DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation

The inverse correlation between DNA methylation and lineage-specific gene expression during T helper cell development is well documented. However, the specific functions of the de novo methyltransferases Dnmt3a and Dnmt3b in cytokine gene regulation have not been defined. We demonstrate that the exp...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (2), p.541-546
Main Authors: Yu, Qing, Zhou, Baohua, Zhang, Yanlu, Nguyen, Evelyn T, Du, Jianguang, Glosson, Nicole L, Kaplan, Mark H
Format: Article
Language:English
Subjects:
Acetylation
animal disease models
Animal models
Animals
Asthma
Biological Sciences
CD4-positive T-lymphocytes
Cellular immunity
Conditional mutant
Cytokines
Development
DNA
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA methylation
DNA Methylation - immunology
DNA methyltransferase
DNA Primers - genetics
Gene expression
Gene Expression Regulation - immunology
Gene regulation
Genes
Genetic loci
Helper cells
Histones
Inflammation
Interleukin 13
Interleukin-13 - metabolism
loci
Lung
Lymphocytes T
Methylation
Methyltransferase
methyltransferases
Mice
Mice, Inbred C57BL
Mice, Transgenic
mutants
pneumonia
Polarization
Respiratory Hypersensitivity - immunology
Respiratory tract diseases
Rodents
T lymphocytes
Th2 Cells - immunology
Th2 Cells - metabolism
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Summary:The inverse correlation between DNA methylation and lineage-specific gene expression during T helper cell development is well documented. However, the specific functions of the de novo methyltransferases Dnmt3a and Dnmt3b in cytokine gene regulation have not been defined. We demonstrate that the expression of Dnmt3a and Dnmt3b are induced to a greater extent in T helper 2 (Th2) cells than in T helper 1 cells during polarization. Using conditional mutant mice, we determined that Dnmt3a, but not Dnmt3b, regulated expression of T helper cell cytokine genes, with the Il13 gene most prominently affected. Dnmt3a deficiency was accompanied by decreases in DNA methylation and changes in the H3K27 acetylation/methylation status at the Il13 locus. Dnmt3a-dependent regulation of Il13 also occurred in vivo because Dnmt3afl/flCd4cre mice exhibited increased lung inflammation in a murine asthma model, compared with littermate controls. Based on these observations, we conclude that Dnmt3a is required for controlling normal Il13 gene expression and functions as a rate-limiting factor to restrict T helper 2-mediated inflammation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1103803109