Biopolym. Cell. 2012; 28(4):252-260.
http://dx.doi.org/10.7124/bc.000057
Огляди
Інсулятори ссавців: регуляторні механізми і структура хроматину
1, 2Ульянов С. В., 1Маркова О. Н., 1, 3Гаврилов О. А., 1, 2Разін С. В.
  1. Інститут біології гена РАН
    вул Вавілова 34/5, Москва, Російська Федерація, 119334
  2. Кафедра молекулярної біології, біологічний факультет, Московський державний університет імені М. В. Ломоносова
    Ленінські гори, Російська Федерація, 119991
  3. Університет Осло, Центр медичних досліджень в Росії
    вул Вавілова 34/5, Москва, Російська Федерація, 119334

Abstract

Інсулятори було відкрито як геномні елементи, здатні переривати зв’язок між промотором і енхансером (активність, яка блокує функціонування енхансера), та обмежувати поширення гетерохроматину (бар’єрна активність). У дрозофіли існує декілька типів інсуляторів, які працюють із залученням різних білків. Всі описані інсулятори у ссавців працюють за участі багатофункціонального транскрипційного фактора CTCF. Біологічні функції інсуляторів ссавців не до кінця з’ясовані. Хоча багато хто вважає, що вони розмежовують хроматинові домени, прямих свідчень цьому практично немає. Найпоказовішою є участь інсуляторів у роботі центрів встановлення імпринтингу (imprinting choice regions). Результати низки недавно опублікованих робіт свідчать про те, що для встановлення імпринтингу суттєвим є вбудовування інактивованого гена в окремий топологічний домен (петлю). В цьому та в багатьох інших випадках інсулятори працюють як архітектурні елементи, які підтримують тривимірну організацію геному. Взаємодія між парами інсуляторів, у яких поряд з CTCF істотну роль відіграє когезин, організує геном у різного роду петлі.
Keywords: хроматиновий домен, бар’єрний елемент, енхансер-блокуючий елемент, CTCF, імпринтинг.
Повний текст: (PDF, англійською)

References

[1] Kellum R., Schedl P. A group of scs elements function as boundaries in enhancer-blocking assay Mol. Cell. Biol 1992 12, N 5:2424–2431.
[2] Kellum R., Schedl P. A position-effect assay for boundaries of higher order chromosomal domains Cell 1991 64, N 5:941–950.
[3] West A. G., Gaszner M., Felsenfeld G. Insulators: many functions, many mechanisms Genes Dev 2002 16, N 3:271–288.
[4] Udvardy A., Maine S., Schedl P. The 87A7 chromomere. Identification of novel chromatin structures flanking the heat shock locus that may define the boundaries of higher order domains J. Mol. Biol 1985 185, N 2:341–358.
[5] Recillas-Targa F., Bell A. C., Felsenfeld G. Positional enhancerblocking activity of the chicken beta-globin insulator in transiently transfected cells Proc. Natl Acad. Sci. USA 1999 96, N 25:14354–14359.
[6] Brasset E., Vaury C. Insulators are fundamental components of the eukaryotic genomes Heredity (Edinb) 2005 94, N 6:571–576.
[7] Bell A. C., Felsenfeld G. Stopped at the border: boundaries and insulators Curr. Opin. Genet. Dev 1999 9, N 2:191–198.
[8] Bell A. C., West A. G., Felsenfeld G. Insulators and boundaries: versatile regulatory elements in the eukaryotic genome Science 2001 291, N 5503–P. 447–450.
[9] Felsenfeld G., Burgess-Beusse B., Farrell C., Gaszner M., Ghirlando R., Huang S., Jin C., Litt M., Magdinier F., Mutskov V., Nakatani Y., Tagami H., West A., Yusufzai T. Chromatin boundaries and chromatin domains Cold Spring Harb. Symp. Quant. Biol 2004 69:245–250.
[10] Wallace J. A., Felsenfeld G. We gather together: insulators and genome organization Curr. Opin. Genet. Dev 2007 17, N 5:400–407.
[11] Lunyak V. V. Boundaries. Boundaries... Boundaries??? Curr. Opin. Cell Biol 2008 20, N 3:281–287.
[12] Chung J. H., Whiteley M., Felsenfeld G. A 5' element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila Cell 1993 74, N 3:505–514.
[13] Pikaart M. J., Recillas-Targa F., Felsenfeld G. Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators Genes Dev 1998 12, N 18:2852–2862.
