Abstract
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. We revealed that MYSM1 intrinsically represses plasma cell differentiation and antibody production. Mechanistic studies demonstrated that MYSM1 is a transcriptional activator of Pax5, the repressors of plasma cell differentiation, by facilitating key transcriptional factor recruitment and coordinating histone modifications at the Pax5 loci. Hence, this study uncovers a critical role for MYSM1 in epigenetically repressing plasma cell differentiation and antibody production, in addition to its opposing, active role in B cell development. Importantly, this study further provides a new target and strategy to modulate antibody production and responses with profound therapeutic implications.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibody Formation / genetics*
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Basic-Leucine Zipper Transcription Factors / genetics
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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DNA-Binding Proteins / genetics
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Endopeptidases / genetics*
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Epigenesis, Genetic*
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Gene Expression Regulation*
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Immunoglobulins / blood
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Immunoglobulins / immunology
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Immunologic Memory
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Lymphocyte Activation / immunology
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Mice
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Mice, Knockout
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PAX5 Transcription Factor / genetics
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Plasma Cells / cytology
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Plasma Cells / immunology
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Plasma Cells / metabolism
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Positive Regulatory Domain I-Binding Factor 1
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Protein Binding
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Proto-Oncogene Proteins / metabolism
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Regulatory Factor X Transcription Factors
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Ubiquitin-Specific Proteases
Substances
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Bach2 protein, mouse
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Basic-Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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Immunoglobulins
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PAX5 Transcription Factor
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Pax5 protein, mouse
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Prdm1 protein, mouse
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Proto-Oncogene Proteins
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Regulatory Factor X Transcription Factors
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Trans-Activators
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Transcription Factors
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proto-oncogene protein Spi-1
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Positive Regulatory Domain I-Binding Factor 1
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Endopeptidases
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MYSM1 protein, mouse
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Ubiquitin-Specific Proteases