Genome-wide Studies of CCCTC-binding Factor (CTCF) and Cohesin Provide Insight into Chromatin Structure and Regulation*

Eukaryotic genomes are organized into higher order chromatin architectures by protein-mediated long-range interactions in the nucleus. CCCTC-binding factor (CTCF), a sequence-specific transcription factor, serves as a chromatin organizer in building this complex chromatin structure by linking chromosomal domains. Recent genome-wide studies mapping the binding sites of CTCF and its interacting partner, cohesin, using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) revealded that CTCF globally co-localizes with cohesin. This partnership between CTCF and cohesin is emerging as a novel and perhaps pivotal aspect of gene regulatory mechanisms, in addition to playing a role in the organization of higher order chromatin architecture.

[1]  J. Kissil,et al.  Cohesins localize with CTCF at the KSHV latency control region and at cellular c‐myc and H19/Igf2 insulators , 2008, The EMBO journal.

[2]  Herbert Schulz,et al.  RAD21 Cooperates with Pluripotency Transcription Factors in the Maintenance of Embryonic Stem Cell Identity , 2011, PloS one.

[3]  Manolis Kellis,et al.  RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo , 2007, Nature Genetics.

[4]  P. Neiman,et al.  CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms , 1993, Molecular and cellular biology.

[5]  P. Fraser,et al.  Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus , 2009, Nature.

[6]  Ryan Dale,et al.  Cell type specificity of chromatin organization mediated by CTCF and cohesin , 2010, Proceedings of the National Academy of Sciences.

[7]  Dustin E. Schones,et al.  Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. , 2008, Genome research.

[8]  B. Hallgrímsson,et al.  Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl +/− Mouse, a Model of Cornelia de Lange Syndrome , 2009, PLoS genetics.

[9]  Y. Kim,et al.  Conserved, developmentally regulated mechanism couples chromosomal looping and heterochromatin barrier activity at the homeobox gene A locus , 2011, Proceedings of the National Academy of Sciences.

[10]  J. Zlatanova,et al.  CTCF and its protein partners: divide and rule? , 2009, Journal of Cell Science.

[11]  H. Aburatani,et al.  Cohesin mediates transcriptional insulation by CCCTC-binding factor , 2008, Nature.

[12]  Igor Chernukhin,et al.  CTCF Regulates Growth and Erythroid Differentiation of Human Myeloid Leukemia Cells* , 2005, Journal of Biological Chemistry.

[13]  Z. Weng,et al.  The Insulator Binding Protein CTCF Positions 20 Nucleosomes around Its Binding Sites across the Human Genome , 2008, PLoS genetics.

[14]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[15]  David A. Orlando,et al.  Mediator and Cohesin Connect Gene Expression and Chromatin Architecture , 2010, Nature.

[16]  D. Komura,et al.  A wave of nascent transcription on activated human genes , 2009, Proceedings of the National Academy of Sciences.

[17]  J. J. Breen,et al.  BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  David J. Reiss,et al.  CTCF physically links cohesin to chromatin , 2008, Proceedings of the National Academy of Sciences.

[19]  G. Felsenfeld,et al.  Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene , 2000, Nature.

[20]  Rolf Ohlsson,et al.  Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation , 2004, Nature Genetics.

[21]  V. Corces,et al.  CTCF: Master Weaver of the Genome , 2009, Cell.

[22]  Rolf Ohlsson,et al.  The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. , 2004, Genome research.

[23]  Victor V Lobanenkov,et al.  Does CTCF mediate between nuclear organization and gene expression? , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[24]  Victor V Lobanenkov,et al.  Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive , 2000, Current Biology.

[25]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[26]  A. Baniahmad,et al.  Modulation of thyroid hormone receptor silencing function by co-repressors and a synergizing transcription factor. , 2000, Biochemical Society Transactions.

[27]  D. Dorsett,et al.  Cohesin Selectively Binds and Regulates Genes with Paused RNA Polymerase , 2011, Current Biology.

[28]  Helen Zhao,et al.  The insulator binding protein CTCF associates with the nuclear matrix. , 2003, Experimental cell research.

