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National Institute of Environmental Health Sciences

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Publication Detail

Title: CpG and methylation-dependent DNA binding and dynamics of the methylcytosine binding domain 2 protein at the single-molecule level.

Authors: Pan, Hai; Bilinovich, Stephanie M; Kaur, Parminder; Riehn, Robert; Wang, Hong; Williams Jr, David C

Published In Nucleic Acids Res, (2017 Sep 06)

Abstract: The methylcytosine-binding domain 2 (MBD2) protein recruits the nucleosome remodeling and deacetylase complex (NuRD) to methylated DNA to modify chromatin and regulate transcription. Importantly, MBD2 functions within CpG islands that contain 100s to 1000s of potential binding sites. Since NuRD physically rearranges nucleosomes, the dynamic mobility of this complex is directly related to function. In these studies, we use NMR and single-molecule atomic force microscopy and fluorescence imaging to study DNA binding dynamics of MBD2. Single-molecule fluorescence tracking on DNA tightropes containing regions with CpG-rich and CpG-free regions reveals that MBD2 carries out unbiased 1D diffusion on CpG-rich DNA but subdiffusion on CpG-free DNA. In contrast, the protein stably and statically binds to methylated CpG (mCpG) regions. The intrinsically disordered region (IDR) on MBD2 both reduces exchange between mCpG sites along the DNA as well as the dissociation from DNA, acting like an anchor that restricts the dynamic mobility of the MBD domain. Unexpectedly, MBD2 binding to methylated CpGs induces DNA bending that is augmented by the IDR region of the protein. These results suggest that MBD2 targets NuRD to unmethylated or methylated CpG islands where its distinct dynamic binding modes help maintain open or closed chromatin, respectively.

PubMed ID: 28637186 Exiting the NIEHS site

MeSH Terms: 5-Methylcytosine/chemistry*; 5-Methylcytosine/metabolism; Animals; Binding Sites; Chickens; Cloning, Molecular; CpG Islands*; DNA Methylation; DNA-Binding Proteins/chemistry*; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; DNA/chemistry*; DNA/metabolism; Escherichia coli/genetics; Escherichia coli/metabolism; Fluorescence Polarization; Gene Expression; Humans; Magnetic Resonance Spectroscopy; Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism*; Mi-2 Nucleosome Remodeling and Deacetylase Complex/ultrastructure; Nucleic Acid Conformation; Nucleosomes/metabolism*; Nucleosomes/ultrastructure; Protein Binding; Protein Isoforms/chemistry; Protein Isoforms/genetics; Protein Isoforms/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Single Molecule Imaging

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