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CTCF

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Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene.[1][2] CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination[3] and regulation of chromatin architecture.[4]

Discovery[edit | edit source]

CCCTC-Binding factor or CTCF was initially discovered as a negative regulator of the chicken c-myc gene. This protein was found to be binding to three regularly spaced repeats of the core sequence CCCTC and thus was named CCCTC binding factor.[5]

Function[edit | edit source]

The primary role of CTCF is thought to be in regulating the 3D structure of chromatin.[4] CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the nuclear lamina.[6] It also defines the boundaries between active and heterochromatic DNA.

Since the 3D structure of DNA influences the regulation of genes, CTCF's activity influences the expression of genes. CTCF is thought to be a primary part of the activity of insulators, sequences that block the interaction between enhancers and promoters. CTCF binding has also been both shown to promote and repress gene expression. It is unknown whether CTCF affects gene expression solely through its looping activity, or if it has some other, unknown, activity.[4]

Observed activity[edit | edit source]

The binding of CTCF has been shown to have many effects, which are enumerated below. In each case, it is unknown if CTCF directly evokes the outcome or if it does so indirectly (in particular through its looping role).

Transcriptional regulation[edit | edit source]

The protein CTCF plays a heavy role in repressing the insulin-like growth factor 2 gene, by binding to the H-19 imprinting control region (ICR) along with differentially-methylated region-1 (DMR1) and MAR3.[7][8]

Insulation[edit | edit source]

Binding of targeting sequence elements by CTCF can block the interaction between enhancers and promoters, therefore limiting the activity of enhancers to certain functional domains. Besides acting as enhancer blocking, CTCF can also act as a chromatin barrier[9] by preventing the spread of heterochromatin structures.

Regulation of chromatin architecture[edit | edit source]

CTCF physically binds to itself to form homodimers,[10] which causes the bound DNA to form loops.[11] CTCF also occurs frequently at the boundaries of sections of DNA bound to the nuclear lamina.[6] Using chromatin immuno-precipitation (ChIP) followed by ChIP-seq, it was found that CTCF localizes with cohesin genome-wide and affects gene regulatory mechanisms and the higher-order chromatin structure.[12]

Regulation of RNA splicing[edit | edit source]

CTCF binding has been shown to influence mRNA splicing.[13]

DNA binding[edit | edit source]

CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation).[14] This sequence is defined by 11 zinc finger motifs in its structure. CTCF's binding is disrupted by CpG methylation of the DNA it binds to.[15]

CTCF binds to an average of about 55,000 DNA sites in 19 diverse cell types (12 normal and 7 immortal) and in total 77,811 distinct binding sites across all 19 cell types.[16] CTCF’s ability to bind to multiple sequences through the usage of various combinations of its zinc fingers earned it the status of a “multivalent protein”.[1] More than 30,000 CTCF binding sites have been characterized.[17] The human genome contains anywhere between 15,000-40,000 CTCF binding sites depending on cell type, suggesting a widespread role for CTCF in gene regulation.[9][14][18] In addition CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified.[9][19] On the other hand, high-resolution nucleosome mapping studies have demonstrated that the differences of CTCF binding between cell types may be attributed to the differences in nucleosome locations.[20]

Protein-protein interactions[edit | edit source]

CTCF binds to itself to form homodimers.[10] This activity is one possibility of the mechanism of its looping activity.

CTCF has also been shown to interact with Y box binding protein 1.[21] CTCF also co-localizes with cohesin, which stabilizes the repressive loops organized by the CTCF.[22]

References[edit | edit source]

