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Gene Review

CTCF  -  CCCTC-binding factor (zinc finger protein)

Homo sapiens

Synonyms: 11-zinc finger protein, CCCTC-binding factor, CTCFL paralog, Transcriptional repressor CTCF

Disease relevance of CTCF


High impact information on CTCF

  • In vertebrates, insulator's function requires association with the CCCTC-binding factor (CTCF), a protein that recognizes long and diverse nucleotide sequences [5].
  • The majority of them fit to a consensus motif highly conserved and suitable for predicting possible insulators driven by CTCF in other vertebrate genomes [5].
  • Here, we describe 13,804 CTCF-binding sites in potential insulators of the human genome, discovered experimentally in primary human fibroblasts [5].
  • Using ChiP-Seq-technology, the number of binding sites was increased to 26,814, also revealing a modified consensus sequence found in 95% of the sites [6]
  • 5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease [7].
  • An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity [8].

Chemical compound and disease context of CTCF

  • We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor [9].

Biological context of CTCF


Anatomical context of CTCF

  • These results demonstrate that CTCF is a common determinant to different pathways of death signaling in immature B cells [13].
  • CT genes are normally expressed in BORIS-positive male germ cells deficient in CTCF and meCpG contents, but are strictly silenced in somatic cells [1].
  • The forced down-regulation of CTCF expression using small interfering RNA in imprinted prostate cell lines resulted in an increase in IGF2 expression and a relaxation of imprinting [14].
  • The insulator binding protein CTCF associates with the nuclear matrix [15].
  • In all cell lines analyzed, including cells of lung, renal, monocytic and T-cell origin, the IRAK2 luciferase reporter construct, containing an intact CTCF-binding site, showed strong promoter activity [16].

