DNA methylation and the histone modification have a key role in epigenetics and control gene expression, development and differentiation dynamically. Altered epigenetic modifications for gene regulations in response to extracellular signals, are well documented at histone levels, but still unclear at DNA level, particularly active DNA demethylation for gene activation. A team led by Professor Shigeaki Kato of the Institute of Molecular and Cellular Biosciences, The university of Tokyo, they found that DNA methylation/demethylation is hormonally switched to control transcription of the CYP27B1 gene regulation. Reflecting the known transrepression of the CYP27B1 gene by vitamin D (VD) through the nVDRE, induction of methylation of ^5mCpG sites by VD is found in this gene promoter, with histone deacetylation.

Mi-Sun Kim et al. applied of a complex containing the nVDRE binding protein (VDIR), DNA methyl transferases, Dnmt1 and 3b, are identified together with MBD4. As PTH is a known hormone to activate the CYP27B1 gene, a further PTH treatment derepresses transcription coupling with demethylation of the ^5mCpG sites in this promoter. Phosphorylation of MBD4 by PTH-activated PKC potentiates its DNA glycosylase activity for ^5mCpG, that is indispensable for PTH-induced DNA demethylation as well as transcriptional derepression. A base excision repair process requires DNA demethylation in the MBD4-bound promoter. Such PTH-induced DNA demethylation and subsequent transcriptional derepression are impaired in MBD4^-/- mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription. The studies were published in October 15^th 2009 issue of NATURE.

Program member
Shigeaki Kato (Institute of Molecular and Cellular Biosciences, The University of Tokyo)