[14] Recillas-Targa F., Pikaart M. J., Burgess-Beusse B., Bell A. C., Litt M. D., West A. G., Gaszner M., Felsenfeld G. Position-effect protection and enhancer blocking by the chicken beta-globin inslator are separable activities Proc. Natl Acad. Sci. USA 2002 99, N 10:6883–6888.
[15] Rincon-Arano H., Furlan-Magaril M., Recillas-Targa F. Protection against telomeric position effects by the chicken cHS4 beta-globin insulator Proc. Natl Acad. Sci. USA 2007 104, N 35:14044–14049.
[16] Chung J. H., Bell A. C., Felsenfeld G. Characterization of the chicken beta-globin insulator Proc. Natl Acad. Sci. USA 1997 94, N 2:575–580.
[17] Arumugam P. I., Urbinati F., Velu C. S., Higashimoto T., Grimes H. L., Malik P. The 3' region of the chicken hypersensitive site-4 insulator has properties similar to its core and is required for full insulator activity PLoS ONE 2009 4, N 9:e6995.
[18] Reitman M., Lee E., Westphal H., Felsenfeld G. Site-independent expression of the chicken betaA-globin gene in transgenic mice Nature 1990 348, N 6303:749–752.
[19] Bell A. C., West A. G., Felsenfeld G. The protein CTCF is required for the enhancer-blocking activity of vertebrate insulators Cell 1999 98, N 3:387–396.
[20] Wendt K. S., Yoshida K., Itoh T., Bando M., Koch B., Schirghuber E., Tsutsumi S., Nagae G., Ishihara K., Mishiro T., Yahata K., Imamoto F., Aburatani H., Nakao M., Imamoto N., Maeshima K., Shirahige K., Peters J. M. Cohesin mediates transcriptional insulation by CCCTC-binding factor Nature 2008 451, N 7180:796–801.
[21] Xiao T., Wallace J., Felsenfeld G. Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity Mol. Cell. Biol 2011 31, N 11:2174–2183.
[22] Huang S., Li X., Yusufzai T. M., Qiu Y., Felsenfeld G. USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier Mol. Cell. Biol 2007 27, N 22:7991–8002.
[23] Li X., Wang S., Li Y., Deng C., Steiner L. A., Xiao H., Wu C., Bungert J., Gallagher P. G., Felsenfeld G., Qiu Y., Huang S. Chromatin boundaries require functional collaboration between the hSET1 and NURF complexes Blood 2011 118, N 5:1386– 1394.
[24] Farrell C. M., West A. G., Felsenfeld G. Conserved CTCF insulator elements flank the mouse and human beta-globin loci Mol. Cell. Biol 2002 22, N 11:3820–3831.
[25] Li Q., Stamatoyannopoulos G. Hypersensitive site 5 of the human beta locus control region functions as a chromatin insulator Blood 1994 84, N 5:1399–1401.
[26] Tanimoto K., Liu Q., Bungert J., Engel J. D. Effects of altered gene order or orientation of the locus control region on human beta-globin gene expression in mice Nature 1999 398, N 6725:344–348.
[27] Li Q., Zhang M., Han H., Rohde A., Stamatoyannopoulos G. Evidence that DNase I hypersensitive site 5 of the human betaglobin locus control region functions as a chromosomal insulator in transgenic mice Nucleic Acids Res 2002 30, N 11:2484–2491.
[28] Bell A. C., Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene Nature 2000 405, N 6785:482–485.
[29] Hark A. T., Schoenherr C. J., Katz D. J., Ingram R. S., Levorse J. M., Tilghman S. M. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus Nature 2000 405, N 6785:486–489.
[30] Kanduri C., Fitzpatrick G., Mukhopadhyay R., Kanduri M., Lobanenkov V., Higgins M., Ohlsson R. A differentially methylated imprinting control region within the Kcnq1 locus harbors a methylation-sensitive chromatin insulator J. Biol. Chem 2002 277, N 20:18106–18110.
[31] Fitzpatrick G. V., Pugacheva E. M., Shin J. Y., Abdullaev Z., Yang Y., Khatod K., Lobanenkov V. V., Higgins M. J. Allele-specific binding of CTCF to the multipartite imprinting control region KvDMR1 Mol. Cell. Biol 2007 27, N 7:2636–2647.
