CTCF
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| Location (UCSC) | Chr 16: 67.56 – 67.64 Mb | Chr 8: 105.64 – 105.68 Mb | |||||||
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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.[5][6] CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination[7] and regulation of chromatin architecture.[8]
Discovery
CCCTC-Binding factor or CTCF was initially discovered as a negative regulator of the chicken
Function
The primary role of CTCF is thought to be in regulating the 3D structure of chromatin.[8] CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the nuclear lamina.[10] 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
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
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[14] by preventing the spread of heterochromatin structures.
Regulation of chromatin architecture
CTCF physically binds to itself to form homodimers,[15]
which causes the bound DNA to form loops.
Regulation of RNA splicing
CTCF binding has been shown to influence mRNA splicing.[21]
DNA binding
CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation).[22][23] 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.[24] On the other hand, CTCF binding may set boundaries for the spreading of DNA methylation.[25] In recent studies, CTCF binding loss is reported to increase localized CpG methylation, which reflected another epigenetic remodeling role of CTCF in human genome.[26][27][28]
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.[29] 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”.[5] More than 30,000 CTCF binding sites have been characterized.[30] 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.[14][22][31] 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.[14][32] 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.[33] Methylation loss at CTCF-binding site of some genes has been found to be related to human diseases, including male infertility.[23]
Protein-protein interactions
CTCF binds to itself to form
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000102974 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005698 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 8649389.
- PMID 18550811.
- PMID 22424610.
- ^ PMID 19563753.
- PMID 2284094.
- ^ S2CID 4429401.
- PMID 31164150.
- PMID 11525835.
- PMID 12897849.
- ^ PMID 19056695.
- ^ PMID 14759373.
- PMID 19074263.
- PMID 24185899.
- PMID 22952237.
- PMID 25497547.
- PMID 25732821.
- PMID 21964334.
- ^ PMID 17382889.
- ^ PMID 23975186.
- S2CID 4387329.
- PMID 30948436.
- PMID 34849858.
- PMID 32503656.
- PMID 24794443.
- PMID 22955980.
- PMID 17981843.
- PMID 17442748.
- PMID 18654629.
- S2CID 34509771.
- PMID 10906122.
- PMID 20720539.
- PMID 31665434.
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. 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. PMID 12191639.
- Kuhn EJ, Geyer PK (2004). "Genomic insulators: connecting properties to mechanism". Curr. Opin. Cell Biol. 15 (3): 259–65. 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. 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. 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. S2CID 34221526.
- 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. S2CID 18266832.
- 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. 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. 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. S2CID 4387329.
- 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. S2CID 4421547.
- 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. 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. S2CID 27442721.
- Dintilhac A, Bernués J (2002). "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences" (PDF). J. Biol. Chem. 277 (9): 7021–8. S2CID 39560486.
- 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, 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. 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. PMID 11997516.
External links
- CCCTC-binding+factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook CTCF
- Human CTCF genome location and CTCF gene details page in the UCSC Genome Browser.
- https://www.ctcfemory.com/ A Group for families affected by CTCF mutations
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