On how mammalian transcription factors recognize methylated DNA

DNA methylation is an epigenetic mark that is essential for the development of mammals; it is frequently altered in diseases ranging from cancer to psychiatric disorders. The presence of DNA methylation attracts specialized methyl-DNA binding factors that can then recruit chromatin modifiers. These methyl-CpG binding proteins (MBPs) have key biological roles and can be classified into three structural families: methyl-CpG binding domain (MBD), zinc finger, and SET and RING finger-associated (SRA) domain. The structures of MBD and SRA proteins bound to methylated DNA have been previously determined and shown to exhibit two very different modes of methylated DNA recognition. The last piece of the puzzle has been recently revealed by the structural resolution of two different zinc finger proteins, Kaiso and ZFP57, in complex with methylated DNA. These structures show that the two methyl-CpG binding zinc finger proteins adopt differential methyl-CpG binding modes. Nonetheless, there are similarities with the MBD proteins suggesting some commonalities in methyl-CpG recognition across the various MBP domains. These fresh insights have consequences for the analysis of the many other zinc finger proteins present in the genome, and for the biology of methyl-CpG binding zinc finger proteins.

[1]  Yusuke Nakamura,et al.  ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain , 2004, Oncogene.

[2]  S. Jacobsen,et al.  The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix , 2008, Nature.

[3]  Hendrik G. Stunnenberg,et al.  A SILAC-Based Screen for Methyl-CpG Binding Proteins Identifies RBP-J as a DNA Methylation and Sequence-Specific Binding Protein , 2011, PloS one.

[4]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[5]  A. Bird,et al.  Kaiso-Deficient Mice Show Resistance to Intestinal Cancer , 2006, Molecular and Cellular Biology.

[6]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[7]  Guillaume J. Filion,et al.  A Family of Human Zinc Finger Proteins That Bind Methylated DNA and Repress Transcription , 2006, Molecular and Cellular Biology.

[8]  Zohar Mukamel,et al.  Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues , 2012, Nature Genetics.

[9]  A. Bird,et al.  DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. , 2005, Molecular cell.

[10]  David C. Williams,et al.  Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence , 2011, Nucleic acids research.

[11]  Iris Antes,et al.  Recognition of 5-Hydroxymethylcytosine by the Uhrf1 SRA Domain , 2011, PloS one.

[12]  S. Jacobsen,et al.  UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells , 2007, Science.

[13]  P. Defossez,et al.  The Human Proteins MBD5 and MBD6 Associate with Heterochromatin but They Do Not Bind Methylated DNA , 2010, PloS one.

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

[15]  N. Sonenberg,et al.  UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells , 2007, Science.

[16]  A. Bird,et al.  MeCP2 binding to DNA depends upon hydration at methyl-CpG. , 2008, Molecular cell.

[17]  C. Arrowsmith,et al.  Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1 , 2008, Nature.

[18]  Juan M. Vaquerizas,et al.  A census of human transcription factors: function, expression and evolution , 2009, Nature Reviews Genetics.

[19]  M. Nakao,et al.  Solution Structure of the Methyl-CpG Binding Domain of Human MBD1 in Complex with Methylated DNA , 2001, Cell.

[20]  Yi Zhang,et al.  Active DNA demethylation: many roads lead to Rome , 2010, Nature Reviews Molecular Cell Biology.

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

[22]  Christoph Bock,et al.  Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk , 2012, Genome research.

[23]  Yusuke Nakamura,et al.  Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism , 2008, Nature.

[24]  Mitsuyoshi Nakao,et al.  Sequence-specific recognition of methylated DNA by human zinc-finger proteins , 2010, Nucleic acids research.

[25]  H. Dyson,et al.  Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso , 2012, Proceedings of the National Academy of Sciences.

[26]  Xiaodong Cheng,et al.  An atomic model of Zfp57 recognition of CpG methylation within a specific DNA sequence. , 2012, Genes & development.

[27]  W. Reik.  Stability and flexibility of epigenetic gene regulation in mammalian development , 2007, Nature.

[28]  Peter A. Jones.  Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[29]  Albert B. Reynolds,et al.  The p120ctn-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides , 2002, Nucleic Acids Res..

[30]  D. Patel,et al.  Structure-Based Mechanistic Insights into DNMT1-Mediated Maintenance DNA Methylation , 2012, Science.

[31]  P. Wright,et al.  Kaiso uses all three zinc fingers and adjacent sequence motifs for high affinity binding to sequence‐specific and methyl‐CpG DNA targets , 2012, FEBS letters.

[32]  M. Isalan,et al.  Engineered zinc finger proteins that respond to DNA modification by HaeIII and HhaI methyltransferase enzymes. , 2000, Journal of molecular biology.

[33]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[34]  A. Bird,et al.  The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. , 2001, Genes & development.

[35]  D. Trono,et al.  In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions , 2011, Molecular cell.

[36]  A. Feinberg,et al.  Comprehensive High‐Throughput Arrays for Relative Methylation (CHARM) , 2010, Current protocols in human genetics.

[37]  P. Leder,et al.  A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. , 2008, Developmental cell.

[38]  R. Sandberg,et al.  CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing , 2011, Nature.

[39]  A. Bird,et al.  Genomic DNA methylation: the mark and its mediators. , 2006, Trends in biochemical sciences.

[40]  Cara Merusi,et al.  Recruitment of MBD1 to target genes requires sequence-specific interaction of the MBD domain with methylated DNA , 2010, Nucleic acids research.

[41]  A. Bird,et al.  Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). , 2004, Nucleic acids research.

[42]  R. Lister,et al.  Finding the fifth base: genome-wide sequencing of cytosine methylation. , 2009, Genome research.

[43]  E. Li.  Chromatin modification and epigenetic reprogramming in mammalian development , 2002, Nature Reviews Genetics.

[44]  Zachary D. Smith,et al.  Gel-free multiplexed reduced representation bisulfite sequencing for large-scale DNA methylation profiling , 2012, Genome Biology.

[45]  R. Emerson,et al.  Adaptive Evolution in Zinc Finger Transcription Factors , 2009, PLoS genetics.

[46]  K. Mitsuya,et al.  The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA , 2007, Nature.

[47]  P. Defossez,et al.  Many paths to one goal? The proteins that recognize methylated DNA in eukaryotes. , 2009, The International journal of developmental biology.