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

Ludwig, Anne K. and Zhang, Peng and Hastert, Florian D. and Meyer, Stephanie and Rausch, Cathia and Herce, Henry D. and Müller, Udo and Lehmkuhl, Anne and Hellmann, Ines and Trummer, Carina and Storm, Christian and Leonhardt, Heinrich and Cardoso, M. Cristina (2017):
Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.
45, In: Nucleic acids research, (5), pp. 2438-2457, ISSN 1362-4962, [Article]

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.

Item Type: Article
Erschienen: 2017
Creators: Ludwig, Anne K. and Zhang, Peng and Hastert, Florian D. and Meyer, Stephanie and Rausch, Cathia and Herce, Henry D. and Müller, Udo and Lehmkuhl, Anne and Hellmann, Ines and Trummer, Carina and Storm, Christian and Leonhardt, Heinrich and Cardoso, M. Cristina
Title: Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.
Language: English
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.

Journal or Publication Title: Nucleic acids research
Volume: 45
Number: 5
Divisions: 10 Department of Biology
10 Department of Biology > Vegetation ecology - Restoration
10 Department of Biology > Cell Biology and Epigenetics
Date Deposited: 04 Jan 2017 11:01
Identification Number: pmid:27923996
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