Browsing by Author "Nimer, Stephen D."

Now showing 1 - 4 of 4
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    ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis
    (American Association for the Advancement of Science, 2017-01-20) Li, Zhaomin; Zhang, Peng; Yan, Aimin; Guo, Zhengyu; Ban, Yuguang; Li, Jin; Chen, Shi; Yang, Hui; He, Yongzheng; Li, Jianping; Guo, Ying; Zhang, Wen; Hajiramezanali, Ehsan; An, Huangda; Fajardo, Darlene; Harbour, J. William; Ruan, Yijun; Nimer, Stephen D.; Yu, Peng; Chen, Xi; Xu, Mingjiang; Yang, Feng-Chun; Department of Pediatrics, IU School of Medicine
    ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin-cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.
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    Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice.
    (Elsevier, 2015-11-24) Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zeng; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng-Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, IU School of Medicine
    TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.
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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.