Associations of CTCF with chemical compounds


Physical interactions of CTCF


Regulatory relationships of CTCF


Other interactions of CTCF


Analytical, diagnostic and therapeutic context of CTCF


  1. Reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter coincides with derepression of this cancer-testis gene in lung cancer cells. Hong, J.A., Kang, Y., Abdullaev, Z., Flanagan, P.T., Pack, S.D., Fischette, M.R., Adnani, M.T., Loukinov, D.I., Vatolin, S., Risinger, J.I., Custer, M., Chen, G.A., Zhao, M., Nguyen, D.M., Barrett, J.C., Lobanenkov, V.V., Schrump, D.S. Cancer Res. (2005) [Pubmed]
  2. Epigenetic regulation of the human retinoblastoma tumor suppressor gene promoter by CTCF. De La Rosa-Velázquez, I.A., Rincón-Arano, H., Benítez-Bribiesca, L., Recillas-Targa, F. Cancer Res. (2007) [Pubmed]
  3. Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cui, H., Niemitz, E.L., Ravenel, J.D., Onyango, P., Brandenburg, S.A., Lobanenkov, V.V., Feinberg, A.P. Cancer Res. (2001) [Pubmed]
  4. 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. Filippova, G.N., Lindblom, A., Meincke, L.J., Klenova, E.M., Neiman, P.E., Collins, S.J., Doggett, N.A., Lobanenkov, V.V. Genes Chromosomes Cancer (1998) [Pubmed]
  5. Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome. Kim, T.H., Abdullaev, Z.K., Smith, A.D., Ching, K.A., Loukinov, D.I., Green, R.D., Zhang, M.Q., Lobanenkov, V.V., Ren, B. Cell (2007) [Pubmed]
  6. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Jothi, R., Cuddapah, S., Barski, A., Cui, K., Zhao, K. Nucleic. Acids. Res. (2008) [Pubmed]
  7. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G.B., Silengo, M.C., Riccio, A. Nat. Genet. (2004) [Pubmed]
  8. Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Yu, W., Ginjala, V., Pant, V., Chernukhin, I., Whitehead, J., Docquier, F., Farrar, D., Tavoosidana, G., Mukhopadhyay, R., Kanduri, C., Oshimura, M., Feinberg, A.P., Lobanenkov, V., Klenova, E., Ohlsson, R. Nat. Genet. (2004) [Pubmed]
  9. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Prawitt, D., Enklaar, T., Gärtner-Rupprecht, B., Spangenberg, C., Oswald, M., Lausch, E., Schmidtke, P., Reutzel, D., Fees, S., Lucito, R., Korzon, M., Brozek, I., Limon, J., Housman, D.E., Pelletier, J., Zabel, B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Bell, A.C., Felsenfeld, G. Nature (2000) [Pubmed]
  11. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Hark, A.T., Schoenherr, C.J., Katz, D.J., Ingram, R.S., Levorse, J.M., Tilghman, S.M. Nature (2000) [Pubmed]
  12. CTCF binding and higher order chromatin structure of the H19 locus are maintained in mitotic chromatin. Burke, L.J., Zhang, R., Bartkuhn, M., Tiwari, V.K., Tavoosidana, G., Kurukuti, S., Weth, C., Leers, J., Galjart, N., Ohlsson, R., Renkawitz, R. EMBO J. (2005) [Pubmed]
  13. CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells. Qi, C.F., Martensson, A., Mattioli, M., Dalla-Favera, R., Lobanenkov, V.V., Morse, H.C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  14. A loss of insulin-like growth factor-2 imprinting is modulated by CCCTC-binding factor down-regulation at senescence in human epithelial cells. Fu, V.X., Schwarze, S.R., Kenowski, M.L., Leblanc, S., Svaren, J., Jarrard, D.F. J. Biol. Chem. (2004) [Pubmed]
  15. The insulator binding protein CTCF associates with the nuclear matrix. Dunn, K.L., Zhao, H., Davie, J.R. Exp. Cell Res. (2003) [Pubmed]
  16. Transcriptional regulator CTCF controls human interleukin 1 receptor-associated kinase 2 promoter. Kuzmin, I., Geil, L., Gibson, L., Cavinato, T., Loukinov, D., Lobanenkov, V., Lerman, M.I. J. Mol. Biol. (2005) [Pubmed]
  17. IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switch. Li, T., Vu, T.H., Ulaner, G.A., Littman, E., Ling, J.Q., Chen, H.L., Hu, J.F., Behr, B., Giudice, L., Hoffman, A.R. Mol. Hum. Reprod. (2005) [Pubmed]
  18. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Ulaner, G.A., Vu, T.H., Li, T., Hu, J.F., Yao, X.M., Yang, Y., Gorlick, R., Meyers, P., Healey, J., Ladanyi, M., Hoffman, A.R. Hum. Mol. Genet. (2003) [Pubmed]
  19. Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor. Lutz, M., Burke, L.J., LeFevre, P., Myers, F.A., Thorne, A.W., Crane-Robinson, C., Bonifer, C., Filippova, G.N., Lobanenkov, V., Renkawitz, R. EMBO J. (2003) [Pubmed]
  20. Identification, genome mapping, and CTCF binding of potential insulators within the FXYD5-COX7A1 locus of human Chromosome 19q13.12. Akopov, S.B., Ruda, V.M., Batrak, V.V., Vetchinova, A.S., Chernov, I.P., Nikolaev, L.G., Bode, J., Sverdlov, E.D. Mamm. Genome (2006) [Pubmed]
  21. DNA methylation in the CTCF-binding site I and the expression pattern of the H19 gene: does positive expression predict poor prognosis in early stage head and neck carcinomas? Esteves, L.I., Javaroni, A.C., Nishimoto, I.N., Magrin, J., Squire, J.A., Kowalski, L.P., Rainho, C.A., Rogatto, S.R. Mol. Carcinog. (2005) [Pubmed]
  22. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Filippova, G.N., Thienes, C.P., Penn, B.H., Cho, D.H., Hu, Y.J., Moore, J.M., Klesert, T.R., Lobanenkov, V.V., Tapscott, S.J. Nat. Genet. (2001) [Pubmed]
  23. A region to the N-terminal side of the CTCF zinc finger domain is essential for activating transcription from the amyloid precursor protein promoter. Vostrov, A.A., Taheny, M.J., Quitschke, W.W. J. Biol. Chem. (2002) [Pubmed]
  24. CTCF regulates growth and erythroid differentiation of human myeloid leukemia cells. Torrano, V., Chernukhin, I., Docquier, F., D'Arcy, V., León, J., Klenova, E., Delgado, M.D. J. Biol. Chem. (2005) [Pubmed]
  25. Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involves interaction between the CTCF-complex and Smads. Burton, T., Liang, B., Dibrov, A., Amara, F. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  26. Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region. Kanduri, M., Kanduri, C., Mariano, P., Vostrov, A.A., Quitschke, W., Lobanenkov, V., Ohlsson, R. Mol. Cell. Biol. (2002) [Pubmed]
  27. CTCF binding at the insulin-like growth factor-II (IGF2)/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues. Ulaner, G.A., Yang, Y., Hu, J.F., Li, T., Vu, T.H., Hoffman, A.R. Endocrinology (2003) [Pubmed]
  28. Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF. Chernukhin, I.V., Shamsuddin, S., Robinson, A.F., Carne, A.F., Paul, A., El-Kady, A.I., Lobanenkov, V.V., Klenova, E.M. J. Biol. Chem. (2000) [Pubmed]
  29. Molecular weight abnormalities of the CTCF transcription factor: CTCF migrates aberrantly in SDS-PAGE and the size of the expressed protein is affected by the UTRs and sequences within the coding region of the CTCF gene. Klenova, E.M., Nicolas, R.H., U, S., Carne, A.F., Lee, R.E., Lobanenkov, V.V., Goodwin, G.H. Nucleic Acids Res. (1997) [Pubmed]
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