CTCF

转录阻抑物CTCF，也被称为11锌指蛋白或CCCTC结合因子，是由人类CTCF基因编码的转录因子。CTCF参与多个细胞进程，包括转录调控、绝缘子活性调控、V(D)J重组、染色质结构调控等。 CTCF最早被认为在鸡体内抑制c-myc基因表达。CTCF蛋白和以CCCTC为核心序列的三个规则间隔重复蛋白相结合，故得名CCCTC结合因子。 CTCF的主要功能是调控染色质的3D结构。CTCF和DNA双链结合形成染色质环，并把DNA锚定在细胞结构上（例如核纤层）。此外，CTCF还能充当常染色质和异染色质的边界。 DNA的3D结构会影响基因的调控，因此CTCF的活性会影响基因表达。绝缘子能阻碍增强子和启动子的结合，而CTCF是绝缘子的主要活性部分。 CTCF的结合有多种效应。目前尚不能确定下列功能是直接由CTCF导致。 CTCF对于IGF2的抑制起重要作用。具体机制为CTCF和H19基因的基因铭印（ICR）区域、差异甲基化区域-1（DMR-1）和MAR3区域结合。 CTCF能通过和目标区域结合以阻碍增强子和启动子的相互作用，从而降低增强子对某些功能域的调控能力。除此之外，CTCF还能作为染色质“路障”，阻止异染色质的进一步形成。 CTCF往往以二聚体的形式存在，这会导致DNA形成环状结构。CTCF也经常在DNA和核纤层的结合处出现。使用ChIP-seq技术可以发现CTCF同黏连蛋白一起在基因组内广泛存在，并对染色质的高级结构起调节作用。 CTCF对mRNA剪切有调控作用。 CTCF和共有序列CCGCGNGGNGGCAG相结合。这条序列在其结构域中有11个锌指结构。CTCF和基因的结合被CpG的甲基化所影响。 CTCF在19个细胞系中大约有55000个共同的DNA结合位点（共77811个独特位点）。CTCF能和不同的锌指结构结合，这让它的功能非常多样化。大约有30000个CTCF的位点功能已经被定义。在人类的不同细胞中大约有15000-40000个CTCF结合位点。除此之外，高分辨率的核小体比对现实CTCF的不同结合位点可能和核小体的定位有关。 CTCF可能和Y box结合蛋白1有相互作用。黏连蛋白对CTCF形成的环状结构有稳定作用。 Malik, V. S.; Reusser, F. Restriction enzyme map for streptomycete plasmid pUC3. Plasmid. 1979-10, 2 (4): 627–631 [2018-10-01]. ISSN 0147-619X. PMID 231272. （原始内容存档于2018-10-02）.  Zuccato, E.; Mussini, E.; Spignoli, G.; Pupita, F. Evidence of a lack of enteric side-effects induced by DEAE-dextran in man. Pharmacological Research Communications. 1987-8, 19 (8): 547–553 [2018-10-01]. ISSN 0031-6989. PMID 2448833. （原始内容存档于2018-10-02）.  请检查|date=中的日期值 (帮助) Ishikawa, H. [Effect of anesthetized antral mucosa on anti-peristaltic discharge]. Nihon Heikatsukin Gakkai Zasshi. 1987-4, 23 (2): 115–124 [2018-10-01]. ISSN 0374-3527. PMID 3444155. （原始内容存档于2018-10-02）.  请检查|date=中的日期值 (帮助) Dahlgren, C. Difference in extracellular radical release after chemotactic factor and calcium ionophore activation of the oxygen radical-generating system in human neutrophils. Biochimica Et Biophysica Acta. 1987-08-19, 930 (1): 33–38 [2018-10-01]. ISSN 0006-3002. PMID 3040116. （原始内容存档于2018-10-02）.  Lobanenkov, V. V.; Nicolas, R. H.; Adler, V. V.; Paterson, H.; Klenova, E. M.; Polotskaja, A. V.; Goodwin, G. H. 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. 1990-12, 5 (12): 1743–1753 [2018-10-01]. ISSN 0950-9232. PMID 2284094. （原始内容存档于2018-10-02）.  Guelen, Lars; Pagie, Ludo; Brasset, Emilie; Meuleman, Wouter; Faza, Marius B.; Talhout, Wendy; Eussen, Bert H.; de Klein, Annelies; Wessels, Lodewyk. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008-06-12, 453 (7197): 948–951 [2018-10-01]. ISSN 1476-4687. PMID 18463634. doi:10.1038/nature06947. （原始内容存档于2018-10-02）.  Dunn, Katherine L.; Davie, James R. The many roles of the transcriptional regulator CTCF. Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire. 2003-6, 81 (3): 161–167 [2018-10-01]. ISSN 0829-8211. PMID 12897849. doi:10.1139/o03-052. （原始内容存档于2018-10-02）.  请检查|date=中的日期值 (帮助) Malyshev, Iu I.; Iarygin, A. S.; Malyshev, M. Iu. [Surgical correction of multivalvular defects in patients who had earlier undergone heart surgery]. Grudnaia Khirurgiia (Moscow, Russia). 1989-11, (6): 17–20 [2018-10-01]. ISSN 0017-4866. PMID 2612964. （原始内容存档于2018-10-02）.  Yusufzai, Timur M.; Tagami, Hideaki; Nakatani, Yoshihiro; Felsenfeld, Gary. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Molecular Cell. 2004-01-30, 13 (2): 291–298 [2018-10-01]. ISSN 1097-2765. PMID 14759373. （原始内容存档于2018-10-02）.  