Densely methylated DNA traps Methyl-CpG–binding domain protein 2 but permits free diffusion by Methyl-CpG–binding domain protein 3

Abstract

The methyl-CpG–binding domain 2 and 3 proteins (MBD2 and MBD3) provide structural and DNA-binding function for the Nucleosome Remodeling and Deacetylase (NuRD) complex. The two proteins form distinct NuRD complexes and show different binding affinity and selectivity for methylated DNA. Previous studies have shown that MBD2 binds with high affinity and selectivity for a single methylated CpG dinucleotide while MBD3 does not. However, the NuRD complex functions in regions of the genome that contain many CpG dinucleotides (CpG islands). Therefore, in this work, we investigate the binding and diffusion of MBD2 and MBD3 on more biologically relevant DNA templates that contain a large CpG island or limited CpG sites. Using a combination of single-molecule and biophysical analyses, we show that both MBD2 and MBD3 diffuse freely and rapidly across unmethylated CpG-rich DNA. In contrast, we found methylation of large CpG islands traps MBD2 leading to stable and apparently static binding on the CpG island while MBD3 continues to diffuse freely. In addition, we demonstrate both proteins bend DNA, which is augmented by methylation. Together, these studies support a model in which MBD2-NuRD strongly localizes to and compacts methylated CpG islands while MBD3-NuRD can freely mobilize nucleosomes independent of methylation status. The methyl-CpG–binding domain 2 and 3 proteins (MBD2 and MBD3) provide structural and DNA-binding function for the Nucleosome Remodeling and Deacetylase (NuRD) complex. The two proteins form distinct NuRD complexes and show different binding affinity and selectivity for methylated DNA. Previous studies have shown that MBD2 binds with high affinity and selectivity for a single methylated CpG dinucleotide while MBD3 does not. However, the NuRD complex functions in regions of the genome that contain many CpG dinucleotides (CpG islands). Therefore, in this work, we investigate the binding and diffusion of MBD2 and MBD3 on more biologically relevant DNA templates that contain a large CpG island or limited CpG sites. Using a combination of single-molecule and biophysical analyses, we show that both MBD2 and MBD3 diffuse freely and rapidly across unmethylated CpG-rich DNA. In contrast, we found methylation of large CpG islands traps MBD2 leading to stable and apparently static binding on the CpG island while MBD3 continues to diffuse freely. In addition, we demonstrate both proteins bend DNA, which is augmented by methylation. Together, these studies support a model in which MBD2-NuRD strongly localizes to and compacts methylated CpG islands while MBD3-NuRD can freely mobilize nucleosomes independent of methylation status. The methyl-CpG–binding domain (MBD) family of proteins binds methylated DNA through a conserved domain that recognizes the symmetrically related methylcytosines in a cytosine-guanosine dinucleotide (CpG) (1Hendrich B. Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins.Mol. Cell. Biol. 1998; 18: 6538-6547Crossref PubMed Scopus (1089) Google Scholar). The structure of this domain bound to a single methylated CpG (mCpG) site has been determined for most members of the MBD family (2Ohki I. Shimotake N. Fujita N. Jee J. Ikegami T. Nakao M. et al.Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA.Cell. 2001; 105: 487-497Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 3Ho K.L. McNae I.W. Schmiedeberg L. Klose R.J. Bird A.P. Walkinshaw M.D. MeCP2 binding to DNA depends upon hydration at methyl-CpG.Mol. Cell. 2008; 29: 525-531Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 4Scarsdale J.N. Webb H.D. Ginder G.D. Williams Jr., D.C. Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence.Nucleic Acids Res. 2011; 39: 6741-6752Crossref PubMed Scopus (80) Google Scholar, 5Walavalkar N.M. Cramer J.M. Buchwald W.A. Scarsdale J.N. Williams Jr., D.C. Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches.Nucleic Acids Res. 2014; 42: 11218-11232Crossref PubMed Scopus (24) Google Scholar, 6Cramer J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 7Otani J. Arita K. Kato T. Kinoshita M. Kimura H. Suetake I. et al.Structural basis of the versatile DNA recognition ability of the methyl-CpG binding domain of methyl-CpG binding domain protein 4.J. Biol. Chem. 2013; 288: 6351-6362Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8Liu K. Xu C. Lei M. Yang A. Loppnau P. Hughes T.R. et al.Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.J. Biol. Chem. 2018; 293: 7344-7354Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 9Liu K. Lei M. Wu Z. Gan B. Cheng H. Li Y. et al.Structural analyses reveal that MBD3 is a methylated CG J. PubMed Scopus Google Scholar). However, biologically relevant DNA methylation regions of the genome that contain to of CpG sites (CpG Bird A. CpG islands and the of 2011; PubMed Scopus Google Scholar, A. J. A. M. DNA methylation in the islands of 2013; PubMed Scopus Google Scholar, J.N. DNA methylation and in the human PubMed Scopus Google Scholar, J.N. of DNA methylation on Acids Res. 2013; PubMed Scopus Google Scholar, A. B. P. et methylation of and CpG island human and PubMed Scopus Google Scholar). methylation of CpG islands in and with and we have MBD proteins bind and diffuse these CpG islands to the in a more biologically relevant In the work, we on the structure and of the MBD2 and MBD3 two proteins a of the MBD across the (1Hendrich B. Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins.Mol. Cell. Biol. 1998; 18: 6538-6547Crossref PubMed Scopus (1089) Google Scholar, J.M. L. B. C. et of a complex to Scopus Google Scholar). to the structure and function of the Nucleosome Remodeling and Deacetylase (NuRD) M. W.A. A. et and two distinct complexes with different and Cell. Biol. PubMed Scopus Google complex that can and The NuRD complex M. M. M. et of the the and (NuRD) J. PubMed Scopus Google Scholar, The NuRD 2013; PubMed Scopus Google Scholar, A. J.M. M. et and complex NuRD is Biol. PubMed Scopus Google Scholar, Y. H. P. Bird A. of the NuRD a complex and a with DNA PubMed Scopus Google of a of which has that provide and function and The MBD2 and MBD3 proteins form distinct NuRD complexes that to have M. W.A. A. et and two distinct complexes with different and Cell. Biol. PubMed Scopus Google Scholar, Williams Jr., D.C. The domain 2 and 3 proteins and of the and Biol. Scopus Google Scholar, A. Li M. et of the MBD2-NuRD complex MBD3-NuRD high in human PubMed Scopus Google Scholar). The two proteins show different of selectivity for to a single to the DNA-binding site (1Hendrich B. Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins.Mol. Cell. Biol. 1998; 18: 6538-6547Crossref PubMed Scopus (1089) Google Scholar, 6Cramer J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, T. and of the MBD protein 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, M. The domain of human MBD3 does bind to with and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). MBD2 to selectivity for a dinucleotide to unmethylated CpG (1Hendrich B. Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins.Mol. Cell. Biol. 1998; 18: 6538-6547Crossref PubMed Scopus (1089) Google Scholar, 4Scarsdale J.N. Webb H.D. Ginder G.D. Williams Jr., D.C. Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence.Nucleic Acids Res. 2011; 39: 6741-6752Crossref PubMed Scopus (80) Google Scholar, Webb H.D. Scarsdale J.N. Walavalkar N.M. Ginder G.D. et of methyl-CpG binding domain protein 2 the of the NuRD Acids Res. PubMed Scopus (44) Google Scholar, H. Y. Y. et and for and of Acids Res. PubMed Scopus Google Scholar). In contrast, MBD3 binds DNA with affinity and or selectivity for J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, H. Y. Y. et and for and of Acids Res. PubMed Scopus Google Scholar). with this binding studies found that MBD2-NuRD binds at islands with MBD3 localizes to methylated and unmethylated CpG islands with T. and of the MBD protein 