[29]  Ian X. Y. Leung,et al.  Intra- and inter-chromosomal interactions correlate with CTCF binding genome wide , 2010, Molecular systems biology.

[30]  Nicholas J. Schork,et al.  CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells , 2011, Proceedings of the National Academy of Sciences.

[31]  C. Schoenherr,et al.  Sumoylation modulates a domain in CTCF that activates transcription and decondenses chromatin , 2010, Journal of cellular biochemistry.

[32]  Julian Haase,et al.  Pericentric Chromatin Is Organized into an Intramolecular Loop in Mitosis , 2008, Current Biology.

[33]  M. Gustafsson,et al.  Subdiffraction Multicolor Imaging of the Nuclear Periphery with 3D Structured Illumination Microscopy , 2008, Science.

[34]  D. Dorsett.  Cohesin: genomic insights into controlling gene transcription and development. , 2011, Current opinion in genetics & development.

[35]  G. Felsenfeld,et al.  We gather together: insulators and genome organization. , 2007, Current opinion in genetics & development.

[36]  Petra C. Schwalie,et al.  A CTCF-independent role for cohesin in tissue-specific transcription. , 2010, Genome research.

[37]  A. Musio,et al.  X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations , 2006, Nature Genetics.

[38]  Hui Ling Chen,et al.  CTCF Mediates Interchromosomal Colocalization Between Igf2/H19 and Wsb1/Nf1 , 2006, Science.

[39]  A. West,et al.  The Protein CTCF Is Required for the Enhancer Blocking Activity of Vertebrate Insulators , 1999, Cell.

[40]  Raymond K. Auerbach,et al.  A User's Guide to the Encyclopedia of DNA Elements (ENCODE) , 2011, PLoS biology.

[41]  D. Dorsett,et al.  Cohesin and CTCF: cooperating to control chromosome conformation? , 2008, BioEssays : news and reviews in molecular, cellular and developmental biology.

[42]  I. Krantz,et al.  Cohesin and human disease. , 2008, Annual review of genomics and human genetics.

[43]  Michael B. Eisen,et al.  Control of Embryonic Stem Cell Lineage Commitment by Core Promoter Factor, TAF3 , 2011, Cell.

[44]  N. Galjart,et al.  Critical Role for the Transcription Regulator CCCTC-Binding Factor in the Control of Th2 Cytokine Expression1 , 2009, The Journal of Immunology.

[45]  Zhe Zhang,et al.  Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells , 2009, PLoS biology.

[46]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[47]  T. Itoh,et al.  Cohesin relocation from sites of chromosomal loading to places of convergent transcription , 2004, Nature.

[48]  A. Dean,et al.  Enhancer blocking by chicken beta-globin 5'-HS4: role of enhancer strength and insulator nucleosome depletion. , 2006, The Journal of biological chemistry.

[49]  H. Aburatani,et al.  Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster , 2009, The EMBO journal.

[50]  F. Alt,et al.  CTCF Binding Elements Mediate Control of V(D)J Recombination , 2011, Nature.

[51]  E. Klenova,et al.  Regulation of the transcription factor, CTCF, by phosphorylation with protein kinase CK2 , 2005, FEBS letters.

[52]  Michael Q. Zhang,et al.  Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome , 2007, Cell.

[53]  Kim Nasmyth,et al.  Cohesin: its roles and mechanisms. , 2009, Annual review of genetics.

[54]  P. Neiman,et al.  An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes , 1996, Molecular and cellular biology.

[55]  G. Pfeifer,et al.  Maternal-specific footprints at putative CTCF sites in the H19 imprinting control region give evidence for insulator function , 2000, Current Biology.

[56]  C. Kanduri,et al.  Multiple Nucleosome Positioning Sites Regulate the CTCF-Mediated Insulator Function of the H19 Imprinting Control Region† , 2002, Molecular and Cellular Biology.

[57]  K. Maggert,et al.  The CCCTC-Binding Factor (CTCF) of Drosophila Contributes to the Regulation of the Ribosomal DNA and Nucleolar Stability , 2011, PloS one.

[58]  L. Wessels,et al.  Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions , 2008, Nature.

[59]  R. Goldman,et al.  Nuclear lamins: building blocks of nuclear architecture. , 2002, Genes & development.

