Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.

Autor:	Ludwig AK; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Zhang P; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Hastert FD; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Meyer S; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Rausch C; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Herce HD; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Müller U; Human Biology and BioImaging, Department of Biology II, LMU Munich, 82152 Martinsried, Germany., Lehmkuhl A; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Hellmann I; Anthropology and Human Genomics, Department Biology II, LMU Munich, 82152 Martinsried, Germany., Trummer C; Human Biology and BioImaging, Department of Biology II, LMU Munich, 82152 Martinsried, Germany., Storm C; Chemical Plant Ecology, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Leonhardt H; Human Biology and BioImaging, Department of Biology II, LMU Munich, 82152 Martinsried, Germany., Cardoso MC; Cell Biology and Epigenetics, Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2017 Mar 17; Vol. 45 (5), pp. 2438-2457.
DOI:	10.1093/nar/gkw1197
Abstrakt:	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. (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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