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

Qing Yu, Baohua Zhou, Yanlu Zhang, Evelyn T Nguyen, Jianguang Du, Nicole L Glosson, Mark H Kaplan

Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Proceedings of the National Academy of Sciences of the United States of America 2012 Jan 10

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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 Dnmt3a(fl/fl)Cd4cre 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.

Citation

Qing Yu, Baohua Zhou, Yanlu Zhang, Evelyn T Nguyen, Jianguang Du, Nicole L Glosson, Mark H Kaplan. DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. Proceedings of the National Academy of Sciences of the United States of America. 2012 Jan 10;109(2):541-6