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Methyl Cpg Binding Proteins: Coupling Chromatin Architecture to Gene Regulation

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Methyl Cpg Binding Proteins: Coupling Chromatin Architecture to Gene Regulation Oncogene (2001) 20, 3166 ± 3173 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Methyl CpG binding proteins: coupling chromatin architecture to gene regulation Paul A Wade*,1 1Emory University School of Medicine, Department of Pathology and Laboratory Medicine, Woodru Memorial Research Building ± Room 7105B, 1639 Pierce Drive, Atlanta, GA 30322, USA A correlation between DNA methylation and transcrip- been substantiated via mutation of the methyltransfer- tional silencing has existed for many years. Recently, ase enzymes themselves which leads to developmental substantial progress has been reported in the search for defects and death prior to or shortly after birth (Okano proteins that interpret the regulatory information et al., 1999; Li et al., 1992). Several excellent recent inherent in DNA methylation and translate this informa- reviews describe the DNA methyltransferases and their tion into functional states, resulting in the identi®cation biology (Bestor, 2000; Robertson and Wole, 2000; of a family of highly conserved proteins, the MBD Hendrich and Bird, 2000), this review will focus instead family. Direct connections between these proteins and on proteins that function downstream of the DNA histone modi®cation enzymes have emerged as a common methylation signal. While higher plants clearly possess theme, implying that DNA methylation exerts its eects sophisticated gene regulatory circuits featuring DNA primarily through repressive chromatin architecture. methylation, this review will focus on methyl CpG Recent structural determinations of the DNA binding binding proteins in animals. domain of two MBD family members, MeCP2 and Formally, DNA methylation might lead to transcrip- MBD1, provide a framework to model the interactions of tional repression through multiple mechanisms. Methy- this family with DNA. Comparative sequence analysis lation is known to interfere with the ability of some and experimental DNA binding data can be interpreted transcription factors to bind their cognate recognition using this structural framework allowing one to contrast sequences. It might also result in structural eects on the members of the MBD family with each other and to nucleosomes themselves or eects on nucleosome predict the properties of new family members. The positioning, nucleosome stability, or assembly of higher identi®cation of mutations in MeCP2, the founding order chromatin structures. However, work over the member of this family, as causal for the neurological last decade has led to the accumulation of a body of developmental disorder Rett Syndrome provides addi- data suggesting that the functional properties of tional information regarding amino acid residues crucial methylated DNA result primarily from the action of to the functions of this interesting protein family. a conserved family of proteins that selectively bind Oncogene (2001) 20, 3166 ± 3173. methylated CpG dinucleotides (Bird and Wole, 1999). Keywords: DNA methylation; MeCP2; Rett Syndrome; histone deacetylase; chromatin MeCP2 ± the prototype methyl CpG binding protein The prototype methyl CpG binding protein is MeCP2, a polypeptide capable of binding selectively to a single Methylation is a common form of DNA modi®cation symmetrically methylated CpG (Lewis et al., 1992). in animals, occurring at the position ®ve of cytosine This protein is associated with chromosomes through- residues almost exclusively within the context of CpG out the cell cycle, colocalizes with methyl CpG rich dinucleotides. CpG methylation is non-random and the DNA (Lewis et al., 1992), and consists of two majority of potential sites in mammalian genomes are functional domains (Figure 1). The methyl CpG modi®ed (Cooper and Krawczak, 1989). Methylation binding domain or MBD is sucient to direct speci®c participates in the partitioning of genomes into active binding to methylated DNA (Nan et al., 1993). and inactive functional compartments (Cross and Bird, Regions outside the MBD contribute to overall binding 1995; Razin, 1998). The constitutents of the inactive energy through non-speci®c, presumably electrostatic compartment associated with DNA methylation in- interactions (Meehan et al., 1992). A second functional clude imprinted genes, the inactive female X chromo- domain, the transcriptional repression domain or some, and parasitic DNA elements (Bestor, 2000). The TRD, is required for transcriptional repression in vitro essential nature of DNA methylation in mammals has and in vivo (Nan et al., 1997; Jones et al., 1998; Kaludov and Wole, 2000). As expected for a chromosomal protein, MeCP2 is released from nuclei *Correspondence: PA Wade by treatment with nucleases or by extraction with salt, Methyl CpG binding proteins PA Wade 3167 Figure 1 Mammalian MBD family members. The ®gure depicts the mammalian MBD family in cartoon fashion. Notable sequence motifs are indicated in the ®gure and discussed in the text although it presents a biphasic extraction pro®le