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{{Short description|Transcription factor}}
{{for|the prison|Colorado Territorial Correctional Facility}}
{{for|the prison|Colorado Territorial Correctional Facility}}
{{Infobox_gene}}
{{PBB|geneid=10664}}
'''Transcriptional repressor CTCF''' also known as '''James 2 pints Smith''' or '''CCCTC-binding factor''' is a [[transcription factor]] that in humans is encoded by the ''CTCF'' [[gene]].<ref name="pmid8649389">{{cite journal | author = Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV | title = An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes | journal = Mol. Cell. Biol. | volume = 16 | issue = 6 | pages = 2802–13 |date=June 1996 | pmid = 8649389 | pmc = 231272 | doi = | url = | issn = }}</ref><ref name="pmid18550811">{{cite journal | author = Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A | title = CTCF physically links cohesin to chromatin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 24 | pages = 8309–14 |date=June 2008 | pmid = 18550811 | pmc = 2448833 | doi = 10.1073/pnas.0801273105 | url = | issn = }}</ref> CTCF is involved in many cellular processes, including [[Regulation of gene expression|transcriptional regulation]], [[Insulator (genetics)|insulator]] activity, [[V(D)J recombination]]<ref name="pmid22424610">{{cite journal | author = Chaumeil J, Skok JA | title = The role of CTCF in regulating V(D)J recombination | journal = Curr. Opin. Immunol. | volume = 24 | issue = 2 | pages = 153–9 |date=April 2012 | pmid = 22424610 | doi = 10.1016/j.coi.2012.01.003 }}</ref> and regulation of [[chromatin]] architecture.<ref name="Phillips_Corces_2009">{{cite journal | author = Phillips JE, Corces VG | title = CTCF: master weaver of the genome | journal = Cell | volume = 137 | issue = 7 | pages = 1194–211 |date=June 2009 | pmid = 19563753 | pmc = 3040116 | doi = 10.1016/j.cell.2009.06.001 }}</ref>
'''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]].<ref name="pmid8649389">{{cite journal | vauthors = Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV | title = An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes | journal = Mol. Cell. Biol. | volume = 16 | issue = 6 | pages = 2802–13 |date=June 1996 | pmid = 8649389 | pmc = 231272 | doi = 10.1128/mcb.16.6.2802}}</ref><ref name="pmid18550811">{{cite journal | vauthors = Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A | title = CTCF physically links cohesin to chromatin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 24 | pages = 8309–14 |date=June 2008 | pmid = 18550811 | pmc = 2448833 | doi = 10.1073/pnas.0801273105 | bibcode = 2008PNAS..105.8309R | doi-access = free }}</ref> CTCF is involved in many cellular processes, including [[Regulation of gene expression|transcriptional regulation]], [[Insulator (genetics)|insulator]] activity, [[V(D)J recombination]]<ref name="pmid22424610">{{cite journal | vauthors = Chaumeil J, Skok JA | title = The role of CTCF in regulating V(D)J recombination | journal = Curr. Opin. Immunol. | volume = 24 | issue = 2 | pages = 153–9 |date=April 2012 | pmid = 22424610 | doi = 10.1016/j.coi.2012.01.003 | pmc=3444155}}</ref> and regulation of [[chromatin]] architecture.<ref name="Phillips_Corces_2009">{{cite journal | author1 = Phillips JE| author2 =Corces VG | author-link2 =Victor Corces| title = CTCF: master weaver of the genome | journal = Cell | volume = 137 | issue = 7 | pages = 1194–211 |date=June 2009 | pmid = 19563753 | pmc = 3040116 | doi = 10.1016/j.cell.2009.06.001 }}</ref>


== Discovery ==
== 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.<ref name="pmid2284094">{{cite journal | author = Lobanenkov VV, Nicolas RH, Adler VV, Paterson H, Klenova EM, Polotskaja AV, Goodwin GH | title = 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 | journal = Oncogene | volume = 5 | issue = 12 | pages = 1743–53 |date=December 1990 | pmid = 2284094 | doi = }}</ref>
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.<ref name="pmid2284094">{{cite journal | vauthors = Lobanenkov VV, Nicolas RH, Adler VV, Paterson H, Klenova EM, Polotskaja AV, Goodwin GH | title = 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 | journal = Oncogene | volume = 5 | issue = 12 | pages = 1743–53 |date=December 1990 | pmid = 2284094 }}</ref>


