Biology:CTCF

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Short description: Transcription factor


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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] In a recent study, it has been shown that, in addition to demarcating TADs, CTCF mediates promoter–enhancer loops, often located in promoter-proximal regions, to facilitate the promoter–enhancer interactions within one TAD.[7] This is in line with the concept that a subpopulation of CTCF associates with the RNA polymerase II (Pol II) protein complex to activate transcription. It is likely that CTCF helps to bridge the transcription factor-bound enhancers to transcription start site-proximal regulatory elements and to initiate transcription by interacting with Pol II, thus supporting a role of CTCF in facilitating contacts between transcription regulatory sequences. This model has been demonstrated by the previous work on the beta-globin locus.

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.[8][9]

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[10] by preventing the spread of heterochromatin structures.

Regulation of chromatin architecture

CTCF physically binds to itself to form homodimers,[11] which causes the bound DNA to form loops.[12] 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.[13][14] It is currently believed that the DNA loops are formed by the "loop extrusion" mechanism, whereby the cohesin ring is actively being translocated along the DNA until it meets CTCF. CTCF has to be in a proper orientation to stop cohesin.[15][16]

Regulation of RNA splicing

CTCF binding has been shown to influence mRNA splicing.[17]

DNA binding

CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation).[18][19] 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.[20] On the other hand, CTCF binding may set boundaries for the spreading of DNA methylation.[21] In recent studies, CTCF binding loss is reported to increase localized CpG methylation, which reflected another epigenetic remodeling role of CTCF in human genome.[22][23][24]

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.[25] 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.[26] The human genome contains anywhere between 15,000 and 40,000 CTCF binding sites depending on cell type, suggesting a widespread role for CTCF in gene regulation.[10][18][27] 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.[10][28] 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.[29] Methylation loss at CTCF-binding site of some genes has been found to be related to human diseases, including male infertility.[19]

Protein-protein interactions

CTCF binds to itself to form homodimers.[11] CTCF has also been shown to interact with Y box binding protein 1.[30] CTCF also co-localizes with cohesin, which extrudes chromatin loops by actively translocating one or two DNA strands through its ring-shaped structure, until it meets CTCF in a proper orientation.[31] CTCF is also known to interact with chromatin remodellers such as Chd4 and Snf2h (SMARCA5).[32]

References

  1. ↑ 1.0 1.1 "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. June 1996. doi:10.1128/mcb.16.6.2802. PMID 8649389. 
  2. ↑ "CTCF physically links cohesin to chromatin". Proc. Natl. Acad. Sci. U.S.A. 105 (24): 8309–14. June 2008. doi:10.1073/pnas.0801273105. PMID 18550811. Bibcode: 2008PNAS..105.8309R. 
  3. ↑ "The role of CTCF in regulating V(D)J recombination". Curr. Opin. Immunol. 24 (2): 153–9. April 2012. doi:10.1016/j.coi.2012.01.003. 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. PMID 19563753. 
  5. ↑ "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. December 1990. PMID 2284094. 
  6. ↑ 6.0 6.1 "Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions". Nature 453 (7197): 948–51. June 2008. doi:10.1038/nature06947. PMID 18463634. Bibcode: 2008Natur.453..948G. 
  7. ↑ "p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes". Epigenetics & Chromatin 12 (1): 31. June 2019. doi:10.1186/s13072-019-0280-y. PMID 31164150. 
  8. ↑ "CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease". Trends Genet. 17 (9): 520–7. 2001. doi:10.1016/S0168-9525(01)02366-6. PMID 11525835. 
  9. ↑ "The many roles of the transcriptional regulator CTCF". Biochem. Cell Biol. 81 (3): 161–7. 2003. doi:10.1139/o03-052. PMID 12897849. 
  10. ↑ 10.0 10.1 10.2 "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. 2009. doi:10.1101/gr.082800.108. PMID 19056695. 
  11. ↑ 11.0 11.1 "CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species". Mol. Cell 13 (2): 291–8. January 2004. doi:10.1016/S1097-2765(04)00029-2. PMID 14759373. 
  12. ↑ "CTCF-dependent enhancer-blocking by alternative chromatin loop formation". Proc. Natl. Acad. Sci. U.S.A. 105 (51): 20398–403. December 2008. doi:10.1073/pnas.0808506106. PMID 19074263. Bibcode: 2008PNAS..10520398H. 
  13. ↑ "Cohesin-mediated interactions organize chromosomal domain architecture". The EMBO Journal 32 (24): 3119–3129. December 2013. doi:10.1038/emboj.2013.237. PMID 24185899. 
  14. ↑ "Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation". J. Biol. Chem. 287 (37): 30906–13. September 2012. doi:10.1074/jbc.R111.324962. PMID 22952237. 
  15. ↑ "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping". Cell 159 (7): 1665–1680. December 2014. doi:10.1016/j.cell.2014.11.021. PMID 25497547. 
  16. ↑ "Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture". Cell Reports 10 (8): 1297–1309. March 2015. doi:10.1016/j.celrep.2015.02.004. PMID 25732821. 
  17. ↑ "CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing". Nature 479 (7371): 74–9. November 2011. doi:10.1038/nature10442. PMID 21964334. PMC 7398428. Bibcode: 2011Natur.479...74S. https://zenodo.org/record/1233317. 
  18. ↑ 18.0 18.1 "Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome". Cell 128 (6): 1231–45. March 2007. doi:10.1016/j.cell.2006.12.048. PMID 17382889. 
  19. ↑ 19.0 19.1 "Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males". Epigenetics 8 (9): 990–7. September 2013. doi:10.4161/epi.25798. PMID 23975186. 
  20. ↑ "Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene". Nature 405 (6785): 482–5. May 2000. doi:10.1038/35013100. PMID 10839546. Bibcode: 2000Natur.405..482B. 
  21. ↑ "DNA de-methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries". Genome Research 29 (5): 750–61. May 2019. doi:10.1101/gr.239707.118. PMID 30948436. 
  22. ↑ "Novel role of prostate cancer risk variant rs7247241 on PPP1R14A isoform transition through allelic TF binding and CpG methylation". Human Molecular Genetics 31 (10): 1610–1621. May 2022. doi:10.1093/hmg/ddab347. PMID 34849858. 
  23. ↑ "CTCF loss mediates unique DNA hypermethylation landscapes in human cancers". Clinical Epigenetics 12 (1): 80. June 2020. doi:10.1186/s13148-020-00869-7. PMID 32503656. 
  24. ↑ "CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer". Cell Reports 7 (4): 1020–1029. May 2014. doi:10.1016/j.celrep.2014.04.004. PMID 24794443. 
  25. ↑ "Widespread plasticity in CTCF occupancy linked to DNA methylation". Genome Res. 22 (9): 1680–8. September 2012. doi:10.1101/gr.136101.111. PMID 22955980. 
  26. ↑ "CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators". Nucleic Acids Res. 36 (Database issue): D83–7. January 2008. doi:10.1093/nar/gkm875. PMID 17981843. 
  27. ↑ "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. 2007. doi:10.1073/pnas.0701811104. PMID 17442748. Bibcode: 2007PNAS..104.7145X. 
  28. ↑ "The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome". PLOS Genetics 4 (7): e1000138. 2008. doi:10.1371/journal.pgen.1000138. PMID 18654629. 
  29. ↑ "Genome-wide nucleosome positioning during embryonic stem cell development". Nat Struct Mol Biol 19 (11): 1185–92. 2012. doi:10.1038/nsmb.2419. PMID 23085715. 
  30. ↑ "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. September 2000. doi:10.1074/jbc.M001538200. PMID 10906122. 
  31. ↑ Kagey MH; Newman JJ; Bilodeau S; Zhan Y; Orlando DA; van Berkum NL; Ebmeier CC; Goossens J et al. (September 2010). "Mediator and cohesin connect gene expression and chromatin architecture". Nature 467 (7314): 430–5. doi:10.1038/nature09380. PMID 20720539. Bibcode: 2010Natur.467..430K. 
  32. ↑ "CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length". Nucleic Acids Research 47 (21): 11181–11196. September 2019. doi:10.1093/nar/gkz908. PMID 31665434. 

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