[32] Valadez-Graham V., Razin S. V., Recillas-Targa F. CTCF-dependent enhancer blockers at the upstream region of the chicken alpha-globin gene domain Nucleic Acids Res 2004 32, N 4:1354–1362.
[33] Zhong X. P., Krangel M. S. Enhancer-blocking activity within the DNase I hypersensitive site 2 to 6 region between the TCR alpha and Dad1 genes J. Immunol 1999 163, N 1:295–300.
[34] Filippova G. N., Thienes C. P., Penn B. H., Cho D. H., Hu Y. J., Moore J. M., Klesert T. R., Lobanenkov V. V., Tapscott S. J. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus Nat. Genet 2001 28, N 4:335–343.
[35] Raab J. R., Chiu J., Zhu J., Katzman S., Kurukuti S., Wade P. A., Haussler D., Kamakaka R. T. Human tRNA genes function as chromatin insulators EMBO J 2011 31, N 2:330–350.
[36] Roman A. C., Gonzalez-Rico F. J., Fernandez-Salguero P. M. B1-SINE retrotransposons: establishing genomic insulatory networks Mob. Genet. Elements 2011 1, N 1:66–70.
[37] Lunyak V. V., Prefontaine G. G., Nunez E., Cramer T., Ju B. G., Ohgi K. A., Hutt K., Roy R., Garcia-Diaz A., Zhu X., Yung Y., Montoliu L., Glass C. K., Rosenfeld M. G. Developmentally regulated activation of a SINE B2 repeat as a domain boundary in organogenesis Science 2007 317, N 5835:248–251.
[38] Willoughby D. A., Vilalta A., Oshima R. G. An Alu element from the K18 gene confers position-independent expression in transgenic mice J. Biol. Chem 2000 275, N 2:759–768.
[39] de Laat W., Grosveld F. Spatial organization of gene expression: the active chromatin hub Chromosome Res 2003 11, N 5:447–459.
[40] Kooren J., Palstra R. J., Klous P., Splinter E., von Lindern M., Grosveld F., de Laat W. Beta-globin active chromatin Hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice J. Biol. Chem 2007 282, N 22:16544– 16552.
[41] Gavrilov A. A., Razin S. V. Spatial configuration of the chicken alpha-globin gene domain: immature and active chromatin hubs Nucleic Acids Res 2008 36, N 14:4629–4640.
[42] Zhu X., Ling J., Zhang L., Pi W., Wu M., Tuan D. A facilitated tracking and transcription mechanism of long-range enhancer function Nuceic Acids Res 2007 35, N 16:5532–5544.
[43] Herendeen D. R., Kassavetis G. A., Geiduschek E. P. A transcriptional enhancer whose function imposes a requirement that proteins track along DNA Science 1992 256, N 5061:1298– 1303.
[44] Hou C., Zhao H., Tanimoto K., Dean A. CTCF-dependent enhancer-blocking by alternative chromatin loop formation Proc. Natl Acad. Sci. USA 2008 105, N 51:20398–20403.
[45] Zhao H., Dean A. An insulator blocks spreading of histone acetylation and interferes with RNA polymerase II transfer between an enhancer and gene Nucleic Acids Res 2004 32, N 16:4903–4919.
[46] Raab J. R., Kamakaka R. T. Insulators and promoters: closer than we think Nat. Rev. Genet 2010 11, N 6:439–446.
[47] Tokuda N., Sasai M., Chikenji G. Roles of DNA looping in enhancer-blocking activity Biophys. J 2011 100, N 1:126– 134.
[48] Kurukuti S., Tiwari V. K., Tavoosidana G., Pugacheva E., Murrell A., Zhao Z., Lobanenkov V., Reik W., Ohlsson R. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2 Proc. Natl Acad. Sci. USA 2006 103, N 28:10684–10689.
[49] Danzer J. R., Wallrath L. L. Mechanisms of HP1-mediated gene silencing in Drosophila Development 2004 131, N 15:3571–3580.
[50] Bi X., Broach J. R. UASrpg can function as a heterochromatin boundary element in yeast Genes Dev 1999 13, N 9:1089–1101.
[51] Ferrari S., Simmen K. C., Dusserre Y., Muller K., Fourel G., Gilson E., Mermod N. Chromatin domain boundaries delimited by a histone-binding protein in yeast J. Biol. Chem 2004 279, N 53:55520–55530.
[52] Litt M. D., Simpson M., Recillas-Targa F., Prioleau M. N., Felsenfeld G. Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci EMBO J 2001 20, N 9:2224–2235.
