1. ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan
2. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
3. Department of Molecular Cell Biology, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

Correspondence to: Shigeaki Kato^1,2 Correspondence and requests for materials should be addressed to S.K. (Email: uskato@mail.ecc.u-tokyo.ac.jp).

Abstract

Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals^{1, 2}. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood^{3, 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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