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Regulation of DNA Demethylation during Maturation of CD4⁺ Naive T Cells by the Conserved Noncoding Sequence 1¹

Kazuhisa Aoki^*, Noriko Sato, Atsumi Yamaguchi, Osamu Kaminuma, Takumi Hosozawa^* and Shoichiro Miyatake^2,*

^* Cytokine Project, Allergy and Immunology Project, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; and Department of Environmental Health and Toxicology, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan

Demethylation of transcriptional regulatory elements and gene coding regions is an important step in the epigenetic regulation of gene expression. Several noncoding conserved regions are required for the efficient transcription of cytokine genes. In this paper, we show that the deletion of one such sequence, conserved noncoding sequence 1 (CNS-1), interferes with the efficient demethylation of Th2 cytokine genes but has little effect on histone modifications in the area. Th2 cells derived from CD4 single-positive (SP) mature thymocytes exhibit more rapid demethylation of CNS-1 and Th2-specific cytokine genes and produce more Th2 cytokines than do Th2 cells derived from CD4-positive peripheral naive T cells. De-repression of the Th1 cytokine IFN- was also detected in Th2-primed CD4 SP thymocytes but not in naive T cells. Our results indicate that susceptibility to demethylation determines the efficiency and kinetics of cytokine gene transcription. The extrathymic maturation step undergone by naive T cells suppresses robust and rapid cytokine expression, whereas mature CD4 SP thymocytes maintain a rapid and less-specific cytokine expression profile. Finally, we detected the methyl cytosine binding protein MBD2 at CNS-1 in mature thymocytes, suggesting that this protein may regulate the demethylation of this region.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology and by the Japan Health Science Foundation awarded to S.M.

² Address correspondence and reprint requests to Dr. Shoichiro Miyatake, Cytokine Project, The Tokyo Metropolitan Institute of Medical Science, 3-18-22, Honkomagome, Bunkyo-ku, 113-8613 Tokyo, Japan. E-mail address: miyataki-si{at}igakuken.or.jp

³ Abbreviations used in this paper: AcK9/14H3, acetylation of histone H3 lysine 9/14; ChIP, chromatin immunoprecipitation; CNS, conserved noncoding sequence; HSS3, hypersensitive site 3; MBP, methyl-CpG-binding domain protein; MeK4H3, methylation of histone H3 lysine 4; PolII, RNA polymerase II; SP, single positive; TSA, trichostatin A; TSS, transcription start site; F, forward primer; R, reverse primer.