DNA demethylation in hormone-induced transcriptional derepression Export

@article{citeulike:5977558, abstract = {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.}, author = {Kim, Mi-Sun and Kondo, Takeshi and Takada, Ichiro and Youn, Min-Young and Yamamoto, Yoko and Takahashi, Sayuri and Matsumoto, Takahiro and Fujiyama, Sally and Shirode, Yuko and Yamaoka, Ikuko and Kitagawa, Hirochika and Takeyama, Ken-Ichi and Shibuya, Hiroshi and Ohtake, Fumiaki and Kato, Shigeaki}, citeulike-article-id = {5977558}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nature08456}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nature08456}, day = {15}, doi = {10.1038/nature08456}, issn = {0028-0836}, journal = {Nature}, keywords = {dna\_demethylation, dna\_methylation, dna\_methyltransferases, epigenetics, histones}, month = {October}, number = {7266}, pages = {1007--1012}, posted-at = {2009-11-06 11:05:02}, priority = {2}, publisher = {Nature Publishing Group}, title = {DNA demethylation in hormone-induced transcriptional derepression}, url = {http://dx.doi.org/10.1038/nature08456}, volume = {461}, year = {2009} }

TY - JOUR ID - citeulike:5977558 L3 - citeulike-article-id:5977558 N2 - 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. IS - 7266 JF - Nature SN - 0028-0836 EP - 1012 TI - DNA demethylation in hormone-induced transcriptional derepression PB - Nature Publishing Group VL - 461 SP - 1007 KW - dna_demethylation KW - dna_methylation KW - dna_methyltransferases KW - epigenetics KW - histones AU - Kim, Mi-Sun AU - Kondo, Takeshi AU - Takada, Ichiro AU - Youn, Min-Young AU - Yamamoto, Yoko AU - Takahashi, Sayuri AU - Matsumoto, Takahiro AU - Fujiyama, Sally AU - Shirode, Yuko AU - Yamaoka, Ikuko AU - Kitagawa, Hirochika AU - Takeyama, Ken-Ichi AU - Shibuya, Hiroshi AU - Ohtake, Fumiaki AU - Kato, Shigeaki PY - 2009/10/15/ UR - http://dx.doi.org/10.1038/nature08456 ER -