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Xiao-Xia Jiang, Yu Liu, Hong Li, Yaping Gao, Rong Mu, Jianping Guo, Jing Zhang, Yan-Mei Yang, Fengjun Xiao, Bing Liu, Changyong Wang, Beifen Shen, Si-Yi Chen, Zhanguo Li, Guang Yang
The aberrant expansion of B1a cells has been observed in several murine autoimmune disease models; however, the mechanism of such proliferation of B1a cells is still limited. Here, we identify that Myb Like, SWIRM And MPN Domains 1 (MYSM1), a histone H2A deubiquitinase, plays an intrinsic role in the proliferation of B1a cells where MYSM1 deficiency results in the increased proliferation of B1a cells in mice. We demonstrate that MYSM1 recruits c-Myc to the promoter of miR-150 and stimulates the transcription of miR-150...
August 31, 2016: Oncotarget
X F Huang, V Nandakumar, G Tumurkhuu, T Wang, X Jiang, B Hong, L Jones, H Won, H Yoshii, K Ozato, A Masumi, S-Y Chen
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...
2016: Cell Death & Disease
Ping Li, Yan-Mei Yang, Suzi Sanchez, Dian-Chao Cui, Rui-Jie Dang, Xiao-Yan Wang, Qiu-Xia Lin, Yan Wang, Changyong Wang, Da-Fu Chen, Si-Yi Chen, Xiao-Xia Jiang, Ning Wen
Deubiquitinase MYSM1 has been shown to play a critical role in hematopoietic cell differentiation and hematopoietic stem cell (HSC) maintenance. Mesenchymal stem cells (MSCs) are multipotent stromal cells within the bone marrow. MSCs are progenitors to osteoblasts, chondrocytes, adipocytes, and myocytes. Although, MSCs have been extensively studied, the roles of MYSM1 in these cells remain unclear. Here we describe the function of MYSM1 on MSC maintenance and differentiation. In this report, we found that Mysm1-/- mice had a lower bone mass both in long bone and calvaria compared with their control counterpart...
2016: Scientific Reports
Swarupa Panda, Jonas A Nilsson, Nelson O Gekara
Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses...
October 20, 2015: Immunity
Xiao-Xia Jiang, YuChia Chou, Lindsey Jones, Tao Wang, Suzi Sanchez, Xue F Huang, Lei Zhang, Changyong Wang, Si-Yi Chen
B cell-mediated antibody response plays critical roles in protective immunity, as well as in the pathogenesis of allergic and autoimmune diseases. Epigenetic histone and DNA modifications regulate gene transcription and immunity; however, so far, little is known about the role of epigenetic regulation in antibody responses. In this study, we found that mice deficient in the histone H2A deubiquitinase MYSM1, despite their severe defect in B cell development, exhibit an enhanced antibody response against both T cell-dependent and independent antigens...
2015: Scientific Reports
Tangui Le Guen, Fabien Touzot, Isabelle André-Schmutz, Chantal Lagresle-Peyrou, Benoit France, Laetitia Kermasson, Nathalie Lambert, Capucine Picard, Patrick Nitschke, Wassila Carpentier, Christine Bole-Feysot, Annick Lim, Marina Cavazzana, Isabelle Callebaut, Jean Soulier, Nada Jabado, Alain Fischer, Jean-Pierre de Villartay, Patrick Revy
BACKGROUND: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear...
December 2015: Journal of Allergy and Clinical Immunology
Michael Förster, Jad I Belle, Jessica C Petrov, Edward J Ryder, Simon Clare, Anastasia Nijnik
MYSM1 is a chromatin-interacting deubiquitinase recently shown to be essential for hematopoietic stem cell (HSC) function and normal progression of hematopoiesis in both mice and humans. However, it remains unknown whether the loss of function in Mysm1-deficient HSCs is due to the essential role of MYSM1 in establishing the HSC pool during development or due to a continuous requirement for MYSM1 in adult HSCs. In this study we, for the first time, address these questions first, by performing a detailed analysis of hematopoiesis in the fetal livers of Mysm1-knockout mice, and second, by assessing the effects of an inducible Mysm1 ablation on adult HSC functions...