[60]  Ewan Birney,et al.  Cell-type specific and combinatorial usage of diverse transcription factors revealed by genome-wide binding studies in multiple human cells. , 2012, Genome research.

[61]  Christel Krueger,et al.  Cohesin Is Required for Higher-Order Chromatin Conformation at the Imprinted IGF2-H19 Locus , 2009, PLoS genetics.

[62]  Kathryn E. Crosier,et al.  Positive regulation of c-Myc by cohesin is direct, and evolutionarily conserved. , 2010, Developmental biology.

[63]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[64]  D. Dorsett,et al.  Regulation of the Drosophila Enhancer of split and invected-engrailed Gene Complexes by Sister Chromatid Cohesion Proteins , 2009, PloS one.

[65]  K. Nasmyth,et al.  The cohesin ring concatenates sister DNA molecules , 2008, Nature.

[66]  Stephan Sauer,et al.  Cohesins Functionally Associate with CTCF on Mammalian Chromosome Arms , 2008, Cell.

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

[68]  Victor V Lobanenkov,et al.  CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Haiping Hao,et al.  Two Forms of Loops Generate the Chromatin Conformation of the Immunoglobulin Heavy-Chain Gene Locus , 2011, Cell.

[70]  A. Feinberg,et al.  Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity. , 2002, Cancer research.

[71]  Jane M J Lin,et al.  Identification and Characterization of Cell Type–Specific and Ubiquitous Chromatin Regulatory Structures in the Human Genome , 2007, PLoS genetics.

[72]  Michael D. Wilson,et al.  Waves of Retrotransposon Expansion Remodel Genome Organization and CTCF Binding in Multiple Mammalian Lineages , 2012, Cell.

[73]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[74]  I. Krantz,et al.  Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B , 2004, Nature Genetics.

[75]  Matthew T. Maurano,et al.  Widespread Site-Dependent Buffering of Human Regulatory Polymorphism , 2012, PLoS genetics.

[76]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[77]  A. Wood,et al.  Condensin and cohesin complexity: the expanding repertoire of functions , 2010, Nature Reviews Genetics.

[78]  I. Krantz,et al.  Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B , 2004, Nature Genetics.

[79]  William Stafford Noble,et al.  A Three-Dimensional Model of the Yeast Genome , 2010, Nature.

[80]  G. Felsenfeld,et al.  CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. , 2004, Molecular cell.

[81]  A. Vostrov,et al.  The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation. , 1997, The Journal of biological chemistry.

[82]  P. Neiman,et al.  Functional Phosphorylation Sites in the C-Terminal Region of the Multivalent Multifunctional Transcriptional Factor CTCF , 2001, Molecular and Cellular Biology.

[83]  Elphège P. Nora,et al.  Regulation of X-chromosome inactivation by the X-inactivation centre , 2011, Nature Reviews Genetics.

[84]  Earl F. Glynn,et al.  Genome-Wide Mapping of the Cohesin Complex in the Yeast Saccharomyces cerevisiae , 2004, PLoS biology.

[85]  Chee Seng Chan,et al.  CTCF-Mediated Functional Chromatin Interactome in Pluripotent Cells , 2011, Nature Genetics.

[86]  M. Vigneron,et al.  CTCF Interacts with and Recruits the Largest Subunit of RNA Polymerase II to CTCF Target Sites Genome-Wide , 2007, Molecular and Cellular Biology.

[87]  T. Kohwi-Shigematsu,et al.  SATB1 targets chromatin remodelling to regulate genes over long distances , 2002, Nature.

[88]  Jeannie T. Lee,et al.  CTCF, a Candidate Trans-Acting Factor for X-Inactivation Choice , 2001, Science.

[89]  B. Steensel,et al.  Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C) , 2006, Nature Genetics.

[90]  C. Nusbaum,et al.  Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. , 2006, Genome research.

[91]  S. Tapscott,et al.  CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus , 2001, Nature Genetics.

[92]  L. Beatty,et al.  The CTCF Insulator Protein Is Posttranslationally Modified by SUMO , 2008, Molecular and Cellular Biology.

[93]  A. Dejean,et al.  Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus , 2007, Nature Cell Biology.