  1. ↑ 1.0 1.1 Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV (June 1996). "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. 16 (6): 2802–13. PMC 231272. PMID 8649389.
  2. ↑ Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A (June 2008). "CTCF physically links cohesin to chromatin". Proc. Natl. Acad. Sci. U.S.A. 105 (24): 8309–14. doi:10.1073/pnas.0801273105. PMC 2448833. PMID 18550811.
  3. ↑ Chaumeil J, Skok JA (April 2012). "The role of CTCF in regulating V(D)J recombination". Curr. Opin. Immunol. 24 (2): 153–9. doi:10.1016/j.coi.2012.01.003. PMC 3444155. PMID 22424610.
  4. ↑ 4.0 4.1 4.2 Phillips JE, Corces VG (June 2009). "CTCF: master weaver of the genome". Cell. 137 (7): 1194–211. doi:10.1016/j.cell.2009.06.001. PMC 3040116. PMID 19563753.
  5. ↑ Lobanenkov VV, Nicolas RH, Adler VV, Paterson H, Klenova EM, Polotskaja AV, Goodwin GH (December 1990). "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. 5 (12): 1743–53. PMID 2284094.
  6. ↑ 6.0 6.1 Guelen L, Pagie L, Brasset E, Meuleman W, Faza MB, Talhout W, Eussen BH, de Klein A, Wessels L, de Laat W, van Steensel B (June 2008). "Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions". Nature. 453 (7197): 948–51. doi:10.1038/nature06947. PMID 18463634.
  7. ↑ Ohlsson R, Renkawitz R, Lobanenkov V (2001). "CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease". Trends Genet. 17 (9): 520–7. doi:10.1016/S0168-9525(01)02366-6. PMID 11525835.
  8. ↑ Dunn KL, Davie JR (2003). "The many roles of the transcriptional regulator CTCF". Biochem. Cell Biol. 81 (3): 161–7. doi:10.1139/o03-052. PMID 12897849.
  9. ↑ 9.0 9.1 9.2 Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K (2009). "Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains". Genome Res. 19 (1): 24–32. doi:10.1101/gr.082800.108. PMC 2612964. PMID 19056695.
  10. ↑ 10.0 10.1 Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G (January 2004). "CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species". Mol. Cell. 13 (2): 291–8. doi:10.1016/S1097-2765(04)00029-2. PMID 14759373.
  11. ↑ Hou C, Zhao H, Tanimoto K, Dean A (December 2008). "CTCF-dependent enhancer-blocking by alternative chromatin loop formation". Proc. Natl. Acad. Sci. U.S.A. 105 (51): 20398–403. doi:10.1073/pnas.0808506106. PMC 2629272. PMID 19074263.
  12. ↑ Lee BK, Iyer VR (September 2012). "Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation". J. Biol. Chem. 287 (37): 30906–13. doi:10.1074/jbc.R111.324962. PMC 3438923. PMID 22952237.
  13. ↑ Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S (November 2011). "CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing". Nature. 479 (7371): 74–9. doi:10.1038/nature10442. PMID 21964334.
  14. ↑ 14.0 14.1 Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B (March 2007). "Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome". Cell. 128 (6): 1231–45. doi:10.1016/j.cell.2006.12.048. PMC 2572726. PMID 17382889.
  15. ↑ Bell AC, Felsenfeld G (May 2000). "Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene". Nature. 405 (6785): 482–5. doi:10.1038/35013100. PMID 10839546.
  16. ↑ Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, Thurman RE, Kaul R, Myers RM, Stamatoyannopoulos JA (September 2012). "Widespread plasticity in CTCF occupancy linked to DNA methylation". Genome Res. 22 (9): 1680–8. doi:10.1101/gr.136101.111. PMC 3431485. PMID 22955980.
  17. ↑ Bao L, Zhou M, Cui Y (January 2008). "CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators". Nucleic Acids Res. 36 (Database issue): D83–7. doi:10.1093/nar/gkm875. PMC 2238977. PMID 17981843.
  18. ↑ Xie X, Mikkelsen TS, Gnirke A, Lindblad-Toh K, Kellis M, Lander ES (2007). "Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites". Proc. Natl. Acad. Sci. U.S.A. 104 (17): 7145–50. doi:10.1073/pnas.0701811104. PMC 1852749. PMID 17442748.
  19. ↑ Fu Y, Sinha M, Peterson CL, Weng Z (2008). "The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome". PLOS Genetics. 4 (7): e1000138. doi:10.1371/journal.pgen.1000138. PMC 2453330. PMID 18654629.
  20. ↑ Teif VB, Vainshtein Y, Caudron-Herger M, Mallm JP, Marth C, Höfer T, Rippe K (2012). "Genome-wide nucleosome positioning during embryonic stem cell development". Nat Struct Mol Biol. 19 (11): 1185–92. doi:10.1038/nsmb.2419. PMID 23085715.
  21. ↑ Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM (September 2000). "Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF". J. Biol. Chem. 275 (38): 29915–21. doi:10.1074/jbc.M001538200. PMID 10906122.
  22. ↑ Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA (September 2010). "Mediator and cohesin connect gene expression and chromatin architecture". Nature. 467 (7314): 430–5. doi:10.1038/nature09380. PMC 2953795. PMID 20720539.

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