Results: 5

1.
Figure 5

Figure 5. Nuclear localization of MBD proteins in mouse and human cells. From: Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin?.

A, C, D. Mouse 3T3 cells transfected with plasmids expressing human GFP-tagged MBD proteins display identical localization that coincides with the heterochromatic chromocenters B. The chromocenters in mouse cells (the same cells as in A) as visualized by staining with DAPI. E, G and H. GFP-tagged MBD proteins transfected into human HeLa cells show localization specific to each protein. F. The DNA of same cells as shown in E was also stained with DAPI. Note that pericentric heterochromatin does not form chromocenters in human cells.

Thomas Clouaire, et al. Cell Mol Life Sci. ;65(10):1509-1522.
2.
Figure 4

Figure 4. Complexes of MBDs with co-repressor proteins. From: Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin?.

A. MeCP2 co-immunoprecipitates with Sin3A/HDAC1 complex from most cell types. HDAC1 removes acetyl groups (*Ac) from histone tails and is responsible for MeCP2-mediated repression. Histone tails free of acetylation can be modified by histone methylase activity associated with MeCP2 to generate heterochromatin. B. MBD1 interacts with SETDB1 histone methylase and SETDB1 co-factor AM/MCAF1. SETDB1 methylates K9 of histone H3 tail to generate silenced chromatin. H3K9me3 is further recognized by heterochromatin protein HP1. C. MBD2 participates in a large protein complex known as NuRD, which includes HDAC1 and HDAC2, which, similar to MeCP2 associated complex, deacetylates histone tails to generate transcriptionally silent chromatin. Methylated CpGs are shown as red dots.

Thomas Clouaire, et al. Cell Mol Life Sci. ;65(10):1509-1522.
3.
Figure 3

Figure 3. Models of how MBD proteins recognize methylated DNA. From: Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin?.

A. The “team” model indicates a non-discriminative binding of MBD proteins to any accessible methylated CpG. Thus most binding sites will be potentially shared and the overall pattern of occupancy will be governed by the concentration of each MBD protein. B. The “team” model would predict redundancy of MBD proteins where the repression of any methylated gene, for example gene A, could be achieved by any methyl-CpG binding protein. C. The “solo” model implies specificity of binding where some MBD proteins discriminate between binding sites either by recognition of bases adjacent to the mCpG or other nearby DNA motifs. Therefore most of the binding sites will not be shared.
D. The “solo” model would imply that each MBD protein by occupying a distinct set of binding sites would regulate a specific subset of genes.

Thomas Clouaire, et al. Cell Mol Life Sci. ;65(10):1509-1522.
4.
Figure 2

Figure 2. Interaction of the MBD domain with methylated DNA. From: Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin?.

A. Schematic representation of the solution structure of MBD domain of MeCP2 [49]. The beta sheets (β), an alpha helix (α1q) and a long loop 1 (L1) are indicated. B. Solution structure of MBD domain of MBD1 [48]. C. MBD domain of MBD1 bound to DNA in the major groove where the methyl-groups (yellow) of methylated cytosines (magenta) are exposed towards the exterior of the double helix [50]. Residues (purple) from the two beta sheets as well as L1 and shorter loot connecting β4 with α1 are involved in interactions with the methyl-groups and the cytosine bases. G bases of the CpG pairs are colored in green. D. Top view of the MBD domain of MBD1 in contact with a pair of symmetrically methylated CpG (the top pair is indicated with brighter colours). The side chains (purple) of Valine 20 and Arginine 22 are involved in recognizing the first (top) methyl-group while those of Tyrosine 34, Arginine 44 and Serine 45 contact the second methyl-group. The figures were generated from published structures by Cn3D software.

Thomas Clouaire, et al. Cell Mol Life Sci. ;65(10):1509-1522.
5.
Figure 1

Figure 1. Families of methyl-CpG binding proteins. From: Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin?.

MBD family proteins share a conserved MBD domain, which is required for binding to methylated DNA. MBD3 carries a mutation (shown in orange) in the MBD domain and does not bind to methylated CpGs. MeCP2 has two AT-hook motifs (ATh) which potentially could bind AT-rich DNA. These motifs are not required for high affinity binding to sequences containing a methylated CpG followed by an [A/T]≥4 run. MBD1 is characterized by two (or three in some isoforms) CxxC-type zinc fingers. The third CxxC motif (orange) binds unmethylated CpGs.
TRD indicates transcriptional repression domains mapped by functional and deletion analyses. GD indicates Glycosylase domain of MBD4 which is involved in excision of CG:TG mismatches. (GR)11 motif of MBD2 is a stretch of Glycine and Arginine residues that can be methylated by PRMT5 protein methylase [98]. (E)12 is a glutamate-rich domain. Kaiso family of proteins is characterized by three homologous C2H2 zinc finger motifs that are required for binding to methylated and in some instances unmethylated DNA. In addition, all proteins of this family carry a BTB/POZ domain likely to be involved in either homo- or heterodimerization or protein-protein interactions. ZBTB4 and ZBTB38 have additional three and seven, respectively, zinc finger motifs.

Thomas Clouaire, et al. Cell Mol Life Sci. ;65(10):1509-1522.

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