title: Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.
abstract: Aberrant DNA methylation is a hallmark of various human disorders, indicating that the spatial and temporal regulation of methylation readers and modifiers is imperative for development and differentiation. In particular, the cross-regulation between 5-methylcytosine binders (MBD) and modifiers (Tet) has not been investigated. Here, we show that binding of Mecp2 and Mbd2 to DNA protects 5-methylcytosine from Tet1-mediated oxidation. The mechanism is not based on competition for 5-methylcytosine binding but on Mecp2 and Mbd2 directly restricting Tet1 access to DNA. We demonstrate that the efficiency of this process depends on the number of bound MBDs per DNA molecule. Accordingly, we find 5-hydroxymethylcytosine enriched at heterochromatin of Mecp2-deficient neurons of a mouse model for Rett syndrome and Tet1-induced reexpression of silenced major satellite repeats. These data unveil fundamental regulatory mechanisms of Tet enzymes and their potential pathophysiological role in Rett syndrome. Importantly, it suggests that Mecp2 and Mbd2 have an essential physiological role as guardians of the epigenome.
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Ludwig
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Florian D
authors.initials: FD
authors.lastname: Hastert
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Cathia
authors.initials: C
authors.lastname: Rausch
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Henry D
authors.initials: HD
authors.lastname: Herce
authors.affiliation: Human Biology and BioImaging, Department of Biology II, LMU Munich, 82152 Martinsried, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Müller
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Lehmkuhl
authors.affiliation: Anthropology and Human Genomics, Department Biology II, LMU Munich, 82152 Martinsried, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Hellmann
authors.affiliation: Human Biology and BioImaging, Department of Biology II, LMU Munich, 82152 Martinsried, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Trummer
authors.affiliation: Chemical Plant Ecology, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Storm
authors.affiliation: Human Biology and BioImaging, Department of Biology II, LMU Munich, 82152 Martinsried, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Leonhardt
authors.affiliation: Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Cardoso
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004276:DNA, Satellite / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D015518:Rett Syndrome / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004276:DNA, Satellite; D004268:DNA-Binding Proteins; C489326:Mbd2 protein, mouse; C497393:Mecp2 protein, mouse; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D004247:DNA