DNA demethylation in hormone-induced transcriptional derepression

• Published in: Nature (London) 2009-10, Vol.461 (7266), p.1007-1012
• Main Authors: Kim, Mi-Sun, Kondo, Takeshi, Takada, Ichiro, Youn, Min-Young, Yamamoto, Yoko, Takahashi, Sayuri, Matsumoto, Takahiro, Fujiyama, Sally, Shirode, Yuko, Yamaoka, Ikuko, Kitagawa, Hirochika, Takeyama, Ken-Ichi, Shibuya, Hiroshi, Ohtake, Fumiaki, Kato, Shigeaki
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; Analysis; Animals; Biological and medical sciences; Cell cycle; Cell Line; Control; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Glycosylases - metabolism; DNA Methylation - drug effects; DNA Methyltransferase 3B; Down-Regulation - drug effects; E coli; Endodeoxyribonucleases - deficiency; Endodeoxyribonucleases - genetics; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Kinases; letter; Mass spectrometry; Methods; Methylation; Mice; Molecular and cellular biology; Molecular genetics; multidisciplinary; Parathyroid Hormone - pharmacology; Phosphorylation; Protein Kinase C - metabolism; Response Elements - genetics; Science; Science (multidisciplinary); Transcription (Genetics); Transcription, Genetic - drug effects; Transcription. Transcription factor. Splicing. Rna processing; Vitamin D; Vitamin D - pharmacology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08456

Active DNA demethylation Kim et al . report that hormonal control of transcription of the cytochrome p450 27B1 ( CYP27B1 ) gene involves DNA methylation and active demethylation of the promoter, directed by hormonal signalling. This suggests that methylation changes at the DNA level contribute to the hormonal control of transcription. Gene regulation is known to be affected by epigenetic modifications at the histone level in response to extracellular signals; however, the effect of modifications at the DNA level, and especially active DNA demethylation, are not well understood. Here, DNA methylation/demethylation is found to be hormonally switched in order to control the transcription of the cytochrome p450 27B1 gene. 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 ( 5m CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene 8 , induces active demethylation of the 5m CpG 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 sites 9 , 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 activity 11 , 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 -/- mice 12 . Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.