Dnmt3a restrains mast cell inflammatory responses

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By utilizing mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2'-deoxycytidine, as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation. Murine bone marrow-derived mast cells were differentiated from DNMT3A-deleted animals (3 weeks old) and wild-type littermates age and sex-matched (females). Cells were cultured in vitro for 4 weeks in the presence of IL-3 prior to analysis.