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Deoxyribonucleic Acid Methyl Transferases 3a and 3b Associate with the Nuclear Orphan Receptor COUP-TFI during Gene Activation

Unité Mixte de Recherche 6026 (R.G., F.D., P.B., L.F., R.L.G., F.G., R.M., G.S.), Centre National de la Recherche Scientifique, Université Rennes I, Institut Fédératif de Recherche 140 Génomique Fonctionnelle Agronomie Santé, Equipe Information et Programmation Cellulaire; Equipe Endocrinologie Moléculaire de la Reproduction, Campus de Beaulieu, 35042 Rennes Cedex, France; and International University Bremen (R.J., A.J.), 28759 Bremen, Germany

Address all correspondence and requests for reprints to: Gilles Salbert, Unité Mixte de Recherche 6026 Centre National de la Recherche Scientifique, Université Rennes I, Institut Fédératif de Recherche 140 Génomique Fonctionnelle Agronomie Santé, Equipe Information et Programmation Cellulaire, Campus de Beaulieu, Bâtiment 13, 35042 Rennes Cedex, France. E-mail: gilles.salbert{at}univ-rennes1.fr.

Transcriptional activation of silent genes can require the erasure of epigenetic marks such as DNA methylation at CpGs (cytosine-guanine dinucleotide). Active demethylation events have been observed, and associated processes are repeatedly suspected to involve DNA glycosylases such as mCpG binding domain protein 4, thymine DNA glycosylase (TDG), Demeter, and repressor of silencing 1. A complete characterization of the molecular mechanisms occurring in metazoan is nonetheless awaited. Here, we report that activation of the endogenous vitronectin gene in P19 cells by the nuclear receptor chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is observed in parallel with the recruitment of TDG and p68 RNA helicase, two components of a putative demethylation complex. Interestingly, when activated, the vitronectin gene was loaded with DNA methyltransferases 3a and 3b (Dnmt3a/b), and a strand-biased decrease in CpG methylation was detected. Dnmt3a was further found to associate with COUP-TFI and TDG in vivo, and cotransfection experiments demonstrated that Dnmt3a/b can enhance COUP-TFI-mediated activation of a methylated reporter gene. These results suggest that Dnmt3a/b could cooperate with the orphan receptor COUP-TFI to regulate transcription of the vitronectin gene.

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Nuclear Receptors:   COUP-TFI

Coregulators:   p68