important, as recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase, whose function in normal and malignant hematopoiesis is unknown, is overexpressed in AML patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs) while its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multi-protein repressor complex that includes DPF2. As part of a feedback loop, PRMT4 expression is repressed post-transcriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decrease proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.