Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1

Jiang, Xiaoxia; Chou, YuChia; Jones, Lindsey; Wang, Tao; Sanchez, Suzi; Huang, Xue F.; Zhang, Lei; Wang, Changyong; Chen, Si-Yi

doi:10.1038/srep13755

Cited by 15 publications

(18 citation statements)

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“…13, 14, 15, 16, 17 Our previous work revealed critical roles of Mysm1-mediated H2A deubiquitination in HSC differentiation, 16 NK cell maturation, 14 and B-cell and dendritic cell (DC) commitments. 13, 18 We found that Mysm1 −/− impairs self-renewal and lineage reconstitution of HSC by abolishing recruitment of key transcriptional factors to the Gfi-1 locus. 16 In the present study, we further investigated the role of Mysm1 in the maintenance of cell lineages by systematically analyzing the impact of Mysm1 deficiency on T-cell lineages.…”

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confidence: 79%

Mysm1 is required for interferon regulatory factor expression in maintaining HSC quiescence and thymocyte development

et al. 2016

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Mysm1−/− mice have severely decreased cellularity in hematopoietic organs. We previously revealed that Mysm1 knockout impairs self-renewal and lineage reconstitution of HSCs by abolishing the recruitment of key transcriptional factors to the Gfi-1 locus, an intrinsic regulator of HSC function. The present study further defines a large LSKs in >8-week-old Mysm1−/− mice that exhibit increased proliferation and reduced cell lineage differentiation compared with those of WT LSKs. We found that IRF2 and IRF8, which are important for HSC homeostasis and commitment as transcription repressors, were expressed at lower levels in Mysm1−/− HSCs, and Mysm1 enhanced function of the IRF2 and IRF8 promoters, suggesting that Mysm1 governs the IRFs for HSC homeostasis. We further found that the lower expressions of IRF2 and IRF8 led to an enhanced transcription of p53 in Mysm1−/− HSCs, which was recently defined to have an important role in mediating Mysm1−/−-associated defects. The study also revealed that Mysm1−/− thymocytes exhibited lower IRF2 expression, but had higher Sca1 expression, which has a role in mediating thymocyte death. Furthermore, we found that the thymocytes from B16 melanoma-bearing mice, which display severe thymus atrophy at late tumor stages, exhibited reduced Mysm1 and IRF2 expression but enhanced Sca1 expression, suggesting that tumors may downregulate Mysm1 and IRF2 for thymic T-cell elimination.

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confidence: 79%

Mysm1 is required for interferon regulatory factor expression in maintaining HSC quiescence and thymocyte development

et al. 2016

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“…These studies elucidated the role of MYSM1 in the de-repression of a range of genes essential for normal stem cell differentiation and lineage specification in hematopoiesis. The genes de-repressed by MYSM1 include: Ebf1 in B cell progenitors [20], Pax5 in naïve B cells [30], miR150 in B1a cells [31], Id2 in NK cell progenitors [32], Flt3 in dendritic cell precursors [33], and Gfi1 in hematopoietic stem and progenitor cells [34] (Figure 2). At many of these loci, loss of MYSM1 resulted in increased binding of PRC1 complex proteins and elevated levels of histone H2AK119ub [20,30,[32][33][34], suggesting that MYSM1 antagonizes PRC1-mediated histone ubiquitination and transcriptional repression.…”

Section: Mysm1 Is a Transcriptional Regulator In Hematopoietic Lineagmentioning

confidence: 99%

“…Increased levels of histone H3K27me3 were also observed at several loci [20,30,33,34], suggesting indirect cross-talk between MYSM1-deficiency and PRC2 complex activity. Regrettably, only a few studies specifically tested whether the catalytic activity of MYSM1 is essential for its transcriptional activity [7].…”

Section: Mysm1 Is a Transcriptional Regulator In Hematopoietic Lineagmentioning

confidence: 99%

“…Regrettably, only a few studies specifically tested whether the catalytic activity of MYSM1 is essential for its transcriptional activity [7]. [20], Pax5 in naïve B cells [30], miR150 in B1a cells [31], Id2 in NK cell progenitors [32], Flt3 in dendritic cell precursors [33], and Gfi1 in hematopoietic stem and progenitor cells [34], through deubiquitination of histone H2AK119ub, and interactions with hematopoietic transcription factors E2A [20], PU.1 [30,33], GATA2 [34], RUNX1 [34], cMYC [31], and NFIL3 [32].…”

Section: Mysm1 Is a Transcriptional Regulator In Hematopoietic Lineagmentioning

confidence: 99%

“…MYSM1 was also shown to interact with many transcriptional regulators through coimmunoprecipitation assays, including essential hematopoietic transcription factors E2A [20], PU.1 [30,33], GATA2 [34], RUNX1 [34], cMYC [31], and NFIL3 [32], as well as the histone acetylase pCAF [20], Pax5 in naïve B cells [30], miR150 in B1a cells [31], Id2 in NK cell progenitors [32], Flt3 in dendritic cell precursors [33], and Gfi1 in hematopoietic stem and progenitor cells [34], through deubiquitination of histone H2AK119ub, and interactions with hematopoietic transcription factors E2A [20], PU.1 [30,33], GATA2 [34], RUNX1 [34], cMYC [31], and NFIL3 [32].…”

Section: Mysm1 Is a Transcriptional Regulator In Hematopoietic Lineagmentioning

confidence: 99%

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Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

Fiore

Liang

Lin

et al. 2020

IJMS

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MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes to the nucleus, where it can interact with chromatin and regulate gene expression, through deubiquitination of histone H2A and non-catalytic contacts with other transcriptional regulators. A cytosolic form of MYSM1 protein was also recently described and demonstrated to regulate signal transduction pathways of innate immunity, by promoting the deubiquitination of TRAF3, TRAF6, and RIP2. In this work we review the current knowledge on the molecular mechanisms of action of MYSM1 protein in transcriptional regulation, signal transduction, and potentially other cellular processes. The functions of MYSM1 in different cell types and aspects of mammalian physiology are also reviewed, highlighting the key checkpoints in hematopoiesis, immunity, and beyond regulated by MYSM1. Importantly, mutations in MYSM1 in human were recently linked to a rare hereditary disorder characterized by leukopenia, anemia, and other hematopoietic and developmental abnormalities. Our growing knowledge of MYSM1 functions and mechanisms of actions sheds important insights into its role in mammalian physiology and the etiology of the MYSM1-deficiency disorder in human.

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