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. We further demonstrated that MYSM1 de-represses EBF1 transcription in B-cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development, but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination.

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. MYSM1 interacts with nuclear factor IL-3 (NFIL3, also known as E4BP4), a critical factor for mouse NK cell development, and the recruitment of nuclear factor Il-3 to the ID2 locus is dependent on MYSM1. Further, we observed that MYSM1 is involved in maintaining an active chromatin at the ID2 locus to promote NK cell development. Hence this study demonstrates the critical epigenetic regulation of NK cell development by the histone H2A deubiquitinase MYSM1 through the transcriptional control of transcription factors important for NK cell development.NFIL3 | histone deubiquitination

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.

The mechanisms controlling differentiation of dendritic cells remain largely unknown. Using knockout mouse model, we identified Mysm1 as a critical regulator in dendritic cell differentiation. Mysm1 knockout mice showed a global reduction of both conventional dendritic cells and plasmacytoid dendritic cells in lymphoid organs and non-lymphoid organs whereas development of granulocyte and macrophage was not severely affected. Hematopoietic progenitors and dendritic cell precursors were significantly decreased in KO mice, and the precursor cells from Mysm1 knockout mice were unable to develop DC upon Flt3L stimulation in vitro. The developmental defect of Mysm1-/- progenitor cells was associated with decreased Flt3 expression. Molecular studies indicate that Mysm1 de-represses transcription of Flt3 gene by regulating histone modifications and mediating the recruitment of transcription factor Pu.1 at the promoter. In conclusion, we have identified a regulator of dendritic cell development, Mysm1, and provided novel mechanism of epigenetic control in steady-state dendritic cell development.