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, L. et binding of MBD2 for methylated 2014; PubMed Scopus Google Scholar, T. Y. A. et localizes at and of 2013; PubMed Scopus Google Scholar, K. M. J. T. M. M. et for MBD2 and MBD3 at methylated CpG and binding to Acids Res. 2013; PubMed Scopus Google Scholar). However, suggests the that both MBD2 and MBD3 on methylation for across the genome J. et methylation of and in PubMed Scopus Google Scholar). Therefore, methylation selectivity of the MBD2 and MBD3 proteins this and function in the In work, we single-molecule analyses to the of the MBD MBD2 on DNA H. P. H. Williams Jr., D.C. CpG and DNA binding and of the binding domain 2 protein at the single-molecule Acids Res. PubMed Scopus Google Scholar). with and we found a in DNA and of the MBD MBD2 on methylated and unmethylated DNA CpG is to the while freely across unmethylated CpG we a for the of MBD2 in DNA Webb H.D. Scarsdale J.N. Walavalkar N.M. Ginder G.D. et of methyl-CpG binding domain protein 2 the of the NuRD Acids Res. PubMed Scopus (44) Google Scholar). The by both the MBD and a of the on unmethylated CpG-rich DNA is for and upon binding DNA. In structural studies of we found that the MBD MBD3 selectivity for a single a J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). on a combination of analyses, and we that MBD3 rapidly and binding leading to these two MBD3 recognizes by does strongly to this site bound to DNA. the DNA-binding of MBD2 and MBD3 with the studies that show both MBD2 and MBD3 to unmethylated CpG while MBD2 more localizes to islands T. and of the MBD protein 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, L. et binding of MBD2 for methylated 2014; PubMed Scopus Google Scholar, T. Y. A. et localizes at and of 2013; PubMed Scopus Google Scholar, K. M. J. T. M. 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Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches.Nucleic Acids Res. 2014; 42: 11218-11232Crossref PubMed Scopus (24) Google Scholar, 6Cramer J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google to the binding and of MBD2 and MBD3 on methylated and unmethylated DNA In the DNA DNA a of DNA to the of DNA at of of the DNA The of the DNA to J. P. N. P. L. Y. et and different to DNA a mechanism to for protein at Acids Res. 2014; 42: PubMed Scopus Google Scholar). DNA DNA to DNA-binding with the DNA or H. P. H. Williams Jr., D.C. CpG and DNA binding and of the binding domain 2 protein at the single-molecule Acids Res. PubMed Scopus Google Scholar, A. L. P. et of DNA a mechanism for Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. P. N. P. L. Y. et and different to DNA a mechanism to for protein at Acids Res. 2014; 42: PubMed Scopus Google Scholar, H. M. A. P. et and binding proteins that to regions on Acids Res. PubMed Google Scholar). MBD proteins we DNA to form DNA with CpG or and CpG-rich regions and The that the MBD with or a of the and diffusion on CpG-rich DNA on DNA. In contrast, both proteins and bind to In this we a that the of the the to investigate these regions DNA binding and diffusion found that the binds DNA with affinity Webb H.D. Scarsdale J.N. Walavalkar N.M. Ginder G.D. et of methyl-CpG binding domain protein 2 the of the NuRD Acids Res. PubMed Scopus (44) Google Scholar). with these that binds to DNA or CpG site with of or we the binding affinity by the in MBD2 DNA binding and this the DNA the DNA we DNA by DNA or unmethylated we to through the A. N. M. J. of Chem. PubMed Scopus Google Scholar). the of the DNA we the of on DNA two apparently and that this apparently we a single protein or on which that a diffusion for on DNA we the of on DNA by to N.M. H. B. dynamic DNA by proteins by of proteins.Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, N.M. a to for while Acids Res. 2011; 39: PubMed Scopus Google Scholar). diffusion and by the of and a The distribution of diffusion J. Full Text PDF PubMed Scopus Google Scholar). The diffusion by on the DNA on DNA CpG sites In addition, on the to diffusion on DNA to DNA, the for on DNA different diffusion on DNA to DNA CpG sites In more and diffusion on DNA of bound and on and binding binding 2 to 3 for in a of and on different DNA 2 to 4 for in a The 2 to 3 for The 2 to 4 for DNA methylation the of on DNA, we on the DNA methylation. DNA methylated CpG with a methylation of the DNA by with the the and to form DNA to unmethylated and DNA, the binding of on DNA is with the binding of to by binding affinity while the of on unmethylated DNA on the of the protein bound apparently and the proteins on the DNA is with the at the regions on DNA that to of of on DNA that recognizes islands through stable and apparently static the DNA upon we in to the complexes on unmethylated or DNA on the of the CpG-rich we proteins bound to this to of the DNA. The of on DNA that of to the complexes and the CpG-rich or The binding analysis that binds to the CpG-rich on both the unmethylated and methylated DNA and to we for the DNA to the and CpG-rich regions The by MBD2 at the CpG-rich on the In contrast, at the and In and unmethylated CpG-rich DNA DNA with of by and CpG-rich CpG-rich 2 to 3 for The the the in in a The 2 to 3 for The the the in Previous studies that MBD3 a high affinity for CpG islands of methylation status. by that MBD3 binds DNA with affinity and a for methylated DNA J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). that binds to DNA or CpG sites with of and investigate MBD3 MBD2 in binding to CpG we binding to DNA the of DNA and to both static and on these DNA to static binding by CpG island on and on and methylation on a of static binding on the to the diffusion and of on different DNA diffusion on and DNA and the of on and DNA and diffusion on and of diffusion of on DNA with the apparently static binding by we the diffusion of on these DNA to diffuse a more on on and DNA is that the diffusion of on the methylated DNA to to on unmethylated DNA the of on DNA is and through investigate the DNA upon we to complexes on different and The binding analysis that a for the CpG and DNA regions to of DNA the upon binding at the CpG-rich and on and and and the by at the to is at the and DNA upon to binding to the DNA to we upon binding of DNA of the by the The which the of the CpG-rich that is to we the protein to the DNA a the of to of DNA and of the in the to DNA with a of the to In large at the protein and a to the of which form the and the of these with protein the DNA demonstrate apparently static binding of to islands on the to in work, we found that the MBD MBD2 and can exchange two sites on N.M. Cramer J.M. Buchwald W.A. Scarsdale J.N. Williams Jr., D.C. Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches.Nucleic Acids Res. 2014; 42: 11218-11232Crossref PubMed Scopus (24) Google Scholar). rapidly two we of bound to DNA with CpG sites by is of the in the CpG-rich DNA this the sites on of DNA. shown in and to the MBD2 DNA-binding domain in the demonstrate distinct bound to DNA with or the of the CpG sites these to the of exchange the two sites. both sites these show a single at a that for the methylated DNA. with exchange the two sites. the exchange the in the two states which is in the to exchange with the static binding for to by single-molecule on DNA Therefore, we that rapidly the these sites on the is the and of the The high of CpG sites the island MBD2 in apparently static binding this we a DNA with CpG sites which a CpG island Bird A. CpG islands and the of 2011; PubMed Scopus Google Scholar, Bird A.P. CpG PubMed Scopus Google Scholar). the CpG sites the is to that of the CpG-rich apparently static binding bound to this DNA to the and regions which on the DNA The of at which is of the diffusion on the DNA diffusion a to the demonstrate that the of islands the of apparently static binding by and ability to CpG-rich can rapidly exchange large In contrast, rapidly across both and large The MBD2 and MBD3 proteins provide structural and DNA binding to the NuRD complex. The two proteins form NuRD MBD2 selectivity for The