title: DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation.
abstract: 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.
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Baohua
authors.initials: B
authors.lastname: Zhou
authors.forename: Yanlu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Evelyn T
authors.initials: ET
authors.lastname: Nguyen
authors.forename: Jianguang
authors.initials: J
authors.lastname: Du
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Glosson
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000276:immunology*; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology*; D018793:Interleukin-13 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C000715535:Dnmt3a protein, mouse; D018793:Interleukin-13; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A