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• W1968189901 abstract "Little is known about the developmental functions of chromatin regulators that can deubiquitinate histones. In this issue of Immunity, Jiang et al., 2011Jiang X.-X. Nguyen Q. Chou Y. Wang T. Nandakumar V. Yates P. Jones L. Wang L. Wan H.-J. Lee H.-R. et al.Immunity. 2011; 35 (this issue): 883-896Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar demonstrate that the deubiquitinase MYSM1 is part of an epigenetic switch that turns on B cell development. Little is known about the developmental functions of chromatin regulators that can deubiquitinate histones. In this issue of Immunity, Jiang et al., 2011Jiang X.-X. Nguyen Q. Chou Y. Wang T. Nandakumar V. Yates P. Jones L. Wang L. Wan H.-J. Lee H.-R. et al.Immunity. 2011; 35 (this issue): 883-896Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar demonstrate that the deubiquitinase MYSM1 is part of an epigenetic switch that turns on B cell development. The B cell developmental pathway serves as a powerful experimental model for elucidating the network of transcription factors that orchestrate cell fate specification and commitment (Singh et al., 2005Singh H. Medina K.L. Pongubala J.M. Proc. Natl. Acad. Sci. USA. 2005; 102: 4949-4953Crossref PubMed Scopus (158) Google Scholar). B-lymphocytes develop from lymphoid-primed multipotent progenitors (LMPPs) in the bone marrow that also give rise to myeloid progeny such as macrophages, dendritic cells, and granulocytes. Early B cell development is critically dependent on five transcriptional regulators, PU.1, Ikaros, E2A, EBF1, and Pax5. Of these, PU.1, Ikaros, and E2A are expressed in LMPPs and are important for the development of multiple hematopoietic lineages, whereas EBF1 and Pax5 are sequentially expressed in B-lymphoid progenitors and required specifically for B cell development. EBF1 plays a particularly pivotal role within the network of B lineage transcription factors because its induction directs LMPPs along the B cell pathway and restricts alternate lineage options (Pongubala et al., 2008Pongubala J.M. Northrup D.L. Lancki D.W. Medina K.L. Treiber T. Bertolino E. Thomas M. Grosschedl R. Allman D. Singh H. Nat. Immunol. 2008; 9: 203-215Crossref PubMed Scopus (187) Google Scholar). EBF1 functions synergistically with E2A to activate the transcription of early B lineage genes that encode components of the pre-B cell receptor and the two factors also promote DNA rearrangements at the immunoglobulin heavy-chain (Igh) locus. EBF1 is required for the induction of Pax5, which functions in concert with EBF1 to establish and maintain B cell fate commitment. Comparatively less is known about the interplay of these transcription factors with chromatin modifications that are necessary for the precise developmental control of B lineage gene activity. Alterations in chromatin structure are regulated by a diverse set of histone modifying enzymes as well as by ATP-dependent nucleosome remodeling complexes (Shilatifard, 2006Shilatifard A. Annu. Rev. Biochem. 2006; 75: 243-269Crossref PubMed Scopus (845) Google Scholar). In this issue of Immunity, Jiang et al., 2011Jiang X.-X. Nguyen Q. Chou Y. Wang T. Nandakumar V. Yates P. Jones L. Wang L. Wan H.-J. Lee H.-R. et al.Immunity. 2011; 35 (this issue): 883-896Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar uncover a novel molecular mechanism that appears to involve an E2A-dependent alteration of chromatin structure at the Ebf1 gene resulting in its developmental induction. The mechanism involved recruitment of the MYSM1 histone H2A deubiquitinase, whose localized action resulted in the conversion of pre-existing repressive histone modifications at Ebf1 regulatory sequences into their activating counterparts (Figure 1). Accordingly, genetic ablation of the Mysm1 gene resulted in a block to early B cell development accompanied with the failure to induce EBF1. This developmental block could be rescued by restoration of EBF1 expression. A diverse set of covalent histone modifications have been shown to regulate chromatin structure and gene transcription. These include acetylation, methylation, phosphorylation, SUMOylation, and ubiquitination (Shilatifard, 2006Shilatifard A. Annu. Rev. Biochem. 2006; 75: 243-269Crossref PubMed Scopus (845) Google Scholar). Of these, monoubiquitination of histone H2B has been associated with transcriptional activation, promoted by the onset of additional activating histone modifications, such as methylation of lysine at position 4 of histone H3 (H3K4) and H3K79 (Lee et al., 2010Lee J.