title: Methylation-dependent and -independent genomic targeting principles of the MBD protein family.
abstract: To gain insight into the cellular readout of DNA methylation, we established a strategy for systematically profiling the genome-wide distribution of chromatin-interacting factors. This enabled us to create genomic maps for the methyl-CpG-binding domain (MBD) family of proteins, including disease-relevant mutants, deletions, and isoforms. In vivo binding of MBD proteins occurs predominantly as a linear function of local methylation density, requiring functional MBD domains and methyl-CPGs. This interaction directs specificity of MBD proteins to methylated, CpG-dense, and inactive regulatory regions. In contrast, binding to unmethylated sites varies between MBD proteins and is mediated via alternative domains or protein-protein interactions. Such targeting is exemplified by NuRD-complex-mediated tethering of MBD2 to a subset of unmethylated, active regulatory regions. Interestingly, MBD3 also occupies these sites, but like MBD2, binding is independent of the presence of hydroxymethylation. These functional binding maps reveal methylation-dependent and -independent binding modes and revise current models of DNA methylation readout through MBD proteins.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Tuncay
authors.initials: T
authors.lastname: Baubec
authors.forename: Robert
authors.initials: R
authors.lastname: Ivánek
authors.forename: Florian
authors.initials: F
authors.lastname: Lienert
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001710:Biotin / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells; D055106:Genome-Wide Association Study; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C489323:Mbd1 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D001710:Biotin