Methyl CpG binding proteins: coupling chromatin architecture to gene regulation

Abstract

A correlation between DNA methylation and transcriptional silencing has existed for many years. Recently, substantial progress has been reported in the search for proteins that interpret the regulatory information inherent in DNA methylation and translate this information into functional states, resulting in the identi®cation of a family of highly conserved proteins, the MBD family. Direct connections between these proteins and histone modi®cation enzymes have emerged as a common theme, implying that DNA methylation exerts its e ects primarily through repressive chromatin architecture. Recent structural determinations of the DNA binding domain of two MBD family members, MeCP2 and MBD1, provide a framework to model the interactions of this family with DNA. Comparative sequence analysis and experimental DNA binding data can be interpreted using this structural framework allowing one to contrast the members of the MBD family with each other and to predict the properties of new family members. The identi®cation of mutations in MeCP2, the founding member of this family, as causal for the neurological developmental disorder Rett Syndrome provides additional information regarding amino acid residues crucial to the functions of this interesting protein family. Oncogene (2001) 20, 3166 ± 3173.

MBD3L1 Is a Transcriptional Repressor That Interacts with Methyl-CpG-binding Protein 2 (MBD2) and Components of the NuRD Complex

“…Recruitment of MeCP2 to a promoter leads to transcriptional repression that can be partially relieved by inhibitors of histone deacetylation (6,7). Four additional genes, which encode methyl-CpG binding domain (MBD) 1 proteins, were identified later (8). The five MBD-containing proteins (MBD1, MBD2, MBD3, MBD4, and MeCP2) are homologous within their MBD domains (1)(2)(3).…”

“…Four additional genes, which encode methyl-CpG binding domain (MBD) 1 proteins, were identified later (8). The five MBD-containing proteins (MBD1, MBD2, MBD3, MBD4, and MeCP2) are homologous within their MBD domains (1)(2)(3). MBD2 and MBD3 may be derived from a common ancestor and share Ͼ65% identity over most of the length of the smaller MBD3 protein.…”

“…Mammalian genomes encode several proteins that can bind specifically to methylated CpG sequences, providing one mechanism by which DNA methylation has the capacity to inhibit gene expression (1)(2)(3). The first methyl-CpG-binding protein discovered was MeCP2, a polypeptide that can bind selectively to a single methylated CpG site (4,5).…”

Nuclear receptors and chromatin remodeling machinery

“…Two distinct classes of chromatin modifying enzymes have been identified, one disrupts chromatin structure using ATP-dependent chromatin remodeling, and another whose actions are mediated through covalent modification of histone proteins. The function of histone-modifying enzymes that catalyze post-translational modifications on histones by altering acetylation, methylation, phosphorylation, and/or ubiquitination patterns have been extensively reviewed and will not be discussed further (Berger, 2002;Neely and Workman, 2002;Wade, 2001;Zhang, 2003). Rather this review will focus on ATP-dependent chromatin remodeling complexes which use the energy derived from ATP hydrolysis to disrupt histone-DNA interactions in the context of steroid hormone activated transcription, highlighting recent studies with the glucocorticoid receptor.…”

Interplay of Binding Stoichiometry and Recognition Specificity for the Interaction of MBD2b Protein and Methylated DNA Revealed by Affinity Capillary Electrophoresis Coupled with Laser-Induced Fluorescence Analysis

“…3 MeCP2 is associated with a transcriptional repressor complex containing Sin3 and histone deacetylases in mammalian cells. 14,24,25 MBD2 is associated with MBD3 to form an Mi-2/NuRD complex that contains a chromatin-remodeling ATPase, a histone deacetylase, and other subunits. 25,26 The DNA methylation-dependent transcriptional repression mechanism as described above would not work if MBD proteins could not selectively bind to methylated DNA.…”