== Function ==
== Function ==
The primary role of CTCF is thought to be in regulating the 3D structure of chromatin.<ref name="Phillips_Corces_2009"/> CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the [[nuclear lamina]].<ref name="Guelen_2008">{{cite journal | author = 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 | title = Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions | journal = Nature | volume = 453 | issue = 7197 | pages = 948–51 |date=June 2008 | pmid = 18463634 | doi = 10.1038/nature06947 }}</ref> It also defines the boundaries between active and heterochromatic DNA.
The primary role of CTCF is thought to be in regulating the 3D structure of chromatin.<ref name="Phillips_Corces_2009"/> CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the [[nuclear lamina]].<ref name="Guelen_2008">{{cite journal | vauthors = 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 | title = Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions | journal = Nature | volume = 453 | issue = 7197 | pages = 948–51 |date=June 2008 | pmid = 18463634 | doi = 10.1038/nature06947 | bibcode = 2008Natur.453..948G | s2cid = 4429401 }}</ref> 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 [[Insulator (genetics)|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.<ref name="Phillips_Corces_2009"/>
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 [[Insulator (genetics)|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.<ref name="Phillips_Corces_2009"/> In a recent study, it has been shown that, in addition to demarcating [[Topologically associating domain|TAD]]s, CTCF mediates promoter–enhancer loops, often located in promoter-proximal regions, to facilitate the promoter–enhancer interactions within one TAD.<ref name="PMID31164150">{{cite journal | vauthors = Qu J, Yi G, Zhou H | title = p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes | journal = Epigenetics & Chromatin | date = June 2019 | volume = 12 | issue = 1 | page = 31 | pmid= 31164150 | doi = 10.1186/s13072-019-0280-y | pmc = 6547520 | doi-access = free }}</ref> 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 ==
== Observed activity ==
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=== Transcriptional regulation ===
=== Transcriptional regulation ===
The protein CTCF plays a heavy role in repressing the [[insulin-like growth factor 2]] gene, by binding to the [[H19 (gene)|H-19]] imprinting control region (ICR) along with differentially-methylated region-1 ([[KCNQ1OT1|DMR1]]) and [[ZCCHC5|MAR3]].<ref name="pmid11525835">{{cite journal | author = Ohlsson R, Renkawitz R, Lobanenkov V | title = CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease | journal = Trends Genet. | volume = 17 | issue = 9 | pages = 520–7 | year = 2001 | pmid = 11525835 | doi = 10.1016/S0168-9525(01)02366-6 }}</ref><ref name="pmid12897849">{{cite journal | author = Dunn KL, Davie JR | title = The many roles of the transcriptional regulator CTCF | journal = Biochem. Cell Biol. | volume = 81 | issue = 3 | pages = 161–7 | year = 2003 | pmid = 12897849 | doi = 10.1139/o03-052 }}</ref>
The protein CTCF plays a heavy role in repressing the [[insulin-like growth factor 2]] gene, by binding to the [[H19 (gene)|H-19]] imprinting control region (ICR) along with differentially-methylated region-1 ([[KCNQ1OT1|DMR1]]) and [[ZCCHC5|MAR3]].<ref name="pmid11525835">{{cite journal | vauthors = Ohlsson R, Renkawitz R, Lobanenkov V | title = CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease | journal = Trends Genet. | volume = 17 | issue = 9 | pages = 520–7 | year = 2001 | pmid = 11525835 | doi = 10.1016/S0168-9525(01)02366-6 }}</ref><ref name="pmid12897849">{{cite journal | vauthors = Dunn KL, Davie JR | title = The many roles of the transcriptional regulator CTCF | journal = Biochem. Cell Biol. | volume = 81 | issue = 3 | pages = 161–7 | year = 2003 | pmid = 12897849 | doi = 10.1139/o03-052 }}</ref>


===Insulation===
===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<ref name="pmid19056695">{{cite journal | author = Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K | title = Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains | journal = Genome Res. | volume = 19 | issue = 1 | pages = 24–32 | year = 2009 | pmid = 19056695 | doi = 10.1101/gr.082800.108 | pmc = 2612964 }}</ref> by preventing the spread of heterochromatin structures.
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<ref name="pmid19056695">{{cite journal | vauthors = Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K | title = Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains | journal = Genome Res. | volume = 19 | issue = 1 | pages = 24–32 | year = 2009 | pmid = 19056695 | doi = 10.1101/gr.082800.108 | pmc = 2612964 }}</ref> by preventing the spread of [[heterochromatin]] structures.


===Regulation of chromatin architecture===
===Regulation of chromatin architecture===
CTCF physically binds to itself to form homodimers,<ref name="Yusufzai_2004">{{cite journal | author = Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G | title = CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species | journal = Mol. Cell | volume = 13 | issue = 2 | pages = 291–8 |date=January 2004 | pmid = 14759373 | doi = 10.1016/S1097-2765(04)00029-2 }}</ref>
CTCF physically binds to itself to form homodimers,<ref name="Yusufzai_2004">{{cite journal | vauthors = Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G | title = CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species | journal = Mol. Cell | volume = 13 | issue = 2 | pages = 291–8 |date=January 2004 | pmid = 14759373 | doi = 10.1016/S1097-2765(04)00029-2 | doi-access = free }}</ref>
which causes the bound DNA to form loops.<ref name="pmid19074263">{{cite journal | author = Hou C, Zhao H, Tanimoto K, Dean A | title = CTCF-dependent enhancer-blocking by alternative chromatin loop formation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 51 | pages = 20398–403 |date=December 2008 | pmid = 19074263 | pmc = 2629272 | doi = 10.1073/pnas.0808506106 }}</ref> CTCF also occurs frequently at the boundaries of sections of DNA bound to the [[nuclear lamina]].<ref name="Guelen_2008"/> Using [[Chromatin immunoprecipitation|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.<ref name="pmid22952237">{{cite journal | author = Lee BK, Iyer VR | title = Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation | journal = J. Biol. Chem. | volume = 287 | issue = 37 | pages = 30906–13 |date=September 2012 | pmid = 22952237 | doi = 10.1074/jbc.R111.324962 }}</ref>
which causes the bound DNA to form loops.<ref name="pmid19074263">{{cite journal | vauthors = Hou C, Zhao H, Tanimoto K, Dean A | title = CTCF-dependent enhancer-blocking by alternative chromatin loop formation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 51 | pages = 20398–403 |date=December 2008 | pmid = 19074263 | pmc = 2629272 | doi = 10.1073/pnas.0808506106 | bibcode = 2008PNAS..10520398H | doi-access = free }}</ref> CTCF also occurs frequently at the boundaries of sections of DNA bound to the [[nuclear lamina]].<ref name="Guelen_2008"/> Using [[Chromatin immunoprecipitation|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.<ref>{{cite journal | vauthors = Sofueva S, Yaffe E, Chan WC, Georgopoulou D, Vietri Rudan M, Mira-Bontenbal H, Pollard SM, Schroth GP, Tanay A, Hadjur S | display-authors = 6 | title = Cohesin-mediated interactions organize chromosomal domain architecture | journal = The EMBO Journal | volume = 32 | issue = 24 | pages = 3119–3129 | date = December 2013 | pmid = 24185899 | pmc = 4489921 | doi = 10.1038/emboj.2013.237 }}</ref><ref name="pmid22952237">{{cite journal | vauthors = Lee BK, Iyer VR | title = Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation | journal = J. Biol. Chem. | volume = 287 | issue = 37 | pages = 30906–13 |date=September 2012 | pmid = 22952237 | doi = 10.1074/jbc.R111.324962 | pmc=3438923| doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, Sanborn AL, Machol I, Omer AD, Lander ES, Aiden EL | display-authors = 6 | title = A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping | journal = Cell | volume = 159 | issue = 7 | pages = 1665–1680 | date = December 2014 | pmid = 25497547 | pmc = 5635824 | doi = 10.1016/j.cell.2014.11.021 }}</ref><ref>{{cite journal | vauthors = Vietri Rudan M, Barrington C, Henderson S, Ernst C, Odom DT, Tanay A, Hadjur S | title = Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture | journal = Cell Reports | volume = 10 | issue = 8 | pages = 1297–1309 | date = March 2015 | pmid = 25732821 | pmc = 4542312 | doi = 10.1016/j.celrep.2015.02.004 }}</ref>


===Regulation of RNA splicing===
===Regulation of RNA splicing===
CTCF binding has been shown to influence mRNA splicing.<ref name="pmid21964334">{{cite journal | author = Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S | title = CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing | journal = Nature | volume = 479 | issue = 7371 | pages = 74–9 |date=November 2011 | pmid = 21964334 | doi = 10.1038/nature10442 }}</ref>
CTCF binding has been shown to influence mRNA splicing.<ref name="pmid21964334">{{cite journal | vauthors = Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S | title = CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing | journal = Nature | volume = 479 | issue = 7371 | pages = 74–9 |date=November 2011 | pmid = 21964334 | doi = 10.1038/nature10442 | pmc = 7398428 | bibcode = 2011Natur.479...74S | url = https://zenodo.org/record/1233317 }}</ref>


==DNA binding==
==DNA binding==
CTCF binds to the [[consensus sequence]] CCGCGNGGNGGCAG (in [[Nucleic acid notation|IUPAC notation]]).<ref name="pmid17382889">{{cite journal | author = Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B | title = Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome | journal = Cell | volume = 128 | issue = 6 | pages = 1231–45 |date=March 2007 | pmid = 17382889 | pmc = 2572726 | doi = 10.1016/j.cell.2006.12.048 }}</ref> This sequence is defined by 11 [[zinc finger]] motifs in its structure. CTCF's binding is disrupted by [[DNA methylation|CpG methylation]] of the DNA it binds to.<ref name="pmid10839546">{{cite journal | author = Bell AC, Felsenfeld G | title = Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene | journal = Nature | volume = 405 | issue = 6785 | pages = 482–5 |date=May 2000 | pmid = 10839546 | doi = 10.1038/35013100 }}</ref>
CTCF binds to the [[consensus sequence]] CCGCGNGGNGGCAG (in [[Nucleic acid notation|IUPAC notation]]).<ref name="pmid17382889">{{cite journal | vauthors = Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B | title = Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome | journal = Cell | volume = 128 | issue = 6 | pages = 1231–45 |date=March 2007 | pmid = 17382889 | pmc = 2572726 | doi = 10.1016/j.cell.2006.12.048 }}</ref><ref name = "Rotondo_2013">{{cite journal | vauthors = Rotondo JC, Selvatici R, Di Domenico M, Marci R, Vesce F, Tognon M, Martini F | title = Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males | journal = Epigenetics | volume = 8 | issue = 9 | pages = 990–7 | date = September 2013 | pmid = 23975186 | pmc = 3883776 | doi = 10.4161/epi.25798 }}</ref> This sequence is defined by 11 [[zinc finger]] motifs in its structure. CTCF's binding is disrupted by [[DNA methylation|CpG methylation]] of the DNA it binds to.<ref name="pmid10839546">{{cite journal | vauthors = Bell AC, Felsenfeld G | title = Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene | journal = Nature | volume = 405 | issue = 6785 | pages = 482–5 |date=May 2000 | pmid = 10839546 | doi = 10.1038/35013100 | bibcode = 2000Natur.405..482B | s2cid = 4387329 }}</ref> On the other hand, CTCF binding may set boundaries for the spreading of DNA methylation.<ref name="Wiehle_2019">{{cite journal | vauthors = Wiehle L, Thorn GJ, Raddatz G, Clarkson CT, Rippe K, Lyko F, Breiling A, Teif VB | title = DNA de-methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries | journal = Genome Research| volume = 29 | issue = 5 | pages = 750–61 | date=May 2019 | pmid = 30948436 | pmc = 6499307| doi = 10.1101/gr.239707.118 }}</ref> In recent studies, CTCF binding loss is reported to increase localized CpG methylation, which reflected another epigenetic remodeling role of CTCF in human genome.<ref>{{cite journal | vauthors = Tian Y, Soupir A, Liu Q, Wu L, Huang CC, Park JY, Wang L | title = Novel role of prostate cancer risk variant rs7247241 on PPP1R14A isoform transition through allelic TF binding and CpG methylation | journal = Human Molecular Genetics | volume = 31 | issue = 10 | pages = 1610–1621 | date = May 2022 | pmid = 34849858 | pmc = 9122641 | doi = 10.1093/hmg/ddab347 }}</ref><ref>{{cite journal | vauthors = Damaschke NA, Gawdzik J, Avilla M, Yang B, Svaren J, Roopra A, Luo JH, Yu YP, Keles S, Jarrard DF | display-authors = 6 | title = CTCF loss mediates unique DNA hypermethylation landscapes in human cancers | journal = Clinical Epigenetics | volume = 12 | issue = 1 | pages = 80 | date = June 2020 | pmid = 32503656 | pmc = 7275597 | doi = 10.1186/s13148-020-00869-7 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kemp CJ, Moore JM, Moser R, Bernard B, Teater M, Smith LE, Rabaia NA, Gurley KE, Guinney J, Busch SE, Shaknovich R, Lobanenkov VV, Liggitt D, Shmulevich I, Melnick A, Filippova GN | display-authors = 6 | title = CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer | journal = Cell Reports | volume = 7 | issue = 4 | pages = 1020–1029 | date = May 2014 | pmid = 24794443 | pmc = 4040130 | doi = 10.1016/j.celrep.2014.04.004 }}</ref>


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.<ref name="pmid22955980">{{cite journal | author = 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 | title = Widespread plasticity in CTCF occupancy linked to DNA methylation | journal = Genome Res. | volume = 22 | issue = 9 | pages = 1680–8 |date=September 2012 | pmid = 22955980 | pmc = 3431485 | doi = 10.1101/gr.136101.111 }}</ref>
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.<ref name="pmid22955980">{{cite journal | vauthors = 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 |author-link14=John Stamatoyannopoulos | title = Widespread plasticity in CTCF occupancy linked to DNA methylation | journal = Genome Res. | volume = 22 | issue = 9 | pages = 1680–8 |date=September 2012 | pmid = 22955980 | pmc = 3431485 | doi = 10.1101/gr.136101.111 }}</ref>
CTCF’s ability to bind to multiple sequences through the usage of various combinations of its [[zinc finger]]s earned it the status of a “multivalent protein”.<ref name="pmid8649389"/> More than 30,000 CTCF binding sites have been characterized.<ref name="pmid17981843">{{cite journal | author = Bao L, Zhou M, Cui Y | title = CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators | journal = Nucleic Acids Res. | volume = 36 | issue = Database issue | pages = D83–7 |date=January 2008 | pmid = 17981843 | pmc = 2238977 | doi = 10.1093/nar/gkm875 | url = }}</ref> 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.<ref name="pmid19056695"/><ref name="pmid17382889" /><ref name="pmid17442748">{{cite journal | author = Xie X, Mikkelsen TS, Gnirke A, Lindblad-Toh K, Kellis M, Lander ES | title = Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 17 | pages = 7145–50 | year = 2007 | pmid = 17442748 | doi = 10.1073/pnas.0701811104 | pmc = 1852749 }}</ref> 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.<ref name="pmid19056695"/><ref name="pmid18654629">{{cite journal | author = Fu Y, Sinha M, Peterson CL, Weng Z | title = The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome | journal = PLOS Genetics | volume = 4 | issue = 7 | pages = e1000138 | year = 2008 | pmid = 18654629 | pmc = 2453330 | doi = 10.1371/journal.pgen.1000138 }}</ref> 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.<ref name = "Teif">{{cite journal |pmid=23085715 | doi=10.1038/nsmb.2419 |author=Teif VB, Vainshtein Y, Caudron-Herger M, Mallm JP, Marth C, Höfer T, Rippe K. |title= Genome-wide nucleosome positioning during embryonic stem cell development |journal=Nat Struct Mol Biol. |year= 2012 | volume=19 |issue=11 |pages=1185–92}}</ref>
CTCF's ability to bind to multiple sequences through the usage of various combinations of its [[zinc finger]]s earned it the status of a “multivalent protein”.<ref name="pmid8649389"/> More than 30,000 CTCF binding sites have been characterized.<ref name="pmid17981843">{{cite journal | vauthors = Bao L, Zhou M, Cui Y | title = CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators | journal = Nucleic Acids Res. | volume = 36 | issue = Database issue | pages = D83–7 |date=January 2008 | pmid = 17981843 | pmc = 2238977 | doi = 10.1093/nar/gkm875 }}</ref> 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.<ref name="pmid19056695"/><ref name="pmid17382889" /><ref name="pmid17442748">{{cite journal | vauthors = Xie X, Mikkelsen TS, Gnirke A, Lindblad-Toh K, Kellis M, Lander ES | title = Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 17 | pages = 7145–50 | year = 2007 | pmid = 17442748 | doi = 10.1073/pnas.0701811104 | pmc = 1852749 | bibcode = 2007PNAS..104.7145X | doi-access = free }}</ref> 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.<ref name="pmid19056695"/><ref name="pmid18654629">{{cite journal | vauthors = Fu Y, Sinha M, Peterson CL, Weng Z | title = The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome | journal = PLOS Genetics | volume = 4 | issue = 7 | pages = e1000138 | year = 2008 | pmid = 18654629 | pmc = 2453330 | doi = 10.1371/journal.pgen.1000138 | doi-access = free }}</ref> 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.<ref name = "Teif">{{cite journal |pmid=23085715 | doi=10.1038/nsmb.2419 |vauthors=Teif VB, Vainshtein Y, Caudron-Herger M, Mallm JP, Marth C, Höfer T, Rippe K |title= Genome-wide nucleosome positioning during embryonic stem cell development |journal=Nat Struct Mol Biol |year= 2012 | volume=19 |issue=11 |pages=1185–92| s2cid=34509771 }}</ref> Methylation loss at CTCF-binding site of some genes has been found to be related to human diseases, including male infertility.<ref name="Rotondo_2013"/>


==Protein-protein interactions==
==Protein-protein interactions==


⚫
CTCF binds to itself to form [[Protein dimer|homodimers]].<ref name="Yusufzai_2004"/> CTCF has also been shown to [[Protein-protein interaction|interact]] with [[Y box binding protein 1]].<ref name="pmid10906122">{{cite journal | vauthors = Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM | title = Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29915–21 |date=September 2000 | pmid = 10906122 | doi = 10.1074/jbc.M001538200 | doi-access = free}}</ref> 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.<ref name="pmid20720539">{{cite journal | author1 = Kagey MH| author2 = Newman JJ| author3 = Bilodeau S| author4 = Zhan Y| author5 = Orlando DA| author6 = van Berkum NL| author7 = Ebmeier CC| author8 = Goossens J| author9 = Rahl PB| author10 = Levine SS| author11 = Taatjes DJ| author12 = Dekker J| author-link12 =Job Dekker| author13 = Young RA | author-link13 =Richard A. Young| title = Mediator and cohesin connect gene expression and chromatin architecture | journal = Nature | volume = 467 | issue = 7314 | pages = 430–5 |date=September 2010 | pmid = 20720539 | doi = 10.1038/nature09380 | pmc = 2953795 | bibcode = 2010Natur.467..430K }}</ref> CTCF is also known to interact with chromatin remodellers such as [[Chd4]] and Snf2h ([[SMARCA5]]).<ref name="CTCF-remodellers">{{cite journal | vauthors = Clarkson CT, Deeks EA, Samarista R, Mamayusupova H, Zhurkin VB, Teif VB | title = CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length | journal = Nucleic Acids Research| volume = 47 | issue = 21 | pages = 11181–11196 | date = September 2019 | pmid = 31665434 | pmc = 6868436 | doi = 10.1093/nar/gkz908 }}</ref>
CTCF binds to itself to form [[Protein dimer|homodimers]].<ref name="Yusufzai_2004"/> This activity is one possibility of the mechanism of its looping activity.

⚫
CTCF has also been shown to [[Protein-protein interaction|interact]] with [[Y box binding protein 1]].<ref name="pmid10906122">{{cite journal | author = Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM | title = Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29915–21 |date=September 2000 | pmid = 10906122 | doi = 10.1074/jbc.M001538200 }}</ref> CTCF also co-localizes with [[cohesin]], which stabilizes the repressive loops organized by the CTCF.<ref name="pmid20720539">{{cite journal | author = 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 | title = Mediator and cohesin connect gene expression and chromatin architecture | journal = Nature | volume = 467 | issue = 7314 | pages = 430–5 |date=September 2010 | pmid = 20720539 | doi = 10.1038/nature09380 | pmc = 2953795 }}</ref>


==References==
==References==
Line 44: Line 43:
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | author=Ohlsson R, Renkawitz R, Lobanenkov V |title=CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease |journal=Trends Genet. |volume=17 |issue= 9 |pages= 520–7 |year= 2001 |pmid= 11525835 |doi=10.1016/S0168-9525(01)02366-6 }}
*{{cite journal | vauthors=Ohlsson R, Renkawitz R, Lobanenkov V |title=CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease |journal=Trends Genet. |volume=17 |issue= 9 |pages= 520–7 |year= 2001 |pmid= 11525835 |doi=10.1016/S0168-9525(01)02366-6 }}
*{{cite journal | author=Klenova EM, Morse HC, Ohlsson R, Lobanenkov VV |title=The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer |journal=Semin. Cancer Biol. |volume=12 |issue= 5 |pages= 399–414 |year= 2003 |pmid= 12191639 |doi=10.1016/S1044-579X(02)00060-3 }}
*{{cite journal | vauthors=Klenova EM, Morse HC, Ohlsson R, Lobanenkov VV |title=The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer |journal=Semin. Cancer Biol. |volume=12 |issue= 5 |pages= 399–414 |year= 2003 |pmid= 12191639 |doi=10.1016/S1044-579X(02)00060-3 }}
*{{cite journal | author=Kuhn EJ, Geyer PK |title=Genomic insulators: connecting properties to mechanism |journal=Curr. Opin. Cell Biol. |volume=15 |issue= 3 |pages= 259–65 |year= 2004 |pmid= 12787766 |doi=10.1016/S0955-0674(03)00039-5 }}
*{{cite journal | vauthors=Kuhn EJ, Geyer PK |title=Genomic insulators: connecting properties to mechanism |journal=Curr. Opin. Cell Biol. |volume=15 |issue= 3 |pages= 259–65 |year= 2004 |pmid= 12787766 |doi=10.1016/S0955-0674(03)00039-5 }}
*{{cite journal | author=Recillas-Targa F, De La Rosa-Velázquez IA, Soto-Reyes E, Benítez-Bribiesca L |title=Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis |journal=J. Cell. Mol. Med. |volume=10 |issue= 3 |pages= 554–68 |year= 2007 |pmid= 16989720 |doi=10.1111/j.1582-4934.2006.tb00420.x }}
*{{cite journal | vauthors=Recillas-Targa F, De La Rosa-Velázquez IA, Soto-Reyes E, Benítez-Bribiesca L |title=Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis |journal=J. Cell. Mol. Med. |volume=10 |issue= 3 |pages= 554–68 |year= 2007 |pmid= 16989720 |doi=10.1111/j.1582-4934.2006.tb00420.x |pmc=3933142 }}
*{{cite journal | author=Vostrov AA, Quitschke WW |title=The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation |journal=J. Biol. Chem. |volume=272 |issue= 52 |pages= 33353–9 |year= 1998 |pmid= 9407128 |doi=10.1074/jbc.272.52.33353 }}
*{{cite journal | vauthors=Vostrov AA, Quitschke WW |title=The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation |journal=J. Biol. Chem. |volume=272 |issue= 52 |pages= 33353–9 |year= 1998 |pmid= 9407128 |doi=10.1074/jbc.272.52.33353 |doi-access=free }}
*{{cite journal | author=Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV |title=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 |journal=Genes Chromosomes Cancer |volume=22 |issue= 1 |pages= 26–36 |year= 1998 |pmid= 9591631 |doi=10.1002/(SICI)1098-2264(199805)22:1<26::AID-GCC4>3.0.CO;2-9 }}
*{{cite journal | vauthors=Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV |title=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 |journal=Genes Chromosomes Cancer |volume=22 |issue= 1 |pages= 26–36 |year= 1998 |pmid= 9591631 |doi=10.1002/(SICI)1098-2264(199805)22:1<26::AID-GCC4>3.0.CO;2-9 |s2cid=34221526 }}
*{{cite journal | author=Bell AC, West AG, Felsenfeld G |title=The protein CTCF is required for the enhancer blocking activity of vertebrate insulators |journal=Cell |volume=98 |issue= 3 |pages= 387–96 |year= 1999 |pmid= 10458613 |doi=10.1016/S0092-8674(00)81967-4 }}
*{{cite journal | vauthors=Bell AC, West AG, Felsenfeld G |title=The protein CTCF is required for the enhancer blocking activity of vertebrate insulators |journal=Cell |volume=98 |issue= 3 |pages= 387–96 |year= 1999 |pmid= 10458613 |doi=10.1016/S0092-8674(00)81967-4 |s2cid=18266832 |doi-access=free }}
*{{cite journal | author=Pérez-Juste G, García-Silva S, Aranda A |title=An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells |journal=J. Biol. Chem. |volume=275 |issue= 2 |pages= 1307–14 |year= 2000 |pmid= 10625678 |doi=10.1074/jbc.275.2.1307 }}
*{{cite journal | vauthors=Pérez-Juste G, García-Silva S, Aranda A |title=An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells |journal=J. Biol. Chem. |volume=275 |issue= 2 |pages= 1307–14 |year= 2000 |pmid= 10625678 |doi=10.1074/jbc.275.2.1307 |doi-access=free }}
*{{cite journal | author=Lutz M, Burke LJ, Barreto G, Goeman F, Greb H, Arnold R, Schultheiss H, Brehm A, Kouzarides T, Lobanenkov V, Renkawitz R |title=Transcriptional repression by the insulator protein CTCF involves histone deacetylases |journal=Nucleic Acids Res. |volume=28 |issue= 8 |pages= 1707–13 |year= 2000 |pmid= 10734189 |doi=10.1093/nar/28.8.1707 | pmc=102824 }}
*{{cite journal | vauthors=Lutz M, Burke LJ, Barreto G, Goeman F, Greb H, Arnold R, Schultheiss H, Brehm A, Kouzarides T, Lobanenkov V, Renkawitz R |title=Transcriptional repression by the insulator protein CTCF involves histone deacetylases |journal=Nucleic Acids Res. |volume=28 |issue= 8 |pages= 1707–13 |year= 2000 |pmid= 10734189 |doi=10.1093/nar/28.8.1707 | pmc=102824 }}
*{{cite journal | author=Bell AC, Felsenfeld G |title=Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene |journal=Nature |volume=405 |issue= 6785 |pages= 482–5 |year= 2000 |pmid= 10839546 |doi= 10.1038/35013100 }}
*{{cite journal | vauthors=Bell AC, Felsenfeld G |title=Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene |journal=Nature |volume=405 |issue= 6785 |pages= 482–5 |year= 2000 |pmid= 10839546 |doi= 10.1038/35013100 |bibcode=2000Natur.405..482B |s2cid=4387329 }}
*{{cite journal | author=Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM |title=CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus |journal=Nature |volume=405 |issue= 6785 |pages= 486–9 |year= 2000 |pmid= 10839547 |doi= 10.1038/35013106 }}
*{{cite journal | vauthors=Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM |title=CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus |journal=Nature |volume=405 |issue= 6785 |pages= 486–9 |year= 2000 |pmid= 10839547 |doi= 10.1038/35013106 |bibcode=2000Natur.405..486H |s2cid=4421547 }}
*{{cite journal | author=Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM |title=Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF |journal=J. Biol. Chem. |volume=275 |issue= 38 |pages= 29915–21 |year= 2000 |pmid= 10906122 |doi= 10.1074/jbc.M001538200 }}
*{{cite journal | vauthors=Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM |title=Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF |journal=J. Biol. Chem. |volume=275 |issue= 38 |pages= 29915–21 |year= 2000 |pmid= 10906122 |doi= 10.1074/jbc.M001538200 |doi-access= free}}
*{{cite journal | author=Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT |title=CTCF, a candidate trans-acting factor for X-inactivation choice |journal=Science |volume=295 |issue= 5553 |pages= 345–7 |year= 2002 |pmid= 11743158 |doi= 10.1126/science.1065982 }}
*{{cite journal | vauthors=Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT |title=CTCF, a candidate trans-acting factor for X-inactivation choice |journal=Science |volume=295 |issue= 5553 |pages= 345–7 |year= 2002 |pmid= 11743158 |doi= 10.1126/science.1065982 |s2cid=27442721 |doi-access=free }}
*{{cite journal | author=Dintilhac A, Bernués J |title=HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences |journal=J. Biol. Chem. |volume=277 |issue= 9 |pages= 7021–8 |year= 2002 |pmid= 11748221 |doi= 10.1074/jbc.M108417200 }}
*{{cite journal | vauthors=Dintilhac A, Bernués J |title=HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences |journal=J. Biol. Chem. |volume=277 |issue= 9 |pages= 7021–8 |year= 2002 |pmid= 11748221 |doi= 10.1074/jbc.M108417200 |s2cid=39560486 |url= https://digital.csic.es/bitstream/10261/112516/4/jbc.M108417200.full.pdf |doi-access= free }}
*{{cite journal | author=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 |title=Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity |journal=Cancer Res. |volume=62 |issue= 1 |pages= 48–52 |year= 2002 |pmid= 11782357 |doi= }}
*{{cite journal | vauthors=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 |title=Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity |journal=Cancer Res. |volume=62 |issue= 1 |pages= 48–52 |year= 2002 |pmid= 11782357 }}
*{{cite journal | author=Kanduri M, Kanduri C, Mariano P, Vostrov AA, Quitschke W, Lobanenkov V, Ohlsson R |title=Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region |journal=Mol. Cell. Biol. |volume=22 |issue= 10 |pages= 3339–44 |year= 2002 |pmid= 11971967 |doi=10.1128/MCB.22.10.3339-3344.2002 | pmc=133793 }}
*{{cite journal | vauthors=Kanduri M, Kanduri C, Mariano P, Vostrov AA, Quitschke W, Lobanenkov V, Ohlsson R |title=Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region |journal=Mol. Cell. Biol. |volume=22 |issue= 10 |pages= 3339–44 |year= 2002 |pmid= 11971967 |doi=10.1128/MCB.22.10.3339-3344.2002 | pmc=133793 }}
*{{cite journal | author=Farrell CM, West AG, Felsenfeld G |title=Conserved CTCF insulator elements flank the mouse and human beta-globin loci |journal=Mol. Cell. Biol. |volume=22 |issue= 11 |pages= 3820–31 |year= 2002 |pmid= 11997516 |doi=10.1128/MCB.22.11.3820-3831.2002 | pmc=133827 }}
*{{cite journal | vauthors=Farrell CM, West AG, Felsenfeld G |title=Conserved CTCF insulator elements flank the mouse and human beta-globin loci |journal=Mol. Cell. Biol. |volume=22 |issue= 11 |pages= 3820–31 |year= 2002 |pmid= 11997516 |doi=10.1128/MCB.22.11.3820-3831.2002 | pmc=133827 }}
{{refend}}
{{refend}}


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* {{MeshName|CCCTC-binding+factor}}
* {{MeshName|CCCTC-binding+factor}}
* {{FactorBook|CTCF}}
* {{FactorBook|CTCF}}
* {{UCSC gene info|CTCF}}
* https://www.ctcfemory.com/ A Group for families affected by CTCF mutations


{{PDB Gallery|geneid=10664}}
{{PDB Gallery|geneid=10664}}
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[[Category:Transcription factors]]
[[Category:Transcription factors]]
[[Category:Gene expression]]
[[Category:Gene expression]]
[[Category:Nuclear organization]]

Latest revision as of 16:20, 28 November 2024

For the prison, see Colorado Territorial Correctional Facility.
CTCF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCTCF, MRD21, CCCTC-binding factor, FAP108, CFAP108
External IDsOMIM: 604167; MGI: 109447; HomoloGene: 4786; GeneCards: CTCF; OMA:CTCF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10664

13018

Ensembl

ENSG00000102974

ENSMUSG00000005698

UniProt

P49711

Q61164

RefSeq (mRNA)

NM_001191022
NM_006565
NM_001363916

NM_181322
NM_001358924

RefSeq (protein)

NP_001177951
NP_006556
NP_001350845

Location (UCSC)Chr 16: 67.56 – 67.64 MbChr 8: 105.64 – 105.68 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

[edit]

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.[9]

Function

[edit]

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 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.[8] 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.[11] 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

[edit]

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]

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.[12][13]

Insulation

[edit]

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

[edit]

CTCF physically binds to itself to form homodimers,[15] which causes the bound DNA to form loops.[16] CTCF also occurs frequently at the boundaries of sections of DNA bound to the nuclear lamina.[10] 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.[17][18] 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.[19][20]

Regulation of RNA splicing

[edit]

CTCF binding has been shown to influence mRNA splicing.[21]

DNA binding

[edit]

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

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CTCF binds to itself to form homodimers.[15] CTCF has also been shown to interact with Y box binding protein 1.[34] 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.[35] CTCF is also known to interact with chromatin remodellers such as Chd4 and Snf2h (SMARCA5).[36]

References

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Further reading

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