Insulated neighborhood - Knowledge (XXG)

17: 87:, another type of DNA regulatory element, limit an enhancer's ability to target distal genes when the insulator is located between an enhancer and a potential target. In mammals, insulators are bound by CTCF, but only a minority of CTCF-bound sites function as insulators. CTCF molecules can form homodimers on DNA, which can be co-bound by cohesin; this 1587:

Maurano, MT; Humbert, R; Rynes, E; Thurman, RE; Haugen, E; Wang, H; Reynolds, AP; Sandstrom, R; Qu, H; Brody, J; Shafer, A; Neri, F; Lee, K; Kutyavin, T; Stehling-Sun, S; Johnson, AK; Canfield, TK; Giste, E; Diegel, M; Bates, D; Hansen, RS; Neph, S; Sabo, PJ; Heimfeld, S; Raubitschek, A; Ziegler, S;

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Weischenfeldt, Joachim; Dubash, Taronish; Drainas, Alexandros P.; Mardin, Balca R.; Chen, Yuanyuan; Stütz, Adrian M.; Waszak, Sebsatian M.; Bosco, Graziella; Halvorsen, Ann R.; Raeder, Benjamin; Efthymiopoulos, Theocharis; Erkek, Serap; Siegl, Christine; Brenner, Hermann; Brustugun, Odd T.; Dieter,

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The majority of insulated neighborhoods appear to be maintained during development because CTCF binding and CTCF-CTCF loop structures are very similar across human cell types. While the location of many insulated neighborhood structures are maintained across different cell types, the enhancer-gene

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identified ~13,000 insulated neighborhoods that, on average, each contained three genes and was about 90kb in size. Two lines of evidence argue that the boundaries of insulated neighborhoods are insulating: 1) the vast majority (~90-97%) of enhancer-gene interactions are contained within insulated

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occur in enhancers. Identifying target genes of enhancers with disease-linked variants has been difficult because enhancers may act over long distances, but the constraint on enhancer-gene targeting by insulated neighborhoods refines the prediction of target genes. For example, a DNA variant

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Multiple levels of mammalian genome organization. Chromosomes occupy discrete territories in the nucleus (left). Topologically associating domains (TADs) are regions of the genome with locally high interaction frequency (center). Insulated neighborhoods are loops formed by the interaction of

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Gröschel, S; Sanders, MA; Hoogenboezem, R; de Wit, E; Bouwman, BA; Erpelinck, C; van der Velden, VH; Havermans, M; Avellino, R; van Lom, K; Rombouts, EJ; van Duin, M; Döhner, K; Beverloo, HB; Bradner, JE; Döhner, H; Löwenberg, B; Valk, PJ; Bindels, EM; de Laat, W; Delwel, R (10 April 2014).

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Tang, Z; Luo, OJ; Li, X; Zheng, M; Zhu, JJ; Szalaj, P; Trzaskoma, P; Magalska, A; Wlodarczyk, J; Ruszczycki, B; Michalski, P; Piecuch, E; Wang, P; Wang, D; Tian, SZ; Penrad-Mobayed, M; Sachs, LM; Ruan, X; Wei, CL; Liu, ET; Wilczynski, GM; Plewczynski, D; Li, G; Ruan, Y (17 December 2015).

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Farh, KK; Marson, A; Zhu, J; Kleinewietfeld, M; Housley, WJ; Beik, S; Shoresh, N; Whitton, H; Ryan, RJ; Shishkin, AA; Hatan, M; Carrasco-Alfonso, MJ; Mayer, D; Luckey, CJ; Patsopoulos, NA; De Jager, PL; Kuchroo, VK; Epstein, CB; Daly, MJ; Hafler, DA; Bernstein, BE (19 February 2015).

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Sebastian M; Northcott, Paul A.; Petersen, Iver; Pfister, Stefan M.; Schneider, Martin; Solberg, Steinar K.; Thunissen, Erik; Weichert, Wilko; Zichner, Thomas; Thomas, Roman; Peifer, Martin; Helland, Aslaug; Ball, Claudia R.; Jechlinger, Martin; Sotillo, Rocio; Glimm, Hanno;

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loop structure helps constrain the ability of enhancers within the loop to target genes outside the loop. Loops with CTCF and cohesin at the start and end of the loop that restrict enhancer-gene targeting are "insulated neighborhoods."

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Topologically associating domains (TADs) are megabase-size regions of relatively high DNA interaction frequencies. Mechanistic studies indicate TADs are single insulated neighborhoods or collections of insulated neighborhoods.

83:. Enhancers can regulate transcription of genes at large distances by looping to physically contact their target genes. This property of enhancers makes it difficult to identify an enhancer's target gene(s). 654:

Udvardy, A; Maine, E; Schedl, P (20 September 1985). "The 87A7 chromomere. Identification of novel chromatin structures flanking the heat shock locus that may define the boundaries of higher order domains".

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display altered DNA methylation patterns, so CTCF binding, which is DNA methylation-dependent, is also altered. Altered CTCF-binding disrupts insulated neighborhoods and can lead to oncogene misregulation.

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Chung, JH; Whiteley, M; Felsenfeld, G (13 August 1993). "A 5' element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila".

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because their integrity is important for normal gene regulation. Current evidence suggests that these structures form the mechanistic underpinnings of higher-order chromosome structures, including

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neighborhoods and 2) genetic perturbation of CTCF/cohesin-bound insulated neighborhood anchors leads to local gene dysregulation due to novel interactions outside of the neighborhood.

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Hnisz, D; Weintraub, AS; Day, DS; Valton, AL; Bak, RO; Li, CH; Goldmann, J; Lajoie, BR; Fan, ZP; Sigova, AA; Reddy, J; Borges-Rivera, D; Lee, TI; Jaenisch, R; Porteus, MH;

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Ernst, J; Kheradpour, P; Mikkelsen, TS; Shoresh, N; Ward, LD; Epstein, CB; Zhang, X; Wang, L; Issner, R; Coyne, M; Ku, M; Durham, T; Kellis, M; Bernstein, BE (5 May 2011).

104:, co-bound with cohesin, and containing at least one gene. The CTCF/cohesin-bound regions delimiting an insulated neighborhood are called "anchors." One study in human 164:

Insulated neighborhoods aid in identifying the target genes of disease-associated enhancer variants. The majority of disease-linked DNA variants identified from

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Nora, EP; Lajoie, BR; Schulz, EG; Giorgetti, L; Okamoto, I; Servant, N; Piolot, T; van Berkum, NL; Meisig, J; Sedat, J; Gribnau, J; Barillot, E; Blüthgen, N;

67:(TADs). Insulated neighborhoods are functionally important in understanding gene regulation in normal cells and dysregulated gene expression in disease. 1267: