CTCF

CCCTC-binding factor (zinc finger protein)
PDB rendering based on 1x6h.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1X6H​, 2CT1​
Identifiers
Symbols	CTCF ; MRD21
External IDs	OMIM: 604167 MGI: 109447 HomoloGene: 4786 GeneCards: CTCF Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • transcription factor activity, sequence-specific DNA binding • transcription corepressor activity • protein binding • zinc ion binding • chromatin insulator sequence binding • sequence-specific DNA binding • transcription regulatory region DNA binding Cellular component • chromosome, centromeric region • condensed chromosome • nucleus • nucleoplasm • nucleolus Biological process • negative regulation of transcription from RNA polymerase II promoter • DNA methylation • regulation of gene expression by genetic imprinting • transcription from RNA polymerase II promoter • chromosome segregation • maintenance of DNA methylation • positive regulation of gene expression • chromatin modification • nucleosome positioning • regulation of histone methylation • regulation of histone acetylation • regulation of gene expression, epigenetic • regulation of molecular function, epigenetic • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • regulation of centromeric sister chromatid cohesion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10664	13018
Ensembl	ENSG00000102974	ENSMUSG00000005698
UniProt	P49711	Q61164
RefSeq (mRNA)	NM_001191022	NM_181322
RefSeq (protein)	NP_001177951	NP_851839
Location (UCSC)	Chr 16: 67.56 – 67.64 Mb	Chr 8: 105.64 – 105.68 Mb
PubMed search

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

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

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

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

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

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

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

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

DNA binding

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

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

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. PMID 22424610.
4. 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. 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. 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. 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. 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. 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.

Further reading

• 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.
• Klenova EM, Morse HC, Ohlsson R, Lobanenkov VV (2003). "The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer". Semin. Cancer Biol. 12 (5): 399–414. doi:10.1016/S1044-579X(02)00060-3. PMID 12191639.
• Kuhn EJ, Geyer PK (2004). "Genomic insulators: connecting properties to mechanism". Curr. Opin. Cell Biol. 15 (3): 259–65. doi:10.1016/S0955-0674(03)00039-5. PMID 12787766.
• Recillas-Targa F, De La Rosa-Velázquez IA, Soto-Reyes E, Benítez-Bribiesca L (2007). "Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis". J. Cell. Mol. Med. 10 (3): 554–68. doi:10.1111/j.1582-4934.2006.tb00420.x. PMID 16989720.
• Vostrov AA, Quitschke WW (1998). "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. 272 (52): 33353–9. doi:10.1074/jbc.272.52.33353. PMID 9407128.
• Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV (1998). "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 22 (1): 26–36. doi:10.1002/(SICI)1098-2264(199805)22:1<26::AID-GCC4>3.0.CO;2-9. PMID 9591631.
• Bell AC, West AG, Felsenfeld G (1999). "The protein CTCF is required for the enhancer blocking activity of vertebrate insulators". Cell 98 (3): 387–96. doi:10.1016/S0092-8674(00)81967-4. PMID 10458613.
• Pérez-Juste G, García-Silva S, Aranda A (2000). "An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells". J. Biol. Chem. 275 (2): 1307–14. doi:10.1074/jbc.275.2.1307. PMID 10625678.
• Lutz M, Burke LJ, Barreto G, Goeman F, Greb H, Arnold R, Schultheiss H, Brehm A, Kouzarides T, Lobanenkov V, Renkawitz R (2000). "Transcriptional repression by the insulator protein CTCF involves histone deacetylases". Nucleic Acids Res. 28 (8): 1707–13. doi:10.1093/nar/28.8.1707. PMC 102824. PMID 10734189.
• Bell AC, Felsenfeld G (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.
• Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM (2000). "CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus". Nature 405 (6785): 486–9. doi:10.1038/35013106. PMID 10839547.
• Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM (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.
• Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT (2002). "CTCF, a candidate trans-acting factor for X-inactivation choice". Science 295 (5553): 345–7. doi:10.1126/science.1065982. PMID 11743158.
• Dintilhac A, Bernués J (2002). "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences". J. Biol. Chem. 277 (9): 7021–8. doi:10.1074/jbc.M108417200. PMID 11748221.
• Filippova GN, Qi CF, Ulmer JE, Moore JM, Ward MD, Hu YJ, Loukinov DI, Pugacheva EM, Klenova EM, Grundy PE, Feinberg AP, Cleton-Jansen AM, Moerland EW, Cornelisse CJ, Suzuki H, Komiya A, Lindblom A, Dorion-Bonnet F, Neiman PE, Morse HC 3rd, Collins SJ, Lobanenkov VV (2002). "Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity". Cancer Res. 62 (1): 48–52. PMID 11782357.
• Kanduri M, Kanduri C, Mariano P, Vostrov AA, Quitschke W, Lobanenkov V, Ohlsson R (2002). "Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region". Mol. Cell. Biol. 22 (10): 3339–44. doi:10.1128/MCB.22.10.3339-3344.2002. PMC 133793. PMID 11971967.
• Farrell CM, West AG, Felsenfeld G (2002). "Conserved CTCF insulator elements flank the mouse and human beta-globin loci". Mol. Cell. Biol. 22 (11): 3820–31. doi:10.1128/MCB.22.11.3820-3831.2002. PMC 133827. PMID 11997516.

External links

• CCCTC-binding factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook CTCF