Analysis of the Vertebrate Insulator Protein CTCF-binding Sites in the Human Genome

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2007 Mar 27

PMID 17382889

Citations 633

Authors

Tae Hoon Kim

Ziedulla K Abdullaev

Andrew D Smith

Keith A Ching

Dmitri I Loukinov

Roland D Green

Michael Q Zhang

Victor V Lobanenkov

Bing Ren

Affiliations

Soon will be listed here.

Abstract

Insulator elements affect gene expression by preventing the spread of heterochromatin and restricting transcriptional enhancers from activation of unrelated promoters. In vertebrates, insulator's function requires association with the CCCTC-binding factor (CTCF), a protein that recognizes long and diverse nucleotide sequences. While insulators are critical in gene regulation, only a few have been reported. Here, we describe 13,804 CTCF-binding sites in potential insulators of the human genome, discovered experimentally in primary human fibroblasts. Most of these sequences are located far from the transcriptional start sites, with their distribution strongly correlated with genes. The majority of them fit to a consensus motif highly conserved and suitable for predicting possible insulators driven by CTCF in other vertebrate genomes. In addition, CTCF localization is largely invariant across different cell types. Our results provide a resource for investigating insulator function and possible other general and evolutionarily conserved activities of CTCF sites.

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References

Mukhopadhyay R, Yu W, Whitehead J, Xu J, Lezcano M, Pack S . The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Genome Res. 2004; 14(8):1594-602. PMC: 509268. DOI: 10.1101/gr.2408304. View

Kim T, Ren B . Genome-wide analysis of protein-DNA interactions. Annu Rev Genomics Hum Genet. 2006; 7:81-102. DOI: 10.1146/annurev.genom.7.080505.115634. View

. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science. 2004; 306(5696):636-40. DOI: 10.1126/science.1105136. View

Udvardy A, Maine E, Schedl P . The 87A7 chromomere. Identification of novel chromatin structures flanking the heat shock locus that may define the boundaries of higher order domains. J Mol Biol. 1985; 185(2):341-58. DOI: 10.1016/0022-2836(85)90408-5. View

Baniahmad A, Steiner C, Kohne A, Renkawitz R . Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. Cell. 1990; 61(3):505-14. DOI: 10.1016/0092-8674(90)90532-j. View

Rideout 3rd W, Coetzee G, Olumi A, Jones P . 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science. 1990; 249(4974):1288-90. DOI: 10.1126/science.1697983. View

Lobanenkov V, Nicolas R, Adler V, PATERSON H, Klenova E, Polotskaja A . A novel sequence-specific DNA binding protein which interacts with three regularly spaced direct repeats of the CCCTC-motif in the 5'-flanking sequence of the chicken c-myc gene. Oncogene. 1990; 5(12):1743-53. View

Klenova E, Nicolas R, PATERSON H, Carne A, Heath C, Goodwin G . 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. Mol Cell Biol. 1993; 13(12):7612-24. PMC: 364833. DOI: 10.1128/mcb.13.12.7612-7624.1993. View

Filippova G, Fagerlie S, Klenova E, Myers C, Dehner Y, Goodwin G . An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996; 16(6):2802-13. PMC: 231272. DOI: 10.1128/MCB.16.6.2802. View

10.

Burcin M, Arnold R, Lutz M, Kaiser B, Runge D, Lottspeich F . Negative protein 1, which is required for function of the chicken lysozyme gene silencer in conjunction with hormone receptors, is identical to the multivalent zinc finger repressor CTCF. Mol Cell Biol. 1997; 17(3):1281-8. PMC: 231853. DOI: 10.1128/MCB.17.3.1281. View

11.

Vostrov A, Quitschke W . The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation. J Biol Chem. 1998; 272(52):33353-9. DOI: 10.1074/jbc.272.52.33353. View

12.

Filippova G, Lindblom A, Meincke L, Klenova E, Neiman P, Collins S . A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosomes Cancer. 1998; 22(1):26-36. View

13.

Bell A, West A, Felsenfeld G . The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999; 98(3):387-96. DOI: 10.1016/s0092-8674(00)81967-4. View

14.

Awad T, Bigler J, Ulmer J, Hu Y, Moore J, Lutz M . Negative transcriptional regulation mediated by thyroid hormone response element 144 requires binding of the multivalent factor CTCF to a novel target DNA sequence. J Biol Chem. 1999; 274(38):27092-8. DOI: 10.1074/jbc.274.38.27092. View

15.

Bulger M, Groudine M . Looping versus linking: toward a model for long-distance gene activation. Genes Dev. 1999; 13(19):2465-77. DOI: 10.1101/gad.13.19.2465. View

16.

Filippova G, Cheng M, Moore J, Truong J, Hu Y, Nguyen D . Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev Cell. 2005; 8(1):31-42. DOI: 10.1016/j.devcel.2004.10.018. View

17.

Bernstein B, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey D, Huebert D . Genomic maps and comparative analysis of histone modifications in human and mouse. Cell. 2005; 120(2):169-81. DOI: 10.1016/j.cell.2005.01.001. View

18.

Smith A, Sumazin P, Zhang M . Identifying tissue-selective transcription factor binding sites in vertebrate promoters. Proc Natl Acad Sci U S A. 2005; 102(5):1560-5. PMC: 547828. DOI: 10.1073/pnas.0406123102. View

19.

Moon H, Filippova G, Loukinov D, Pugacheva E, Chen Q, Smith S . CTCF is conserved from Drosophila to humans and confers enhancer blocking of the Fab-8 insulator. EMBO Rep. 2005; 6(2):165-70. PMC: 1299244. DOI: 10.1038/sj.embor.7400334. View

20.

Carrel L, Willard H . X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005; 434(7031):400-4. DOI: 10.1038/nature03479. View