Mysm1 is required for interferon regulatory factor expression in maintaining HSC quiescence and thymocyte development.
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.
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Huang
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Nandakumar
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Tumurkhuu
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Wang
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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X
Jiang
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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B
Hong
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Jones
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Won
Laboratory of Molecular Growth Regulation, Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Yoshii
Laboratory of Molecular Growth Regulation, Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Ozato
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan.
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A
Masumi
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Chen
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation / Q000235:genetics; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D050836:Interferon Regulatory Factor-2 / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D038041:Lymphopoiesis; D008546:Melanoma, Experimental / Q000473:pathology; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D060168:Thymocytes / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases; D000099185:Interferon Regulatory Factor-8
D010450:Endopeptidases; D050836:Interferon Regulatory Factor-2; D050835:Interferon Regulatory Factors; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D064570:Ubiquitin-Specific Proteases; D000099185:Interferon Regulatory Factor-8; C494230:Irf2 protein, mouse; C570173:MYSM1 protein, mouse