Hou, Chunhui; Zhao, Hui; Tanimoto, Keiji; Dean, Ann. CTCF-dependent enhancer-blocking by alternative chromatin loop formation. Proceedings of the National Academy of Sciences of the United States of America. 2008-12-23, 105 (51): 20398–20403 [2018-10-01]. ISSN 1091-6490. PMC 2629272 . PMID 19074263. doi:10.1073/pnas.0808506106. （原始内容存档于2018-10-02）.  Johnson, E. K.; Kardong, K. V.; Mackessy, S. P. Electric shocks are ineffective in treatment of lethal effects of rattlesnake envenomation in mice. Toxicon: Official Journal of the International Society on Toxinology. 1987, 25 (12): 1347–1349 [2018-10-01]. ISSN 0041-0101. PMID 3438923. （原始内容存档于2018-10-02）.  Shukla, Sanjeev; Kavak, Ersen; Gregory, Melissa; Imashimizu, Masahiko; Shutinoski, Bojan; Kashlev, Mikhail; Oberdoerffer, Philipp; Sandberg, Rickard; Oberdoerffer, Shalini. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature. 2011-11-03, 479 (7371): 74–79 [2018-10-01]. ISSN 1476-4687. PMID 21964334. doi:10.1038/nature10442. （原始内容存档于2018-10-02）.  Kroeker, L. [Nursing--a new future]. Krankenpflege (Frankfurt Am Main, Germany). 1989-9, 43 (9): 426–429 [2018-10-01]. ISSN 0944-9183. PMID 2572726. （原始内容存档于2018-10-02）.  请检查|date=中的日期值 (帮助) Bell, A. C.; Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000-05-25, 405 (6785): 482–485 [2018-10-01]. ISSN 0028-0836. PMID 10839546. doi:10.1038/35013100. （原始内容存档于2018-10-02）.  Gomoliako, I. V. [Morphological diagnosis of chronic bronchitis in patients with tuberculosis of the lungs]. Problemy Tuberkuleza. 1991, (4): 64–68 [2018-10-01]. ISSN 0032-9533. PMID 1852749. （原始内容存档于2018-10-02）.  Reiher, H.; Peschke, G.; May, G.; Göbel, U.; Randow, H. [Severe impalement injury with primary surgical, gynecologic and urologic management]. Zentralblatt Fur Chirurgie. 1990, 115 (16): 1041–1043 [2018-10-01]. ISSN 0044-409X. PMID 2238977. （原始内容存档于2018-10-02）.  Suzuki, S. S.; Smith, G. K. Spontaneous EEG spikes in the normal hippocampus. II. Relations to synchronous burst discharges. Electroencephalography and Clinical Neurophysiology. 1988-6, 69 (6): 532–540 [2018-10-01]. ISSN 0013-4694. PMID 2453330. （原始内容存档于2018-10-02）.  请检查|date=中的日期值 (帮助) Teif, Vladimir B.; Vainshtein, Yevhen; Caudron-Herger, Maïwen; Mallm, Jan-Philipp; Marth, Caroline; Höfer, Thomas; Rippe, Karsten. Genome-wide nucleosome positioning during embryonic stem cell development. Nature Structural & Molecular Biology. 2012-11, 19 (11): 1185–1192 [2018-10-01]. ISSN 1545-9985. PMID 23085715. doi:10.1038/nsmb.2419. （原始内容存档于2018-10-02）.  Chernukhin, I. V.; Shamsuddin, S.; Robinson, A. F.; Carne, A. F.; Paul, A.; El-Kady, A. I.; Lobanenkov, V. V.; Klenova, E. M. Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF. The Journal of Biological Chemistry. 2000-09-22, 275 (38): 29915–29921 [2018-10-01]. ISSN 0021-9258. PMID 10906122. doi:10.1074/jbc.M001538200. （原始内容存档于2018-10-02）.  Kagey, Michael H.; Newman, Jamie J.; Bilodeau, Steve; Zhan, Ye; Orlando, David A.; van Berkum, Nynke L.; Ebmeier, Christopher C.; Goossens, Jesse; Rahl, Peter B. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010-09-23, 467 (7314): 430–435 [2018-10-01]. ISSN 1476-4687. PMC 2953795 . PMID 20720539. doi:10.1038/nature09380. （原始内容存档于2018-10-02）.  