Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals1,2. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood3,4,5. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE)6,7, methylation of CpG sites (5mCpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene8, induces active demethylation of the 5mCpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3)6,7 identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites9, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity11, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4-/- mice12. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.
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We thank A. Murayama, K. Saito and A. Matsukage for discussions, Y. Imai and R. Fujiki for technical assistance, K. Sugasawa for plasmids, and M. Yamaki and H. Yamazaki for preparing the manuscript. This work was supported in part by priority areas from the Ministry of Education, Culture, Sports, Science and Technology (to F.O. and S.K.).
Author Contributions M.-S.K., F.O. and S.K. designed the experiments. M.-S.K., S.F. and F.O. performed biochemical assays. M.-S.K., M.-Y.Y., Y.Y., Y.S. and I.Y. conducted the promoter analysis. T.K., S.T. and T.M. carried out the animal study. M.-S.K. and K.-I.T. were responsible for the data interpretation. M.-S.K. and S.K. wrote the manuscript. All authors discussed the results and commented on the manuscript.
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Kim, M., Kondo, T., Takada, I. et al. DNA demethylation in hormone-induced transcriptional derepression. Nature 461, 1007–1012 (2009). https://doi.org/10.1038/nature08456
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