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Dnmt3a restrains mast cell inflammatory responses.

Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1490-E1499. Epub 2017 Feb 06
Cristina Leoni 1 , Sara Montagner 2 , Andrea Rinaldi 3 , Francesco Bertoni 4 , Sara Polletti 5 , Chiara Balestrieri 5 , Silvia Monticelli 6
Cristina Leoni 1 , Sara Montagner 2 , Andrea Rinaldi 3 , Francesco Bertoni 4 , Sara Polletti 5 , Chiara Balestrieri 5 , Silvia Monticelli 6
+ et al

[No authors listed]

Author information
  • 1 Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
  • 2 Institute for Research in Biomedicine, Università della Svizzera italiana (USI), 6500 Bellinzona, Switzerland.
  • 3 Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), USI, 6500 Bellinzona, Switzerland.
  • 4 Oncology Institute of Southern Switzerland (IOSI), 6500 Bellinzona, Switzerland.
  • 5 Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
  • 6 Institute for Research in Biomedicine, Università della Svizzera italiana (USI), 6500 Bellinzona, Switzerland; silvia.monticelli@irb.usi.ch.

摘要


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.

KEYWORDS: DNA methylation, epigenetics, inflammation, mast cells

原始数据


 保存测序数据
Sample name
Organism Experiment title Sample type Library instrument Attributes
cell typegenotypegrowth protocolsample preparationsource name
BMMC.DNMT3A-KO
Mus musculus GSM2420025: BMMC.DNMT3A-KO; Mus musculus; ATAC-seq ATAC-seq Illumina HiSeq 2000 BMMC DNMT3A-KO IL-3 was used as a survival and growth factor Cells were differentiated for 4 weeks in vitro in the presence of IL-3 Primary bone marrow-derived mast cells (BMMCs)
BMMC.WT
Mus musculus GSM2420024: BMMC.WT; Mus musculus; ATAC-seq ATAC-seq Illumina HiSeq 2000 BMMC wild type IL-3 was used as a survival and growth factor Cells were differentiated for 4 weeks in vitro in the presence of IL-3 Primary bone marrow-derived mast cells (BMMCs)