August 15, 2015: Stem Cells and Development
Jad I Belle, David Langlais, Jessica C Petrov, Mercedes Pardo, Russell G Jones, Philippe Gros, Anastasia Nijnik
MYSM1 is a chromatin-binding transcriptional cofactor that deubiquitinates histone H2A. Studies of Mysm1-deficient mice have shown that it is essential for hematopoietic stem cell (HSC) function and lymphopoiesis. Human carriers of a rare MYSM1-inactivating mutation display similar lymphopoietic deficiencies. However, the mechanism by which MYSM1 regulates hematopoietic homeostasis remains unclear. Here, we show that Mysm1-deficiency results in p53 protein elevation in many hematopoietic cell types. p53 is a central regulator of cellular stress responses and HSC homeostasis...
April 9, 2015: Blood
M Gatzka, A Tasdogan, A Hainzl, G Allies, P Maity, C Wilms, M Wlaschek, K Scharffetter-Kochanek
Monoubiquitination of core histone 2A (H2A-K119u) has a critical role in gene regulation in hematopoietic differentiation and other developmental processes. To explore the interplay of histone H2A deubiquitinase Myb-like SWIRM and MPN domain containing1 (2A-DUB/Mysm1) with the p53 axis in the sequential differentiation of mature lymphocytes from progenitors, we systematically analyzed hematopoiesis and early T-cell development using Mysm1(-/-) and p53(-/-)Mysm1(-/-) mice. Mysm1(-/-) thymi were severely hypoplastic with <10% of wild-type cell numbers as a result of a reduction of early thymocyte progenitors in context with defective hematopoietic stem cells, a partial block at the double-negative (DN)1-DN2 transition and increased apoptosis of double-positive thymocytes...
September 2015: Cell Death and Differentiation
Tia DiTommaso, Lynelle K Jones, Denny L Cottle, Anna-Karin Gerdin, Valerie E Vancollie, Fiona M Watt, Ramiro Ramirez-Solis, Allan Bradley, Karen P Steel, John P Sundberg, Jacqueline K White, Ian M Smyth
The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression...
October 2014: PLoS Genetics
Haejung Won, Vijayalakshmi Nandakumar, Peter Yates, Suzi Sanchez, Lindsey Jones, Xue F Huang, Si-Yi Chen
The mechanisms controlling the development of dendritic cells (DCs) remain incompletely understood. Using an Mysm1 knockout (Mysm1(-/-)) mouse model, we identified the histone H2A deubiquitinase Mysm1, as a critical regulator in DC differentiation. Mysm1(-/-) mice showed a global reduction of DCs in lymphoid organs, whereas development of granulocytes and macrophages were not severely affected. Hematopoietic progenitors and DC precursors were significantly decreased in Mysm1(-/-) mice and defective in Fms-like tyrosine kinase-3(Flt3) ligand-induced, but not in granulocyte macrophage-colony-stimulating factor (GM-CSF)-induced DC differentiation in vitro...
October 23, 2014: Blood
Kifayathullah Liakath-Ali, Valerie E Vancollie, Emma Heath, Damian P Smedley, Jeanne Estabel, David Sunter, Tia Ditommaso, Jacqueline K White, Ramiro Ramirez-Solis, Ian Smyth, Karen P Steel, Fiona M Watt
Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities...
2014: Nature Communications
Abdulrahman Alsultan, Hanan E Shamseldin, Mohamed Elfaki Osman, Mansour Aljabri, Fowzan S Alkuraya
No abstract text is available yet for this article.
