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Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process

Abstract

A role for DNA demethylation in transcriptional regulation of genes expressed in differentiated somatic cells remains controversial. Here, we define a small region in the promoter-enhancer of the interleukin-2 (Il2) gene that demethylates in T lymphocytes following activation, and remains demethylated thereafter. This epigenetic change was necessary and sufficient to enhance transcription in reporter plasmids. The demethylation process started as early as 20 minutes after stimulation and was not prevented by a G1 to S phase cell cycle inhibitor that blocks DNA replication. These results imply that this demethylation process proceeds by an active enzymatic mechanism.

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Figure 1: The difference in IL-2 expression between naive and previously activated CD4+ T cells correlated with demethylation of a 600-bp region in the Il2 enhancer.
Figure 2: Demethylation of CpG sites 2–7 was necessary and sufficient for the enhancement of Il2 promoter-driven transcription.
Figure 3: Demethylation in vitro occurred in the absence of DNA replication.
Figure 4: Rapid in vivo response of naive CD4+ T cells to SEA plus LPS.

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Acknowledgements

We thank G. Felsenfeld, R. Germain and F. Magdinier for critical reading of the manuscript, and B. Winders, J.K. Friend and M. Hsie for technical assistance.

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Correspondence to Ronald H. Schwartz.

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Bruniquel, D., Schwartz, R. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4, 235–240 (2003). https://doi.org/10.1038/ni887

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