[53] Mutskov V. J., Farrell C. M., Wade P. A., Wolffe A. P., Felsenfeld G. The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation Genes Dev 2002 16, N 12:1540–1554.
[54] Prioleau M. N., Gendron M. C., Hyrien O. Replication of the chicken beta-globin locus: early-firing origins at the 5' HS4 insulator and the rhoand betaA-globin genes show opposite epigenetic modifications Mol. Cell. Biol 2003 23, N 10:3536– 3549.
[55] West A. G., Huang S., Gaszner M., Litt M. D., Felsenfeld G. Recruitment of histone modifications by USF proteins at a vertebrate barrier element Mol. Cell 2004 16, N 3:453–463.
[56] Dickson J., Gowher H., Strogantsev R., Gaszner M., Hair A., Felsenfeld G., West A. G. VEZF1 elements mediate protection from DNA methylation PLoS Genet 2010 6, N 1 e1000804.
[57] Goldman I. L., Kadulin S. G., Razin S. V. Transgenic animals in medicine: integration and expression of foreign genes, theoretical and applied aspects Med. Sci. Monit 2004 10, N 11 RA274–285.
[58] Parelho V., Hadjur S., Spivakov M., Leleu M., Sauer S., Gregson H. C., Jarmuz A., Canzonetta C., Webster Z., Nesterova T., Cobb B. S., Yokomori K., Dillon N., Aragon L., Fisher A. G., Merkenschlager M. Cohesins functionally associate with CTCF on mammalian chromosome arms Cell 2008 132, N 3:422–433.
[59] Hadjur S., Williams L. M., Ryan N. K., Cobb B. S., Sexton T., Fraser P., Fisher A. G., Merkenschlager M. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus Nature 2009 460, N 7253:410–413.
[60] Nativio R., Wendt K. S., Ito Y., Huddleston J. E., Uribe-Lewis S., Woodfine K., Krueger C., Reik W., Peters J. M., Murrell A. Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus PLoS Genet 2009 5, N 11 e1000739.
[61] Majumder P., Gomez J. A., Chadwick B. P., Boss J. M. The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions J. Exp. Med 2008 205, N 4:785–798.
[62] Yang J., Corces V. G. Chromatin insulators: a role in nuclear organization and gene expression Adv. Cancer Res 2011 110:43–76.
[63] Yang J., Corces V. G. Insulators, long-range interactions, and genome function Curr. Opin. Genet. Dev 2012 22, N 2:79–85.
[64] Krivega I., Dean A. Enhancer and promoter interactions-long distance calls Curr. Opin. Genet. Dev 2012 22, N 2:86–92.
[65] Handoko L., Xu H., Li G., Ngan C. Y., Chew E., Schnapp M., Lee C. W., Ye C., Ping J. L., Mulawadi F., Wong E., Sheng J., Zhang Y., Poh T., Chan C. S., Kunarso G., Shahab A., Bourque G., Cacheux-Rataboul V., Sung W. K., Ruan Y., Wei C. L. CTCF-mediated functional chromatin interactome in pluripotent cells Nat. Genet 2011 43, N 7:630–638.
[66] Mishiro T., Ishihara K., Hino S., Tsutsumi S., Aburatani H., Shirahige K., Kinoshita Y., Nakao M. Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster EMBO J 2009 28, N 9:1234–1245.
[67] Hou C., Dale R., Dean A. Cell type specificity of chromatin organization mediated by CTCF and cohesin Proc. Natl Acad. Sci. USA 2010 107, N 8:3651–3656.
[68] Majumder P., Boss J. M. Cohesin regulates MHC class II genes through interactions with MHC class II insulators J. Immunol 2011 187, N 8:4236–4244.
[69] Majumder P., Boss J. M. CTCF controls expression and chromatin architecture of the human major histocompatibility complex class II locus Mol. Cell. Biol 2010 30, N 17:4211– 4223.
[70] Chien R., Zeng W., Kawauchi S., Bender M. A., Santos R., Gregson H. C., Schmiesing J. A., Newkirk D. A., Kong X., Ball A. R., Calof A. L., Lander A. D., Groudine M. T., Yokomori K. Cohesin mediates chromatin interactions that regulate mammalian beta-globin expression J. Biol. Chem 2011 286, N 20:17870– 17878.