November 28, 2013: Blood
Vijayalakshmi Nandakumar, Yuchia Chou, Linda Zang, Xue F Huang, Si-Yi Chen
Histone modifications play critical roles in regulating immunity; however, little is known about the epigenetic control of natural killer (NK) cell development. Here, we found that NK cell development is severely impaired in mice deficient in the histone H2A deubiquitinase MYSM1. We demonstrated that MYSM1 is required for NK cell maturation but not for NK lineage specification and commitment. We also found that MYSM1 intrinsically controls this NK cell maturation. Mechanistic studies revealed that the expression of transcription factor, inhibitor of DNA-binding protein (ID2), a critical factor for NK cell development, is impaired in Mysm1(-/-) NK cells...
October 8, 2013: Proceedings of the National Academy of Sciences of the United States of America
Tao Wang, Vijayalakshmi Nandakumar, Xiao-Xia Jiang, Lindsey Jones, An-Gang Yang, Xue F Huang, Si-Yi Chen
Epigenetic histone modifications play critical roles in the control of self-renewal and differentiation of hematopoietic stem cells (HSCs). Mysm1 is a recently identified histone H2A deubiquitinase with essential and intrinsic roles for maintaining functional HSCs. In this study, in addition to confirming this function of Mysm1, by using Mysm1-deficient (Mysm1(-/-)) mice, we provide more evidence for how Mysm1 controls HSC homeostasis. Mysm1 deletion drives HSCs from quiescence into rapid cycling and increases their apoptotic rate, resulting in an exhaustion of the stem cell pool, which leads to an impaired self-renewal and lineage reconstituting abilities in the Mysm1-deficient mice...
October 17, 2013: Blood
Ignacio A Demarco, Harinder Singh
Little is known about the developmental functions of chromatin regulators that can deubiquitinate histones. In this issue of Immunity, Jiang et al. (2011) demonstrate that the deubiquitinase MYSM1 is part of an epigenetic switch that turns on B cell development.
December 23, 2011: Immunity
Anastasia Nijnik, Simon Clare, Christine Hale, Claire Raisen, Rebecca E McIntyre, Kosuke Yusa, Aaron R Everitt, Lynda Mottram, Christine Podrini, Mark Lucas, Jeanne Estabel, David Goulding, Niels Adams, Ramiro Ramirez-Solis, Jacqui K White, David J Adams, Robert E W Hancock, Gordon Dougan
Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed...
February 9, 2012: Blood
Xiao-Xia Jiang, Quan Nguyen, YuChia Chou, Tao Wang, Vijayalakshmi Nandakumar, Peter Yates, Lindsey Jones, Lifeng Wang, Haejung Won, Hye-Ra Lee, Jae U Jung, Markus Müschen, Xue F Huang, Si-Yi Chen
Epigenetic 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...
December 23, 2011: Immunity
Yu-Chuen Huang, Jane-Ming Lin, Hui-Ju Lin, Ching-Chu Chen, Shih-Yin Chen, Chang-Hai Tsai, Fuu-Jen Tsai
PURPOSE: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a complex multifactorial pathogenesis. The aim of this study was to identify the susceptibility genes that increase the risk of DR in type 2 diabetes (T2D) and to further elucidate the underlying mechanism of DR pathogenesis. DESIGN: A case-control study. PARTICIPANTS: We included 749 unrelated individuals with T2D (174 with DR and 575 without DR) and 100 nondiabetic controls...
April 2011: Ophthalmology
Ping Zhu, Wenlai Zhou, Jianxun Wang, Janusz Puc, Kenneth A Ohgi, Hediye Erdjument-Bromage, Paul Tempst, Christopher K Glass, Michael G Rosenfeld
Deciphering the epigenetic "code" remains a central issue in transcriptional regulation. Here, we report the identification of a JAMM/MPN(+) domain-containing histone H2A deubiquitinase (2A-DUB, or KIAA1915/MYSM1) specific for monoubiquitinated H2A (uH2A) that has permitted delineation of a strategy for specific regulatory pathways of gene activation. 2A-DUB regulates transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes...
August 17, 2007: Molecular Cell
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