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• W2308045666 abstract "•The protein arginine methyltransferase (PRMT) family has diverse roles in normal and malignant hematopoiesis.•PRMTs regulate histone marks at promoters critical to cell fate determination.•PRMT substrates include transcription factors and chromatin remodeling complexes.•Several PRMTs are overexpressed in the hematologic malignancies. Arginine methylation is an abundant covalent modification that regulates diverse cellular processes, including transcription, translation, DNA repair, and RNA processing. The enzymes that catalyze these marks are known as the protein arginine methyltransferases (PRMTs), and they can generate asymmetric dimethyl arginine (type I arginine methyltransferases), symmetric dimethylarginine (type II arginine methyltransferases), or monomethyarginine (type III arginine methyltransferases). The PRMTs are capable of modifying diverse substrates, from histone components to specific nuclear and cytoplasmic proteins. Additionally, the PRMTs can orchestrate chromatin remodeling by blocking the docking of other epigenetic modifying enzymes or by recruiting them to specific gene loci. In the hematopoietic system, PRMTs can regulate cell behavior, including the critical balance between stem cell self-renewal and differentiation, in at least two critical ways, via (i) the covalent modification of transcription factors and (ii) the regulation of histone modifications at promoters critical to cell fate determination. Given these important functions, it is not surprising that these processes are altered in hematopoietic malignancies, such as acute myeloid leukemia, where they promote increased self-renewal and impair hematopoietic stem and progenitor cell differentiation. Arginine methylation is an abundant covalent modification that regulates diverse cellular processes, including transcription, translation, DNA repair, and RNA processing. The enzymes that catalyze these marks are known as the protein arginine methyltransferases (PRMTs), and they can generate asymmetric dimethyl arginine (type I arginine methyltransferases), symmetric dimethylarginine (type II arginine methyltransferases), or monomethyarginine (type III arginine methyltransferases). The PRMTs are capable of modifying diverse substrates, from histone components to specific nuclear and cytoplasmic proteins. Additionally, the PRMTs can orchestrate chromatin remodeling by blocking the docking of other epigenetic modifying enzymes or by recruiting them to specific gene loci. In the hematopoietic system, PRMTs can regulate cell behavior, including the critical balance between stem cell self-renewal and differentiation, in at least two critical ways, via (i) the covalent modification of transcription factors and (ii) the regulation of histone modifications at promoters critical to cell fate determination. Given these important functions, it is not surprising that these processes are altered in hematopoietic malignancies, such as acute myeloid leukemia, where they promote increased self-renewal and impair hematopoietic stem and progenitor cell differentiation. Recent advances in proteomics and mass spectroscopy have made it possible to study how overall arginine methylation levels change over time as hematopoietic cells differentiate. In one study, primary T-lymphocytes and cell lines were labeled using a methyl-SILAC approach, and the methylated peptides were subjected to mass spectrometry analysis [1Geoghegan V. Guo A. Trudgian D. Thomas B. Acuto O. Comprehensive identification of arginine methylation in primary T cells reveals regulatory roles in cell signalling.Nature Commun. 