and domains of protein the and of In these we protein that the MBD DNA-binding the and domain to binding the domain In work, we that the domains of MBD2 and MBD3 form stable complexes with the domain of Scarsdale J.N. Webb H.D. Walavalkar N.M. et and of for by the MBD2-NuRD A. 2011; PubMed Scopus Google Scholar, N.M. N. Williams Jr., D.C. of the methyl-cytosine binding domain 2 and domain Biol. Chem. 2013; 288: Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, we found that the and MBD2 domains with a a stable that these and more stable in the and regions the binding affinity of MBD3 for methylated DNA a J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google to which single-molecule studies the binds methylated DNA with affinity the MBD domain Webb H.D. Scarsdale J.N. Walavalkar N.M. Ginder G.D. et of methyl-CpG binding domain protein 2 the of the NuRD Acids Res. PubMed Scopus (44) Google Scholar). to the binding and diffusion of MBD2 and MBD3 on different unmethylated and methylated DNA the DNA-binding and the and of the CpG-rich that binds to the DNA the of these with a with the regions that localizes to the by show that and binds to the CpG-rich DNA with the CpG-rich DNA to a in on the CpG-rich In addition, to the with in DNA In contrast, diffusion bound to DNA. the of diffusion of on methylated DNA and Previous studies that MBD3 rapidly and binding J.M. Scarsdale J.N. Walavalkar N.M. Buchwald W.A. Ginder G.D. Williams Jr., D.C. Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA.J. Biol. Chem. 2014; 289: 1294-1302Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). The studies show that this binding diffusion the with this both and show and more diffusion on DNA the with unmethylated CpG-rich DNA diffusion for both methylation diffusion by MBD2 while diffusion by analysis that rapidly we the CpG or the of the static binding on DNA The DNA does the of a CpG island Bird A.P. CpG PubMed Scopus Google methylated or methylated static binding on the methylated and we the diffusion of to across the Therefore, regions the complex for Together, these support a model for the and distinct of the two MBD2 strongly localizes to large and can NuRD to and MBD3 on methylated DNA, NuRD to freely nucleosomes across or model with studies of MBD2 and MBD3 which have shown that MBD2 strongly localizes to islands with while MBD3 localizes to unmethylated CpG islands with and L. et binding of MBD2 for methylated 2014; PubMed Scopus Google Scholar, T. Y. A. et localizes at and of 2013; PubMed Scopus Google Scholar, K. M. J. T. M. M. et for MBD2 and MBD3 at methylated CpG and binding to Acids Res. 2013; PubMed Scopus Google Scholar). that of MBD2 in islands MBD2-NuRD to nucleosomes these MBD2 does bind to a single continues to nucleosomes the methylated a and In contrast, MBD3 does by CpG-rich methylated or that MBD3-NuRD can nucleosomes both and of these regions which does a model suggests that MBD3-NuRD the function of MBD2-NuRD by freely nucleosomes across methylated of MBD3-NuRD by MBD2-NuRD a of methylation across a large has been the and complexes have distinct at in the and distribution of MBD2 and MBD3 on methylated and unmethylated DNA. that MBD2 of DNA In the studies we that the and regions that the regions the and which to of the DNA C. The of DNA Full Text Full Text PDF PubMed Scopus Google Scholar, M. B. Biol. 2018; PubMed Scopus (44) Google Scholar). structural studies of MBD2 and MBD3 bound to DNA have shown of DNA J.N. Webb H.D. Ginder G.D. Williams Jr., D.C. Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence.Nucleic Acids Res. 2011; 39: 6741-6752Crossref PubMed Scopus (80) Google Scholar, 8Liu K. Xu C. Lei M. Yang A. Loppnau P. Hughes T.R. et al.Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.J. Biol. Chem. 2018; 293: 7344-7354Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 9Liu K. Lei M. Wu Z. Gan B. Cheng H. Li Y. et al.Structural analyses reveal that MBD3 is a methylated CG J. PubMed Scopus Google that the we does of the DNA by the protein and is more In a DNA nucleosomes or Therefore, binding to DNA or at of MBD2-NuRD to and regions of the the of MBD on DNA J.N. Webb H.D. Ginder G.D. Williams Jr., D.C. Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence.Nucleic Acids Res. 2011; 39: 6741-6752Crossref PubMed Scopus (80) Google with binding to DNA MBD2 and MBD3 to bind DNA C. The of DNA Full Text Full Text PDF PubMed Scopus Google Scholar, M. B. Biol. 2018; PubMed Scopus (44) Google and biophysical analyses of MBD2 bound to nucleosomes these by suggests that at high MBD3 at et the the and the in Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google Scholar, A. et of the NuRD complex with the structure of Biol. Chem. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, L. P. H. et the and and the NuRD Acids Res. 2018; Scopus Google Scholar, M. C. et the NuRD complex to by J. PubMed Scopus Google Scholar, A.P. et is by and to in the PubMed Scopus Google Scholar, L. J. et a for Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. P. et of of the Nucleosome and (NuRD) PubMed Scopus (44) Google a in these that a methylated of is to to for a of Therefore, a in with for by the complex. we that the that MBD2 and MBD3 in the of these two related MBD2 a affinity for and more compacts of In contrast, MBD3 has methylation selectivity and more at unmethylated and CpG Therefore, MBD2-NuRD to at methylated while MBD3-NuRD at and CpG and MBD2 and MBD3 a with and sites. The the domain of at the to a Webb H.D. Scarsdale J.N. Walavalkar N.M. Ginder G.D. et of methyl-CpG binding domain protein 2 the of the NuRD Acids Res. PubMed Scopus (44) Google Scholar). the the at in or to and with for or 4 at or in and by Using we the by at for the protein by affinity we the and protein with at 4 and the by a affinity both and by and the by DNA DNA with two CpG sites by DNA with the or both sites symmetrically methylated The DNA and by exchange with the determined by at to and The complexes and at a protein of on a at with and in A. M. et model for of a PubMed Scopus Google Scholar, et and Biol. PubMed Scopus Google Scholar). binding to a DNA in and single DNA and on a exchange DNA with CpG symmetrically methylated DNA of CpG sites and with DNA on a in by a Webb H.D. Scarsdale J.N. Walavalkar N.M. Ginder G.D. et of methyl-CpG binding domain protein 2 the of the NuRD Acids Res. PubMed Scopus (44) Google Scholar). of and to DNA on a a of and at DNA to a by of for in a of rapidly at H. a affinity PubMed Scopus Google and a of the a DNA a for we a of the protein which CpG-rich and that contain the CpG-rich or CpG-rich regions the a DNA we the which does contain CpG The CpG-rich the the at the sites to a CpG-rich a In addition, we a CpG the CpG-rich the sites in the the site in is both of the that a with the in the with CpG and at for 2 to methylated DNA with DNA methylation of sites in the CpG-rich DNA we DNA with and the DNA the at we the DNA by of and we of with of the for at A. N. M. J. of Chem. PubMed Scopus Google Scholar). the proteins of MBD2 and of 4 to the and for at we the in the and The of proteins on DNA J. P. N. P. L. Y. et and different to DNA a mechanism to for protein at Acids Res. 2014; 42: PubMed Scopus Google Scholar). we with with a complexes at by a The two a and through in studies J. P. N. P. L. Y. et and different to DNA a mechanism to for protein at Acids Res. 2014; 42: PubMed Scopus Google Scholar). a with and DNA the with a at a of DNA by the in of The of the DNA is determined by to the at a of with or at a The a function of is is the of in the is the of for different is the and is the of the in the determined the diffusion and by a in on the a protein the diffusion and the the diffusion a DNA and protein for at in and and a The with and with The of and for DNA and the in on with at and at a scan of 3 3 a scan of to 2 and a of The The on with for analysis at is this and is the upon The have of to the of this to the at for H. H. and C. M. M. C. and H. P. 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