-S. Smith E. Shilatifard A. Cell. 2010; 142: 682-685Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar). On the other hand, monoubiquitination of histone H2A has been associated with transcriptional silencing. In the mammalian nucleus, H2A is the most abundant ubiquitinated protein. Monoubiquitination of H2A has been linked to Polycomb group complex-dependent gene silencing as well as X chromosome inactivation (Clague et al., 2008Clague M.J. Coulson J.M. Urbé S. Genome Biol. 2008; 9: 202Crossref PubMed Scopus (14) Google Scholar). Furthermore, the dynamic expression of many genes appears to be dependent on a temporal cycle of H2B ubiquitination and deubiquitination (Henry et al., 2003Henry K.W. Wyce A. Lo W.S. Duggan L.J. Emre N.C. Kao C.F. Pillus L. Shilatifard A. Osley M.A. Berger S.L. Genes Dev. 2003; 17: 2648-2663Crossref PubMed Scopus (511) Google Scholar). However, the key biological and molecular functions of the large class of deubuitinating enzymes remain largely unexplored. Jiang et al., 2011Jiang X.-X. Nguyen Q. Chou Y. Wang T. Nandakumar V. Yates P. Jones L. Wang L. Wan H.-J. Lee H.-R. et al.Immunity. 2011; 35 (this issue): 883-896Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar have taken an important step in illuminating this exciting area by undertaking a rigorous genetic and molecular analysis of MYSM1 function in B cell development. The Myb-like, SWIRM, and MPN domain-containing protein 1 (MYSM1) is a histone H2A deubiquitinase and is a component of a multiprotein complex that includes the histone acetyltransferase PCAF (Zhu et al., 2007Zhu P. Zhou W. Wang J. Puc J. Ohgi K.A. Erdjument-Bromage H. Tempst P. Glass C.K. Rosenfeld M.G. Mol. Cell. 2007; 27: 609-621Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Jiang et al., 2011Jiang X.-X. Nguyen Q. Chou Y. Wang T. Nandakumar V. Yates P. Jones L. Wang L. Wan H.-J. Lee H.-R. et al.Immunity. 2011; 35 (this issue): 883-896Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar demonstrate that genetic ablation of the Mysm1 gene resulted in a profound and specific block at an early stage in B cell development. This developmental block was shown to be cell-intrinsic on the basis of transplantation of Mysm1−/− hematopoietic progenitors and the analysis of their progeny in chimeric animals. The developmental block caused by the loss of MYSM1 occurred at a similar stage (pre-pro-B) that had been described for the Ebf1−/− mice, and importantly, Mysm1−/− common lymphoid progenitors (CLPs) evidence a dramatic reduction of the Ebf1 as well as Pax5 genes. In order to determine whether the arrest in early B cell development in MYSM1-deficient lymphoid progenitors was due to low amounts of EBF1, the authors restored the expression of EBF1 in Mysm1−/− hematopoietic progenitors. These cells upon transduction with an EBF1-encoding viral vector were able to form B-lineage colonies that comprised CD19+ B lineage precursors. The rescue of B cell development was not observed in Mysm1−/− hematopoietic progenitors transduced with Pax5, suggesting that MYSM1 controls B cell development by regulating the transcriptional activation of the Ebf1 gene. Next, the authors sought to uncover the molecular mechanism by which MYSM1 induces transcription of the Ebf1 gene during B cell development. Using chromatin crosslinking and immunoprecipitation (ChIP) assays, the authors demonstrated that MYSM1 is associated with the Ebf1α and Ebf1β promoters as well as enhancer regions in wild-type hematopoietic progenitors and this in turn is correlated with low levels of H2A ubiquitination. Consistent with the expectation that MYSM1 is required to deubiquitinate H2A at the Ebf1 gene regulatory elements, the amounts of ubH2A were substantially increased at the Ebf1α and Ebf1β promoters in Mysm1−/− lineage negative (Lin−) progenitors. This molecular defect was associated with a failure to properly induce transcription of the Ebf1 gene. As mentioned above, histone ubiquitination is accompanied by other histone modifications that affect the dynamic structure of chromatin. Therefore, Jiang et al. analyzed additional histone modifications at the Ebf1 promoters and/or enhancer region that were impacted by the loss of MYSM1. The repressive histone mark H3K27me3 was significantly elevated, whereas the activating mark H3K4me3 was decreased in Mysm1−/− Lin− progenitors. Intriguingly, histone modifications induced by MYSM1 appeared to be also required for the binding of the transcription factor E2A to the Ebf1 regulatory elements. These data strongly suggest that MYSM1 deubiquitinates H2A at regulatory elements in the Ebf1 gene, and this is associated