Ohlsson R, Renkawitz R, Lobanenkov V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 2001, 17 (9): 520–7. PMID 11525835. doi:10.1016/S0168-9525(01)02366-6.  Klenova EM, Morse HC, Ohlsson R, Lobanenkov VV. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Semin. Cancer Biol. 2003, 12 (5): 399–414. PMID 12191639. doi:10.1016/S1044-579X(02)00060-3.  Kuhn EJ, Geyer PK. Genomic insulators: connecting properties to mechanism. Curr. Opin. Cell Biol. 2004, 15 (3): 259–65. PMID 12787766. doi:10.1016/S0955-0674(03)00039-5.  Recillas-Targa F, De La Rosa-Velázquez IA, Soto-Reyes E, Benítez-Bribiesca L. Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis. J. Cell. Mol. Med. 2007, 10 (3): 554–68. PMID 16989720. doi:10.1111/j.1582-4934.2006.tb00420.x.  Vostrov AA, Quitschke WW. 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. 1998, 272 (52): 33353–9. PMID 9407128. doi:10.1074/jbc.272.52.33353.  Filippova GN, Lindblom A, Meincke LJ; et al. 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. 1998, 22 (1): 26–36. PMID 9591631. doi:10.1002/(SICI)1098-2264(199805)22:1<26::AID-GCC4>3.0.CO;2-9.  引文格式1维护：显式使用等标签 (link) Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999, 98 (3): 387–96. PMID 10458613. doi:10.1016/S0092-8674(00)81967-4.  Pérez-Juste G, García-Silva S, Aranda A. 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. 2000, 275 (2): 1307–14. PMID 10625678. doi:10.1074/jbc.275.2.1307.  Lutz M, Burke LJ, Barreto G; et al. Transcriptional repression by the insulator protein CTCF involves histone deacetylases. Nucleic Acids Res. 2000, 28 (8): 1707–13. PMC 102824 . PMID 10734189. doi:10.1093/nar/28.8.1707.  引文格式1维护：显式使用等标签 (link) Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000, 405 (6785): 482–5. PMID 10839546. doi:10.1038/35013100.  Hark AT, Schoenherr CJ, Katz DJ; et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 2000, 405 (6785): 486–9. PMID 10839547. doi:10.1038/35013106.  引文格式1维护：显式使用等标签 (link) Chernukhin IV, Shamsuddin S, Robinson AF; et al. 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. 2000, 275 (38): 29915–21. PMID 10906122. doi:10.1074/jbc.M001538200.  引文格式1维护：显式使用等标签 (link) Chao W, Huynh KD, Spencer RJ; et al. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002, 295 (5553): 345–7. PMID 11743158. doi:10.1126/science.1065982.  引文格式1维护：显式使用等标签 (link) Dintilhac A, Bernués J. HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences. J. Biol. Chem. 2002, 277 (9): 7021–8. PMID 11748221. doi:10.1074/jbc.M108417200.  Filippova GN, Qi CF, Ulmer JE; et al. Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity. Cancer Res. 2002, 62 (1): 48–52. PMID 11782357.  引文格式1维护：显式使用等标签 (link) Jia L, Young MF, Powell J; et al. Gene expression profile of human bone marrow stromal cells: high-throughput expressed sequence tag sequencing analysis. Genomics. 2002, 79 (1): 7–17. PMID 11827452. doi:10.1006/geno.2001.6683.  引文格式1维护：显式使用等标签 (link) Kanduri M, Kanduri C, Mariano P; et al. Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region. Mol. Cell. Biol. 2002, 22 (10): 3339–44. PMC 133793 . PMID 11971967. doi:10.1128/MCB.22.10.3339-3344.2002.  引文格式1维护：显式使用等标签 (link) Farrell CM, West AG, Felsenfeld G. Conserved CTCF insulator elements flank the mouse and human beta-globin loci. Mol. Cell. Biol. 2002, 22 (11): 3820–31. PMC 133827 . PMID 11997516. doi:10.1128/MCB.22.11.3820-3831.2002.