2015; 6: 6758Crossref PubMed Scopus (94) Google Scholar]. This analysis identified novel arginine methylated substrates as well as how methylation events change in response to extracellular stimuli (e.g., stimulation of T-cells with CD3, CD28, and interleukin-2). The novel substrates included transcription factors critical for T-cell maturation as well as chromatin-modifying enzymes. These studies clearly indicate that arginine methylation is a dynamically regulated covalent modification in hematopoietic cells. In addition, accumulating evidence suggests that arginine methylation can be a driving force in the initiation and progression of cancer. In this review, we describe in detail those PRMTs with established roles in normal and malignant hematopoiesis: PRMT1, PRMT4, PRMT5, PRMT6, and PRMT7. The known associations between PRMT expression and hematologic malignancies are summarized in Table 1.Table 1Non-histone targets of PRMTs and association with hematologic malignancyPRMTKey nonhistone proteins targetsHematologic malignanciesPRMT1RUNX1, MLL complex, 53BP1, SAM68, SWI/SNFAML 2Shia W.J. Okumura A.J. Yan M. et al.PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential.Blood. 2012; 119: 4953-4962Crossref PubMed Scopus (95) Google ScholarALL 3Zou L. Zhang H. Du C. et al.Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia.J Hematol Oncol. 2012; 5: 42Crossref PubMed Scopus (42) Google ScholarLymphoma 4Leonard S. Gordon N. Smith N. Rowe M. Murray P.G. Woodman C.B. Arginine methyltransferases are regulated by Epstein–Barr virus in B cells and are differentially expressed in Hodgkin's lymphoma.Pathogens. 2012; 1: 52-64Crossref PubMed Scopus (9) Google Scholar, 5Yoshimatsu M. Toyokawa G. Hayami S. et al.Dysregulation of PRMT1 and PRMT6, type I arginine methyltransferases, is involved in various types of human cancers.Int J Cancer. 2011; 128: 562-573Crossref PubMed Scopus (235) Google ScholarPRMT4RUNX1, MLL complex, SWI/SNF, Sm proteinsAML 6Vu L.P. Perna F. Wang L. et al.PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex.Cell Rep. 2013; 5: 1625-1638Abstract Full Text Full Text PDF PubMed Scopus (69) Google ScholarLymphoma 4Leonard S. Gordon N. Smith N. Rowe M. Murray P.G. Woodman C.B. Arginine methyltransferases are regulated by Epstein–Barr virus in B cells and are differentially expressed in Hodgkin's lymphoma.Pathogens. 2012; 1: 52-64Crossref PubMed Scopus (9) Google Scholar, 7Klijn C. Durinck S. Stawiski E.W. Haverty P.M. Jiang Z. Liu H. et al.A comprehensive transcriptional portrait of human cancer cell lines.Nat Biotechnol. 2015; 33: 306-312Crossref PubMed Scopus (416) Google ScholarPRMT5SIN3A/HDAC1, P53, SWI/SNF, E2F, Sm proteinsAML 8Wang L. Pal S. Sif S. Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells.Mol Cell Biol. 2008; 28: 6262-6277Crossref PubMed Scopus (209) Google ScholarMantle cell lymphoma 9Pal S. Baiocchi R.A. Byrd J.C. Grever M.R. Jacob S.T. Sif S. Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma.EMBO J. 2007; 26: 3558-3569Crossref PubMed Scopus (222) Google ScholarPRMT6MLL complex, SIN3A/HDAC1, P53Lymphoma 5Yoshimatsu M. Toyokawa G. Hayami S. et al.Dysregulation of PRMT1 and PRMT6, type I arginine methyltransferases, is involved in various types of human cancers.Int J Cancer. 2011; 128: 562-573Crossref PubMed Scopus (235) Google ScholarPRMT7MLL complex, Sm proteinsUnknown Open table in a new tab PRMT1 is the predominant asymmetric (type I) methyltransferase in mammalian cells, and knockout of Prmt1 in mice results in embryonic lethality at embryonic day 7.5, with a two-fold reduction in total asymmetric arginine methyltransferase activity [10Pawlak M.R. Scherer C.A. Chen J. Roshon M.J. Ruley H.E. Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable.Mol Cell Biol. 2000; 20: 4859-4869Crossref PubMed Scopus (278) Google Scholar, 11Tang J. Frankel A. Cook R.J. et al.PRMT1 is the predominant type I protein arginine methyltransferase in mammalian cells.J Biol Chem. 2000; 275: 7723-7730Crossref PubMed Scopus (347) Google Scholar]. Both histone and nonhistone substrates of PRMT1 have been identified in hematopoietic cells. Knockdown of PRMT1 through siRNA-mediated depletion decreased levels of the activating histone mark H4R3me and increased levels of the repressive H3K9me and H3K27me marks at the β-globin locus in erythrocytes [12Huang S. Litt M. Felsenfeld G. Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications.Genes Dev. 2005; 19: 1885-1893Crossref PubMed Scopus (179) Google Scholar]. The data suggest that PRMT1 promotes an active chromatin state at critical promoters during hematopoietic cell differentiation, as H4R3 methylation by PRMT1 appears to increase the recruitment of the acetyltransferase p300 to histone tails [13An W. Kim J. Roeder R.G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53.Cell. 2004; 117: 735-748Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar]. The ability of the arginine methyltransferases to both directly modify histones and indirectly promote or diminish other histone modifications may explain how changes in PRMT protein expression can have a widespread influence on transcription. The direct and indirect effects of the PRMTs on histone modifications are summarized in Table 2.Table 2Histone modifications and chromatin remodeling by the PRMTsArginine methyltransferaseDirect histone modificationsIndirect effects on histone modificationsPRMT1H4R3Impaired H3K9me and H3K27mePRMT4H3R17 and H3R26Recruitment of p300 to H3, increased histone acetylationPRMT5H2A/H4R3 and H3R8Impaired H3K9acPRMT6H3R2 and H2AR29Impaired binding of MLL methyltransferase complex to H3, decreased H3K4mePRMT7H4R3 and H3R2Impaired H3K4me by MLL4 Open table in a new tab PRMT1 can regulate hematopoietic differentiation through the arginine methylation of RUNX1, a transcription factor critical for definitive hematopoiesis, myeloid differentiation, and lymphocyte development (Fig. 1). Methylation of R206 and R210 by PRMT1 on the C-terminus of RUNX1 impairs its association with the SIN3A co-repressor, which increases the transcriptional activity of the CD41 promoter, a RUNX1 target that is expressed by primitive multipotent progenitor cells and megakaryocytes [14Zhao X. Jankovic V. Gural A. et al.Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity.Genes Dev. 2008; 22: 640-653Crossref PubMed Scopus (138) Google Scholar]. Thus, in this context, PRMT1 appears to regulate transcriptional activation during the normal maturation of the myeloid and erythroid lineages. To determine the biological significance of R206 and R210 methylation, knock-in mouse strains were established, where the arginine residues in RUNX1 were mutated to lysine (from RTAMR to KTAMK) and, thus, were not subject to arginine methylation [15Mizutani S. Yoshida T. Zhao X. Nimer S.D. Taniwaki M. Okuda T. Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis.Br J Haematol. 2015; 170: 859-873Crossref PubMed Scopus (14) Google Scholar]. Homozygous Runx1KTAMK/KTAMK mice are viable, but exhibit defects in CD3+ T-lymphoid cells and CD4+ T-cells in the peripheral lymphoid organs. These findings suggest that methylation of RUNX1 by PRMT1 on these sites is critical for proper peripheral T-cell maintenance. PRMT1 plays important roles in the context of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). PRMT1 is significantly upregulated in newly diagnosed patients with pediatric ALL [3Zou L. Zhang H. Du C. et al.Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia.J Hematol Oncol. 2012; 5: 42Crossref PubMed Scopus (42) Google Scholar]. The t(8:21) translocation, which occurs in 10% of de novo AML, generates the AML1–ETO fusion protein, which interacts with PRMT1. AML1–ETO has been characterized as both a transcriptional activator and a repressor. Knockdown of PRMT1 reduces the transcriptional activation of target genes activated by AML1–ETO, decreasing proliferation and inhibiting self-renewal [2Shia W.J. Okumura A.J. Yan M. et al.PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential.Blood. 