from containing DNA results in changes in the resonance of rat brain nuclei (Meehan et al., 1992). In addition, several residues in this loop, in b strands 2 ± 4 and in puri®ed recombinant Xenopus MeCP2 binds to methyl the alpha helix. These residues de®ne a surface of the CpG dinucleotides in a nucleosomal context. The wedge that likely interacts with DNA (Wake®eld et al., isolated MBD domain retains the capacity to bind 1999). This surface presents a set of basic residues (in methylated nucleosomes albeit with reduced anity strand b2 and the ¯exible loop) immediately ¯anking a compared to the intact protein (Chandler et al., 1999). hydrophobic patch in strand b3. Additional basic Several lines of evidence contributed to the notion residues line the opposite side of the hydrophobic that MeCP2 might function to repress transcription patch (Figure 2). The importance of structural within a chromatin infrastructure. Methylated DNA ¯exibility in the loop has been con®rmed by mutation injected into either mammalian cells or into Xenopus of a conserved glycine residue to proline, which results oocyte nuclei is transcriptionally repressed relative to in a minimally 25-fold reduction in binding anity unmethylated controls. This repression, however, re- (Free et al., 2000). Three solvent exposed hydrophobic quires sucient time to permit chromatin assembly residues (Tyrosine 123, Isoleucine 125, and Alanine (Buschausen et al., 1987; Kass et al., 1997). Further, 131) are postulated to interact with the methyl groups reactivation of genes silenced by aberrant promoter in the major groove, mutation of these residues methylation in cancer cell lines requires inhibition of individually results in reductions in binding anity both DNA methyltransferases and histone deacetylases (Free et al., 2000). (Cameron et al., 1999). The subsequent ®nding that MeCP2 is physically associated with the transcriptional corepressor Sin3 and histone deacetylases in both The MBD family of proteins mammalian cells and Xenopus oocytes (Nan et al., 1998; Jones et al., 1998) identi®ed candidate regulatory A survey of EST databases with the MBD domain of enzymes involved in the assembly of a specialized MeCP2 led to the identi®cation of an additional family chromatin state at methylated loci. The region of member initially termed PCM1 (Cross et al., 1997). interaction of Sin3 with mammalian MeCP2 was found Subsequent searches of the expanding EST databases to be largely coincident with the previously de®ned TRD identi®ed four proteins in mammals that all possessed (Nan et al., 1998). Importantly, in both mammalian cells the MBD sequence motif, MBD1 (identical to PCM1), and Xenopus oocytes, arti®cial recruitment of the MBD2, MBD3, and MBD4 (Hendrich and Bird, 1998). MeCP2 TRD to a promoter leads to transcriptional Outside of the MBD domain itself, these proteins bear repression that is partially relieved by inhibitors of little obvious resemblance to each other (Figure 1; histone deacetylase (Nan et al., 1998; Jones et al., 1998). Hendrich and Bird, 1998). The single exception to this The solution structure of the MBD domain from rat rule is the high degree of similarity between MBD2 and MeCP2 has recently been solved (Wake®eld et al., MBD3 which are approximately 70% identical in the 1999). The MBD is a wedge shaped structure (Figure region de®ned by MBD3 (Hendrich and Bird, 1998). 2) with one face of the wedge composed of a beta sheet The MBD proteins are ubiquitously expressed in and the other face consisting of an alpha helix and somatic tissues, while ES cells fail to express MBD1 hairpin loop (Wake®eld et al., 1999). The vertex of the and express very low levels of MBD2 (Hendrich and wedge is extended by a long loop between two of the Bird, 1998). Additionally, all four of these MBD beta strands that contains several basic residues proteins are alternatively spliced with some splice (Wake®eld et al., 1999). Addition of methyl CpG variants being tissue speci®c and others clearly Oncogene Methyl CpG binding proteins PA Wade 3168 Figure 2 Three dimensional structure of the MBD domain from MeCP2. The structural coordinates for the rat MeCP2 MBD domain (Wake®eld et al., 1999) and the human MBD1 MBD domain were utilized in the Ribbons program to generate the cartoon. Open squares superimposed on the structure are basic residues making up the putative DNA interaction surface. The `hydrophobic patch' residues are indicated by open circles. The conserved tyrosine residue in strand b3 is indicated aecting the MBD domain (Hendrich and Bird, 1998). not a component of the previously de®ned Mi-2/NuRD The genomic structures of the human and murine and Sin3 complexes (Ng et al., 2000). MBD1-MBD4 genes have been determined, all have an Recombinant MBD1 can repress transcription of intron within the MBD domain itself and the human methylated, but not unmethylated, templates in vitro and mouse genes are highly similar in their exon/intron much like MeCP2 (Cross et al., 1997; Fujita et al., organization (Hendrich et al., 1999a). 1999). The various isoforms of MBD1 repress tran- scription in both mammalian and insect cells (Fujita et al., 1999; Ng et al., 2000).
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