Methyl CpG binding proteins: coupling chromatin architecture to gene regulation

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 identification of a family of highly conserved proteins, the MBD family. Direct connections between these proteins and histone modification enzymes have emerged as a common theme, implying that DNA methylation exerts its effects 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 identification 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.

[1]  A. Bird,et al.  Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. , 1999, Genes & development.

[2]  A. Razin,et al.  CpG methylation, chromatin structure and gene silencing—a three‐way connection , 1998, The EMBO journal.

[3]  H. Zoghbi,et al.  Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. , 1999, American journal of human genetics.

[4]  M. Nakao,et al.  Solution structure of the methyl‐CpG‐binding domain of the methylation‐dependent transcriptional repressor MBD1 , 1999, The EMBO journal.

[5]  A. Bird,et al.  Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. , 1993, Nucleic acids research.

[6]  L. Aaltonen,et al.  The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability , 1999, Nature Genetics.

[7]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[8]  H. Zoghbi,et al.  Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. , 2000, American journal of human genetics.

[9]  Paul Tempst,et al.  MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex , 1999, Nature Genetics.

[10]  A. Bird,et al.  Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. , 1992, Nucleic acids research.

[11]  E. Ballestar,et al.  Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. , 2000, Biochemistry.

[12]  A. Bird,et al.  Active Repression of Methylated Genes by the Chromosomal Protein MBD1 , 2000, Molecular and Cellular Biology.

[13]  A. Graessmann,et al.  Chromatin structure is required to block transcription of the methylated herpes simplex virus thymidine kinase gene. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[14]  S. Cross,et al.  CpG islands and genes. , 1995, Current opinion in genetics & development.

[15]  O. Ammerpohl,et al.  The Minimal Repression Domain of MBD2b Overlaps with the Methyl-CpG-binding Domain and Binds Directly to Sin3A* , 2000, The Journal of Biological Chemistry.

[16]  Jean Aicardi,et al.  A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: Report of 35 cases , 1983, Annals of neurology.

[17]  A. Bird,et al.  Mammalian methyltransferases and methyl-CpG-binding domains: proteins involved in DNA methylation. , 2000, Current topics in microbiology and immunology.

[18]  A. Bird,et al.  DNA Recognition by the Methyl-CpG Binding Domain of MeCP2* , 2001, The Journal of Biological Chemistry.

[19]  J. Herman,et al.  Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer , 1999, Nature Genetics.

[20]  B. Hagberg.  Rett's Syndrome: Prevalence and Impact on Progressive Severe Mental Retardation in Girls , 1985, Acta paediatrica Scandinavica.

[21]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[22]  A. Wolffe,et al.  MeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. , 2000, Nucleic acids research.

[23]  A. Wolffe,et al.  The methyl-CpG binding transcriptional repressor MeCP2 stably associates with nucleosomal DNA. , 1999, Biochemistry.

[24]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

[25]  M. Nakao,et al.  Methylation-Mediated Transcriptional Silencing in Euchromatin by Methyl-CpG Binding Protein MBD1 Isoforms , 1999, Molecular and Cellular Biology.

[26]  A. Bird,et al.  Identification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins , 1998, Molecular and Cellular Biology.

[27]  S. Cross,et al.  A component of the transcriptional represser MeCP1 shares a motif with DNA methyltransferase and HRX proteins , 1997, Nature Genetics.

[28]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[29]  P. Huppke,et al.  Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. , 2000, Human molecular genetics.

[30]  H. Zoghbi,et al.  Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes , 2000, Annals of neurology.

[31]  S. Cross,et al.  Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes , 1999, Mammalian Genome.

[32]  P N Barlow,et al.  The solution structure of the domain from MeCP2 that binds to methylated DNA. , 1999, Journal of molecular biology.

[33]  J. Fryns,et al.  A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. , 2000, American journal of human genetics.

[34]  A. Bird,et al.  Absence of genome-wide changes in DNA methylation during development of the zebrafish , 1999, Nature Genetics.

[35]  Stefan U Kass,et al.  DNA methylation directs a time-dependent repression of transcription initiation , 1997, Current Biology.

[36]  E. Cook,et al.  Novel de novo nonsense mutation of MECP2 in a patient with Rett syndrome , 2000, Human mutation.

[37]  T. Bestor,et al.  The DNA methyltransferases of mammals. , 2000, Human molecular genetics.

[38]  A. Wolffe,et al.  DNA methylation in health and disease , 2000, Nature Reviews Genetics.

[39]  C. Woods,et al.  Mutations in the MECP2 gene in a cohort of girls with Rett syndrome , 2000, Journal of medical genetics.

[40]  A. Wolffe,et al.  A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase , 1998, Current Biology.

[41]  A. Wolffe,et al.  Functional consequences of Rett syndrome mutations on human MeCP2. , 2000, Nucleic acids research.

[42]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[43]  J Dragich,et al.  Rett syndrome: a surprising result of mutation in MECP2. , 2000, Human molecular genetics.

[44]  E. Ballestar,et al.  Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation , 1999, Nature Genetics.

[45]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[46]  A. Bird,et al.  The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites , 1999, Nature.

[47]  M. Szyf,et al.  A mammalian protein with specific demethylase activity for mCpG DNA , 1999, Nature.

[48]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[49]  A. Federico,et al.  MECP2 mutation in male patients with non‐specific X‐linked mental retardation , 2000, FEBS letters.

[50]  A. Bellacosa,et al.  Biphasic Kinetics of the Human DNA Repair Protein MED1 (MBD4), a Mismatch-specific DNA N-Glycosylase* , 2000, The Journal of Biological Chemistry.

[51]  E. Golemis,et al.  MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  A. Bird,et al.  MeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin , 1997, Cell.

[53]  A. Bird,et al.  Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency , 1999, Oncogene.

[54]  A. Bird,et al.  Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA , 1992, Cell.