2012; 119: 4953-4962Crossref PubMed Scopus (95) Google Scholar]. PRMT1 is also found in transcriptional regulatory complexes with mixed lineage leukemia (MLL) fusion proteins, such as MLL-EEN. Together, MLL–EEN and PRMT1 promote H4R3 arginine methylation and expression from the HoxA9 promoter [16Cheung N. Chan L.C. Thompson A. Cleary M.L. So C.W. Protein arginine-methyltransferase-dependent oncogenesis.Nat Cell Biol. 2007; 9: 1208-1215Crossref PubMed Scopus (249) Google Scholar]. Interactions of MLL–EEN with PRMT1, or the PRMT1-interacting protein Sam68, enhance hematopoietic cell self-renewal. Conversely, knockdown of PRMT1 inhibits leukemia transformation. More recently, PRMT1 has been found to be required for leukemia induction by the leukemia fusion proteins MLL–GAS7 and MOZ–TIF2 in mice [17Cheung N. Fung T.K. Zeisig B.B. et al.Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia.Cancer Ccell. 2016; 29: 32-48Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Although PRMT1 is overexpressed in Hodgkin's lymphoma (HL) cell lines and primary lymphoid tissue, the significance of PRMT1 in HL pathogenesis is unknown [4Leonard S. Gordon N. Smith N. Rowe M. Murray P.G. Woodman C.B. Arginine methyltransferases are regulated by Epstein–Barr virus in B cells and are differentially expressed in Hodgkin's lymphoma.Pathogens. 2012; 1: 52-64Crossref PubMed Scopus (9) Google Scholar]. The regulation of splicing by the PRMTs is another example of a process in which changes in PRMT expression or activity can contribute to the initiation or maintenance of hematologic malignancies. The spliceosome is a multiprotein complex containing small nuclear ribonucleic proteins, and components of this complex are subject to mutations in 50% of patients with myelodysplastic syndrome [18Yoshida K. Sanada M. Shiraishi Y. et al.Frequent pathway mutations of splicing machinery in myelodysplasia.Nature. 2011; 478: 64-69Crossref PubMed Scopus (1495) Google Scholar]. Specific RNA-binding proteins are recognized as targets of PRMT1, including RBM15, a protein that recruits the splicing factor SF3B1 to intronic regions of genes that are critical for megakaryocytic development (such as GATA1 and RUNX1) [19Zhang L. Tran N.T. Su H. et al.Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing.eLife. 2015; : 4Google Scholar]. Methylation of RBM15 (a gene involved in an acute megakaryocytic leukemia-associated translocation) decreases RBM15 protein levels by triggering ubiquitin–proteosome-mediated degradation. Ultimately, this leads to inhibition of megakaryocytic differentiation. In summary, accumulating evidence suggests that small molecule inhibitors of PRMT1 may exhibit efficacy in AML, ALL, and HL. PRMT4 was first identified as a transcriptional activator; it methylates histone H3 at the unique sites H3R17 and H3R26 and methylates many nonhistone substrates. PRMT4 knockout mice are born, but they die shortly after birth from defects in the differentiation of the lung parenchyma, adipocytes, and muscle cells [20O'Brien K.B. Alberich-Jorda M. Yadav N. et al.CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells.Development. 2010; 137: 2147-2156Crossref PubMed Scopus (65) Google Scholar]. T-cell differentiation is also highly dependent on PRMT4 expression, as PRMT null embryos exhibit severe defects in thymocyte progenitor maturation [21Kim J. Lee J. Yadav N. et al.Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development.J Biol Chem. 2004; 279: 25339-25344Crossref PubMed Scopus (87) Google Scholar]. PRMT4 has also been found to regulate cell fate decisions at the earliest stage of embryogenesis [22Torres-Padilla M.E. Parfitt D.E. Kouzarides T. Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo.Nature. 2007; 445: 214-218Crossref PubMed Scopus (466) Google Scholar]. The blastomere inner cell mass expresses high levels of PRMT4, which positively regulate the expression of key pluripotency genes, including Nanog and Sox2. PRMT4 depletion downregulates these pluripotency genes, leading to embryonic stem cell differentiation [23Wu Q. Bruce A.W. Jedrusik A. et al.CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation.Stem Cells. 