Data are presented from one of two indie experiments. 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. Genomic DNA is usually compacted through its association with histone proteins in an octamer, consisting of two copies of histones H2A, H2B, H3, and H4, to form nucleosomes and chromatin. Histone and DNA modifications determine chromatin structure, while maintaining unique transcription patterns, and cellular identity and functions1,2,3,4. Histones are subject to a variety of post-translational modifications, including methylation, acetylation, phosphorylation, sumoylation, and ubiquitination1,5. Numerous enzymes catalyze histone Rabbit polyclonal to EPHA4 modifications, while an increasing quantity of enzymes that catalyze the removal of these histone marks have been recently recognized1,5, indicating that epigenetic histone modifications are a reversible and highly D3-βArr dynamic process. Recent studies demonstrate that epigenetic histone and DNA modifications at target transcription factor and cytokine loci are of importance in the process of T lymphocyte lineage differentiation and functions6,7,8,9. However, to date, little is known about the epigenetic regulation of B cell differentiation and antibody responses. Histone H2A D3-βArr is usually monoubiquitinated at the conserved residue lysine (K) 119 by histone H2A ubiquitinases10,11,12, which represents a non-degradative, epigenetic transmission5,13. Recently, numerous histone H2A deubiquitinases, including MYSM1, USP16/Ubp-M, USP21, USP22, and PR-DUB/BAP1, have been recognized14,15,16,17,18. H2A deubiquitination activity of the Myb-like, SWIRM, and MPN domains-containing protein 1 D3-βArr (MYSM1) is usually associated with target gene transcription17. The JAMM/MPN domain name possesses an intrinsic metalloprotease activity that hydrolyzes the isopeptide bonds of ubiquitin chains, while the SANT domain name is similar to the DNA-binding domain name of Myb-related proteins19 and the SWIRM domain name frequently exists in the users of the SWI/SNF-family of ATP-dependent chromatin remodeling complexes20. In a recent study, we found that MYSM1 is essential for B cell development by derepressing the transcription of EBF1, Pax5, and other B-lymphoid genes21. Mechanistic studies revealed that MYSM1 is an epigenetic transcriptional switch that orchestrates histone modifications and transcription factor recruitment to the target EBF1 locus. The mature B cell compartment is composed of follicular (FO), B1, and marginal zone (MZ) B cells22,23,24, which are located in unique anatomical sites. B1 B cells are found in the pleural and peritoneal cavities, and MZ B cells reside within the splenic white pulp. B1 B cells and MZ B cells take action to mediate the initial wave of humoral immunity against invading pathogens by quickly generating low affinity, antigen-specific IgM antibodies in a thymus-independent (TI) fashion. In contrast, FO B cells comprise the majority of B cells found in peripheral lymphoid organs and respond to antigens in a thymus-dependent (TD) manner22,23,24. In this study, we unexpectedly observed that MYSM1-deficient mice experienced an enhanced antibody response despite the severe defect in B cell development. Mechanistic studies revealed that MYSM1 intrinsically represses plasma cell differentiation and antibody production by activating the transcription of Pax5, the repressors of plasma cell differentiation, in mature B cells. Furthermore, this study provides a new strategy and target to modulate antibody production and responses with profound therapeutic implications. Results Enhanced main and recall antibody responses in Mysm1?/? mice despite the severe defect in follicular (FO) B cell development In the absence of MYSM1, there is a block in early B cell development with a severe reduction in the frequency and absolute quantity of both peripheral immature and mature B cells21. In order to further define the role of MYSM1 in peripheral B cell subpopulation development, we analyzed splenic subpopulations of B cells in WT and Mysm1?/? mice by circulation cytometry. We observed a drastic decrease in the percentages and numbers of immature, transitional B-lineage precursor marker CD93/AA4.1+ B cell populations (IgM+CD23? (T1), IgM+CD23+ (T2), and IgMloCD23+ (T3)) in the spleens of Mysm1?/? mice relative to WT controls (Fig. 1a,b). Frequencies of both B220+CD93/AA4.1lo mature B cell and B220+CD93/AA4.1high immature B cell populations, and complete B220+ B cell numbers in the spleen and bone marrow of Mysm1?/? mice were drastically reduced (Fig. 1aCc). We further observed a drastic reduction in both the percent and cell number of CD21lo FO B cells (FO I and FO II) in the spleens of Mysm1?/? mice. However, the percentages of CD21hi MZ B cells were increased in the spleens of Mysm1?/? mice. The complete cell numbers of both MZP and MZ B cells were reduced.