[71] Sekimata M., Perez-Melgosa M., Miller S. A., Weinmann A. S., Sabo P. J., Sandstrom R., Dorschner M. O., Stamatoyannopoulos J. A., Wilson C. B. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus Immunity 2009 31, N 4:551–564.
[72] Ferraiuolo M. A., Rousseau M., Miyamoto C., Shenker S., Wang X. Q., Nadler M., Blanchette M., Dostie J. The three-dimensional architecture of Hox cluster silencing Nucleic Acids Res 2010 38, N 21:7472–7484.
[73] Ottaviani A., Schluth-Bolard C., Rival-Gervier S., Boussouar A., Rondier D., Foerster A. M., Morere J., Bauwens S., Gazzo S., Callet-Bauchu E., Gilson E., Magdinier F. Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF EMBO J 2009 28, N 16:2428–2436.
[74] Reddy K. L., Zullo J. M., Bertolino E., Singh H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina Nature 2008 452, N 7184:243–247.
[75] Tolhuis B., Palstra R. J., Splinter E., Grosveld F., de Laat W. Looping and interaction between hypersensitive sites in the active beta-globin locus Mol. Cell 2002 10, N 6:1453–1465.
[76] Razin S. V., Farrell C. M., Recillas-Targa F. Genomic domains and regulatory elements operating at the domain level Int. Rev. Cytol 2003 226:63–125.
[77] Bulger M., Bender M., Farrell C., Felsenfeld G., Wertman B., Groudine M., Hardison R. Open chromatin domain of mammalian -globin genes Blood Cells Mol. Dis 2000 26, N 5:490.
[78] Bulger M., Bender M. A., van Doorninck J. H., Wertman B., Farrell C. M., Felsenfeld G., Groudine M., Hardison R. C. Comparative structural and functional analysis of the olfactory receptor genes flanking the human and mouse b-globin gene clusters Proc. Natl Acad. Sci. USA 2000 97, N 26:14560–14565.
[79] Bender M. A., Byron R., Ragoczy T., Telling A., Bulger M., Groudine M. Flanking HS-62.5 and 3' HS1, and regions upstream of the LCR, are not required for b-globin transcription Blood 2006 108, N 4:1395–1401.
[80] Bender M. A., Reik A., Close J., Telling A., Epner E., Fiering S., Hardison R., Groudine M. Description and targeted deletion of 5' hypersensitive site 5 and 6 of the mouse beta-globin locus control region Blood 1998 92, N 11:4394–4403.
[81] Kim T. H., Abdullaev Z. K., Smith A. D., Ching K. A., Loukinov D. I., Green R. D., Zhang M. Q., Lobanenkov V. V., Ren B. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome Cell 2007 128, N 6:1231–1245.
[82] Jothi R., Cuddapah S., Barski A., Cui K., Zhao K. Genome-wide identification of in vivo protein-DNA binding sites from ChIPSeq data Nucleic Acids Res 2008 36, N 16:5221–5231.
[83] Cuddapah S., Jothi R., Schones D. E., Roh T. Y., Cui K., Zhao K. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains Genome Res 2009 19, N 1:24–32.
[84] Ideraabdullah F. Y., Vigneau S., Bartolomei M. S. Genomic imprinting mechanisms in mammals Mutat. Res 2008 647, N 1–2:77–85.
[85] Murrell A. Setting up and maintaining differential insulators and boundaries for genomic imprinting Biochem. Cell Biol 2011 89, N 5:469–478.
[86] Court F., Baniol M., Hagege H., Petit J. S., Lelay-Taha M. N., Carbonell F., Weber M., Cathala G., Forne T. Long-range chromatin interactions at the mouse Igf2/H19 locus reveal a novel paternally expressed long non-coding RNA Nucleic Acids Res 2011 39, N 14:5893–5906.
[87] Zlatanova J., Caiafa P. CCCTC-binding factor: to loop or to bridge Cell Mol. Life Sci 2009 66, N 10:1647–1660.
[88] Guo C., Yoon H. S., Franklin A., Jain S., Ebert A., Cheng H. L., Hansen E., Despo O., Bossen C., Vettermann C., Bates J. G., Richards N., Myers D., Patel H., Gallagher M., Schlissel M. S., Murre C., Busslinger M., Giallourakis C. C., Alt F. W. CTCFbinding elements mediate control of V(D)J recombination Nature 2011 477, N 7365:424–430.
[89] Dean A. In the loop: long range chromatin interactions and gene regulation Brief. Funct. Genomics 2011 10, N 1:3–10