2009; 27: 2637-2645Crossref PubMed Scopus (92) Google Scholar]. PRMT4 also modifies nonhistone substrates, such as MLL1/2, modulating its binding to specific promoters during differentiation [24Kawabe Y. Wang Y.X. McKinnell I.W. Bedford M.T. Rudnicki M.A. Carm1 regulates Pax7 transcriptional activity through MLL1/2 recruitment during asymmetric satellite stem cell divisions.Cell Stem Cell. 2012; 11: 333-345Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar]. PRMT4 methylates other transcriptional co-activators such as the steroid receptor co-activator AIB1 [25Feng Q. Yi P. Wong J. O'Malley B.W. Signaling within a coactivator complex: Methylation of SRC-3/AIB1 is a molecular switch for complex disassembly.Mol Cell Biol. 2006; 26: 7846-7857Crossref PubMed Scopus (131) Google Scholar]. It has also been implicated in the regulation of splicing through the posttranslational modification of multiple splicing factors, including CA150, SAP49, SmB, and U1C [26Cheng D. Cote J. Shaaban S. Bedford M.T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing.Mol Cell. 2007; 25: 71-83Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar]. In general, methylation of these splicing factors by PRMT4 promotes alternative splicing through exon skipping. Our lab recently reported that PRMT4 is overexpressed in patient AML samples and that PRMT4 negatively regulates myeloid differentiation [6Vu L.P. Perna F. Wang L. et al.PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex.Cell Rep. 2013; 5: 1625-1638Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. PRMT4 levels are highest in undifferentiated human CD34+ cells, with decreased expression as cells undergo cytokine-driven myeloid differentiation in vitro. Furthermore, overexpression of PRMT4 blocks the myeloid differentiation of human HSPCs, whereas its knockdown induces their myeloid differentiation. Our lab identified a feedback loop, whereby PRMT4 modifies RUNX1 on arginine 223, leading to the recruitment of a DPF2-containing repressor complex. Depletion of PRMT4 (or DPF2) results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo, suggesting that targeting PRMT4 may be an effective therapeutic strategy for AML. PRMT4 has also been implicated in modulating the activity of the SWI/SNF (BAF) chromatin-remodeling complex, one of the most commonly mutated protein complexes in cancer. SWI/SNF complexes control the transcriptional regulation of genes involved in differentiation and cell proliferation, and BAF155/SMARCC1, a core component of the SWI/SNF complex, is a substrate of PRMT4 [27Wang L. Zhao Z. Meyer M.B. et al.CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis.Cancer Cell. 2014; 25: 21-36Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar]. Methylation of BAF155 on R1064 affects the targeting of the SWI/SNF complex and upregulation of the c-Myc pathway. Overexpression of PRMT4 and increased BAF155 methylation were both seen in breast cancer samples obtained from patients with the poorest survival outcomes. The regulation of SWI/SNF complexes by PRMT4 does not appear to be limited to solid tumors. Methylation of the transcription factor CEBPB or RUNX1 by PRMT4 interferes with their binding to components of the SWI/SNF complex [6Vu L.P. Perna F. Wang L. et al.PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex.Cell Rep. 2013; 5: 1625-1638Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 28Kowenz-Leutz E. Pless O. Dittmar G. Knoblich M. Leutz A. Crosstalk between C/EBPbeta phosphorylation, arginine methylation, and SWI/SNF/Mediator implies an indexing transcription factor code.EMBO J. 2010; 29: 1105-1115Crossref PubMed Scopus (75) Google Scholar]. In summary, PRMT4 may be an important regulator of SWI/SNF targeting and transcriptional regulation in a variety of cancer cells. PRMT5 was originally identified as a JAK kinase-binding protein in yeast two-hybrid assays; it was later found to possess methyltransferase activity toward arginine residues [29Branscombe T.L. Frankel A. Lee J.H. et al.PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins.J Biol Chem. 2001; 276: 32971-32976Crossref PubMed Scopus (299) Google Scholar, 30Pollack B.P. Kotenko S.V. He W. Izotova L.S. Barnoski B.L. Pestka S. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity.J Biol Chem. 1999; 274: 31531-31542Crossref PubMed Scopus (234) Google Scholar]. We now know that PRMT5 is the major type II enzyme in mammalian cells, catalyzing the symmetric dimethylation of arginine residues in histone (at H2A/H4R3 and H3R8) and numerous nonhistone proteins, including MBD2, p53, HOXA9, and Sm Ribonucleoproteins [31Bandyopadhyay S. Harris D.P. Adams G.N. et al.HOXA9 methylation by PRMT5 is essential for endothelial cell expression of leukocyte adhesion molecules.Mol Cell Biol. 2012; 32: 1202-1213Crossref PubMed Scopus (61) Google Scholar, 32Jansson M. Durant S.T. Cho E.C. et al.Arginine methylation regulates the p53 response.Nat Cell Biol. 2008; 10: 1431-1439Crossref PubMed Scopus (352) Google Scholar, 33Le Guezennec X. Vermeulen M. Brinkman A.B. et al.MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties.Mol Cell Biol. 2006; 26: 843-851Crossref PubMed Scopus (261) Google Scholar, 34Meister G. Eggert C. Buhler D. Brahms H. Kambach C. Fischer U. Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln.Curr Biol. 2001; 11: 1990-1994Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar]. PRMT5-mediated methylation of histones is generally thought to repress gene transcription; indeed, PRMT5 is found in association with multiple co-repressor complexes, including SIN3A/HDAC and MBD2/NuRD [35Karkhanis V. Hu Y.J. Baiocchi R.A. Imbalzano A.N. Sif S. Versatility of PRMT5-induced methylation in growth control and development.Trends Biochem Sci. 2011; 36: 633-641Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. PRMT5 also regulates RNA splicing by methylating the core snRNP components, SmB/B′ and SmD, thereby facilitating biogenesis of the spliceosome [36Meister G. Fischer U. Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs.EMBO J. 2002; 21: 5853-5863Crossref PubMed Scopus (161) Google Scholar, 37Neuenkirchen N. Chari A. Fischer U. Deciphering the assembly pathway of Sm-class U snRNPs.FEBS Lett. 2008; 582: 1997-2003Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Loss of PRMT5 has been reported to affect splicing of numerous genes in neural stem/progenitor cells, including MDM4, a negative regulator of p53 [38Bezzi M. Teo S.X. Muller J. et al.Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.Genes Dev. 2013; 27: 1903-1916Crossref PubMed Scopus (164) Google Scholar, 39Koh C.M. Bezzi M. Low D.H. et al.MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis.Nature. 2015; 523: 96-100Crossref PubMed Scopus (235) Google Scholar]. In addition to transcription regulation and RNA splicing, PRMT5 regulates many other cellular processes, including signal transduction and cell cycle progression [12Huang S. Litt M. Felsenfeld G. Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications.Genes Dev. 2005; 19: 1885-1893Crossref PubMed Scopus (179) Google Scholar, 40Wei T.Y. Juan C.C. Hisa J.Y. et al.Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade.Cancer Sci. 2012; 103: 1640-1650Crossref PubMed Scopus (143) Google Scholar]. PRMT5 functions in the context of several multimeric complexes, which invariably contain the WD40-repeat protein MEP50, but also specific nuclear and cytoplasmic components [41Antonysamy S. Bonday Z. Campbell R.M. et al.Crystal structure of the human PRMT5:MEP50 complex.Proc Natl Acad Sci USA. 2012; 109: 17960-17965Crossref PubMed Scopus (221) Google Scholar]. MEP50 is indispensable for PRMT5 enzymatic activity, whereas these other components regulate PRMT5 localization and substrate specificity. In the cytoplasm, the PRMT5/MEP50 core complex interacts with pICln or RioK1, which directs PRMT5 methyltransferase activity toward Sm proteins or nucleolin, respectively [34Meister G. Eggert C. Buhler D. Brahms H. Kambach C. Fischer U. Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln.Curr Biol. 2001; 11: 1990-1994Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 42Guderian G. Peter C. Wiesner J. et al.RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity.J Biol Chem. 2011; 286: 1976-1986Crossref PubMed Scopus (96) Google Scholar]. In the nucleus, the core PRMT5 complex interacts with COPR5 (coordinator of PRMT5), which promotes the methylation of H4R3 by PRMT5, but also inhibits the ability of PRMT5 to methylate H3 at R8 [43Lacroix M. El Messaoudi S. Rodier G. Le Cam A. Sardet C. Fabbrizio E. The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5.EMBO Rep. 2008; 9: 452-458Crossref PubMed Scopus (94) Google Scholar]. The formation of PRMT5 complexes can be regulated by upstream signaling pathways. For example, our lab has previously found that the myeloproliferative neoplasm-associated mutant JAK2 kinase (JAK2V617F) gains the ability to phosphorylate PRMT5 and disrupt the interaction between PRMT5 and MEP50, thus inhibiting PRMT5 methyltransferase activity [44Liu F. Zhao X. Perna F. et al.JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation.Cancer Cell. 2011; 19: 283-294Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. PRMT5 function is also regulated by its subcellular localization, with cytoplasmic and nuclear PRMT5 having distinct effects on stem cell development and possibly cancer cell proliferation [45Gu Z. Li Y. Lee P. Liu T. Wan C. Wang Z. Protein arginine methyltransferase 5 functions in opposite ways in the cytoplasm and nucleus of prostate cancer cells.PloS One. 2012; 7: e44033Crossref PubMed Scopus (67) Google Scholar]. How cells control the translocation of PRMT5 between the cytoplasm and the nucleus is poorly understood. PRMT5 has been reported to play an important role in maintaining the pluripotency of both embryonic and adult stem cells by inhibiting the expression of differentiation-associated genes [46Chittka A. Nitarska J. Grazini U. Richardson W.D. Transcription factor positive regulatory domain 4 (PRDM4) recruits protein arginine methyltransferase 5 (PRMT5) to mediate histone arginine methylation and control neural stem cell proliferation and differentiation.J Biol Chem. 2012; 287: 42995-43006Crossref PubMed Scopus (61) Google Scholar, 47Tee W.W. Pardo M. Theunissen T.W. et al.Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency.Genes Dev. 2010; 24: 2772-2777Crossref PubMed Scopus (235) Google Scholar]. To study the function of PRMT5 in hematopoietic stem cells (HSCs), our lab generated an inducible PRMT5 conditional knockout mouse. We deleted PRMT5 in the hematopoietic cells of 2-month-old mice and triggered a rapidly fatal bone marrow aplasia. We observed a cell-intrinsic, nonhomeostatic transient expansion of PRMT5-null HSCs, which identified a role for PRMT5 in maintaining stem cell quiescence. However, the exhaustion of both HSCs and hematopoietic progenitor cells (HPCs) in PRMT5-null mice indicated the indispensable role of this methyltransferase in maintaining normal HSPC function. We have completed several mechanistic studies to date that identified severely impaired cytokine signaling and overactive p53 signaling in PRMT5-deficient HSPCs, which may explain some of the phenotypes we observed [48Liu F. Cheng G. Hamard P.J. et al.Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis.J Clin Invest. 2015; 125: 3532-3544Crossref PubMed Scopus (91) Google Scholar]. Growing evidence suggests that PRMT5 is involved in tumorigenesis. Although recurrent mutations of PRMT5 are rarely observed in cancer cells, its expression level is upregulated in leukemia, lymphoma, and many solid tumors [8Wang L. Pal S. Sif S. Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppre" @default.
• W2308045666 created "2016-06-24" @default.
• W2308045666 creator A5020996374 @default.
• W2308045666 creator A5033073898 @default.
• W2308045666 creator A5089486443 @default.
• W2308045666 date "2016-06-01" @default.
• W2308045666 modified "2023-10-09" @default.
• W2308045666 title "Arginine methyltransferases in normal and malignant hematopoiesis" @default.
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• W2308045666 doi "https://doi.org/10.1016/j.exphem.2016.03.009" @default.
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