Dnmt3a restrains mast cell inflammatory responses

Abstract

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 using 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 the 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.DNA methylation | epigenetics | inflammation | mast cells

Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity

“…The biology behind neutrophil granules may be altered in the context of gene mutants seen in CHIP. For example, Dnmt3a-deficient mouse mast cells stimulated with IgE exhibited more pronounced degranulation, with relevance to asthma [58]. This finding was also replicated in Dnmt3a-sufficient cells treated with demethylating agents, suggesting that abnormal DNA methylation is responsible for these abnormalities [58].…”

“…For example, loss of murine Dnmt3a in macrophages abolishes its usual function in de-repressing a type I interferon response [57]. DNMT3A appears important in both mounting an appropriate immune response in infection [57] and repressing it [58], with consequences for lung disease. In sum, broader investigation of CHIP mutations will uncover additional avenues of aberrant inflammatory processes or inappropriate immune response.…”

“…For example, Dnmt3a-deficient mouse mast cells stimulated with IgE exhibited more pronounced degranulation, with relevance to asthma [58]. This finding was also replicated in Dnmt3a-sufficient cells treated with demethylating agents, suggesting that abnormal DNA methylation is responsible for these abnormalities [58]. Considered in context with studies of neutrophils, it is possible that a change in epigenetic control caused by CHIP or other factors disrupts granule biology with potential implications for disease, as granule contents tend to have potent inflammatory or cytotoxic effects.…”

The transcriptional program, functional heterogeneity, and clinical targeting of mast cells

“…Although BMMCs from TET2-deficient mice have differential 5-hmC and transcriptional profiles depending on their deoxygenase activity, increased proliferation observed in TET2-deficient mast cells was independent of its enzymatic activity, suggesting other as-yet-unknown functions of TET2 in mast cells. Another epigenetic regulator, DNA methyltransferase 3a (DNMT3a), has also been suggested to control mast cell functions ( Leoni et al, 2017 ). As opposed to TET2, DNMT3a is a DNA methyltransferase adding methyl groups to CpG elements in DNA ( Denis et al, 2011 ).…”

“…As opposed to TET2, DNMT3a is a DNA methyltransferase adding methyl groups to CpG elements in DNA ( Denis et al, 2011 ). Notably, BMMCs from DNMT3a-deficient mice are hyperresponsive to FcεR1 cross-linking, with increased degranulation and cytokine production ( Leoni et al, 2017 ). Similarly, when reconstituted in mast cell–deficient mouse models, DNMT3a-deficient mast cells showed significantly elevated passive cutaneous anaphylaxis (PCA) responses.…”