with two key molecular outcomes, the replacement of repressive histone marks with their activating counterparts and the facilitation of binding of E2A, which is required for activation of the Ebf1 gene (Figure 1). These observations raise key issues concerning the ordering of molecular events that are required for the developmental induction of the Ebf1 gene. How is MYSM1, which lacks a DNA binding domain and is not known to be associated with a DNA binding subunit, targeted to Ebf1 regulatory elements? Furthermore how does it facilitate the binding of E2A? The authors provide some intriguing clues that suggest a parsimonious explanation. MYSM1 was shown to interact with E2A by coimmunoprecipitation and the two factors could be detected cobound on the Ebf1 promoter and/or enhancer region with sequential immunoprecipitation and ChIP assays. These results implied a concerted molecular mechanism in which E2A is responsible for recruiting MYSM1 to the Ebf1 gene regulatory elements and MYSM1 in turns enhances E2A binding by inducing localized alterations in nucleosome structure. Consistent with this model, MYSM1 was also seen to associate with BRM or Brahma-related gene 1 (BRG-1), the ATPase subunits of the SWI/SNF nucleosome-remodeling complex, at the Ebf1 promoters. The findings of Jiang et al. nicely converge with recent work of Oguro et al., 2010Oguro H. Yuan J. Ichikawa H. Ikawa T. Yamazaki S. Kawamoto H. Nakauchi H. Iwama A. Cell Stem Cell. 2010; 6: 279-286Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, which undertook genetic analysis of the chromatin regulator Bmi1 in the context of hematopoiesis and B cell development. Bmi1 interacts with Ring1B and is associated with components of Polycomb group (PcG) complexes that mediate H2A ubiquitination. Loss of Bmi1 results in enhanced expression of the Ebf1 and Pax5 genes in multipotential hematopoietic progenitors and an increased potential to generate B lineage cells at the expense of the T cell fate. Intriguingly Jiang et al. have shown that loss of MYSM1 results in increased binding of Bmi1 to the Ebf1 promoter region. Thus, it appears that Bmi1, perhaps as a component of a PcG complex, functions in the establishment of a repressed chromatin state at the Ebf1 promoters and enhancer region that is dependent on ubH2A and H3K27me3. This state is then altered by the action of E2A-associated MYSM1, resulting in the developmental induction of the Ebf1 gene (Figure 1). Given that one of the downstream consequences of H2A monoubiquitination is RNA polymerase (pol) II pausing (Stock et al., 2007Stock J.K. Giadrossi S. Casanova M. Brookes E. Vidal M. Koseki H. Brockdorff N. Fisher A.G. Pombo A. Nat. Cell Biol. 2007; 9: 1428-1435Crossref PubMed Scopus (494) Google Scholar), it will be interesting to determine whether the Ebf1 gene, in its repressed state, is already poised for developmental activation with a paused polymerase complex. In this scenario, binding of the E2A-MYSM1 complex may additionally enable release of the paused Pol II complex. Although the data presented by Jiang et al. make a compelling case for the Ebf1 gene as a major biologically relevant target for the E2A-MYSM1 complex during B cell fate specification, there are likely to be other important targets for this complex. ChIPseq analyses of E2A and MYSMI in wild-type and Tcf3−/− or Mysm1−/− hematopoietic progenitors can be used for elucidating the nature of common targets as well as those that are unique to each factor. It is likely that MYSM1 can associate with other transcription factors to target genes for H2A deubiquitination. The proposed genomic analyses can be complemented with a proteomics approach involving the sequencing and characterization of protein subunits of MYSM1 complexes purified from B-lineage progenitors. Nonetheless, the findings of Jiang et al. highlight a major epigenetic switch that needs to be activated by targeted H2A deubiquitination of nucleosomes that span the promoter and enhancer region of the Ebf1 gene to start off B cell development. That is quite A-MYSM! Control of B Cell Development by the Histone H2A Deubiquitinase MYSM1Jiang et al.ImmunityDecember 8, 2011In BriefEpigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B cell development. MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes. Full-Text PDF Open Archive" @default.
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• W1968189901 date "2011-12-01" @default.
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• W1968189901 title "The A-MYSM Power of Deubiquitinases" @default.
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