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2015 | 62 | 3 | 483-489
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Can chromatin conformation technologies bring light into human molecular pathology?

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Regulation of gene expression in eukaryotes involves many complex processes, in which chromatin structure plays an important role. In addition to the epigenetic effects, such as DNA methylation and phosphorylation or histone modifications, gene expression is also controlled by the spatial organization of chromatin. For example, distant regulatory elements (enhancers, insulators) may come into direct physical interaction with target genes or other regulatory elements located in genomic regions of up to several hundred kilobases in size. Such long-range interactions result in the formation of chromatin loops. In the last several years, there has been a rapid increase in our knowledge of the spatial organization of chromatin in the nucleus through the chromosome conformation capture (3C) technology. Here we review and compare the original 3C and 3C-based methods including chromosome conformation capture-on-chip (4C), chromosome conformation capture carbon copy (5C), hi-resolution chromosome confomation capture (HiC). In this article, we discuss different aspects of how the nuclear organization of chromatin is associated with gene expression regulation and how this knowledge is useful in translational medicine and clinical applications. We demonstrate that the knowledge of the chromatin 3D organization may help understand the mechanisms of gene expression regulation of genes involved in the development of human diseases, such as CFTR (responsible for cystic fibrosis) or IGFBP3 (associated with breast cancer pathogenesis). Additionally, 3C-derivative methods have been also useful in the diagnosis of some leukemia subtypes.
Physical description
  • Bau D, Sanyal A, Lajoie BR, Capriotti E, Byron M, Lawrence JB, Dekker J, Marti-Renom MA (2011) The three-dimensional folding of the alpha-globin gene domain reveals formation of chromatin globules. Nat Struct Mol Biol 18: 107-114.
  • Blackledge NP, Ott CJ, Gillen AE, Harris A (2009) An insulator element 3' to the CFTR gene binds CTCF and reveals an active chromatin hub in primary cells. Nucleic Acids Res 37: 1086-1094.
  • Cacabelos R (2014) Epigenomic Networking in drug development: from pathogenic mechanisms to pharmacogenomics. Drug Dev Res 75: 348-365.
  • Carter D, Chakalova L, Osborne CS, Dai YF, Fraser P (2002) Long-range chromatin regulatory interactions in vivo. Nature Genet 32: 623-626.
  • Crutchley JL, Wang XQ, Ferraiuolo MA, Dostie J (2010) Chromatin conformation signatures: ideal human disease biomarkers? Biomark Med 4: 611-629.
  • Davison LJ, Wallace C, Cooper JD, Cope NF, Wilson NK, Smyth DJ, Howson JMM, Saleh N, Al-Jeffery A, Angus KL, Stevens HE, Nutland S, Duley S, Coulson RMR, Walker NM, Burren OS, Rice CM, Cambien F, Zeller T, Munzel T, Lackner K, Blankenberg S, The Cardiogenics Consortium, Fraser P, Gottgens B, Todd JA (2012) Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene. Hum Mol Genet 21: 322-333.
  • Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295: 1306-1311.
  • Dietzel S, Zolghadr K, Hepperger C, Belmont AS (2004) Differential large-scale chromatin compaction and intranuclear positioning of transcribed versus non-transcribed transgene arrays containing beta-globin regulatory sequences. J Cell Sci 117: 4603-4614.
  • Dostie J, Richmond TA, Arnaout RA, Selzer RR, Lee WL, Honan TA, Rubio ED, Krumm A, Lamb J, Nusbaum C, Green RD, Dekker J (2006) Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16: 1299-1309.
  • Engreitz JM, Agarwala V, Mirny LA (2012) Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease. PloS One 7: e44196.
  • Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, Mohamed YB, Orlov YL, Velkov S, Ho A, Mei PH, Chew EG, Huang PY, Welboren WJ, Han Y, Ooi HS, Ariyaratne PN, Vega VB, Luo Y, Tan PY, Choy PY, Wansa KD, Zhao B, Lim KS, Leow SC, Yow JS, Joseph R, Li H, Desai KV, Thomsen JS, Lee YK, Karuturi RK, Herve T, Bourque G, Stunnenberg HG, Ruan X, Cacheux-Rataboul V, Sung WK, Liu ET, Wei CL, Cheung E, Ruan Y (2009) An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462: 58-64.
  • De Graaf CA, van Steensel B (2013) Chromatin organization: form to function. Curr Opin Genet Dev 23: 185-190.
  • Hagege H, Klous P, Braem C, Splinter E, Dekker J, Cathala G, de Laat W, Forne T (2007) Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nature Protocols 2: 1722-1733.
  • Hughes JR, Roberts N, McGowan S, Hay D, Giannoulatou E, Lynch M, De Gobbi M, Taylor S, Gibbons R, Higgs DR (2014) Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nature Genet 46: 205-212.
  • Kelly TK, De Carvalho DD, Jones PA (2010) Epigenetic modifications as therapeutic targets. Nature Biotechnol 28: 1069-1078.
  • Kolovos P, van de Werken HJ, Kepper N, Zuin J, Brouwer RW, Kockx CE, Wendt KS, van IJcken WF, Grosveld F, Knoch TA (2014) Targeted Chromatin Capture (T2C): a novel high resolution high throughput method to detect genomic interactions and regulatory elements. Epigenetics & Chromatin 7: 10.
  • LeBlanc SE, Wu Q, Barutcu AR, Xiao H, Ohkawa Y, Imbalzano AN (2014) The PPARĪ³ locus makes long-range chromatin interactions with selected tissue-specific gene loci during adipocyte differentiation in a protein kinase A dependent manner. PloS One 9: e86140.
  • Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, Sandstrom R, Bernstein B, Bender MA, Groudine M, Gnirke A, Stamatoyannopoulos J, Mirny LA, Lander ES, Dekker J (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326: 289-2893.
  • McBride DJ, Kleinjan DA (2004) Rounding up active cis-elements in the triple C corral: combining conservation, cleavage and conformation capture for the analysis of regulatory gene domains. Brief Funct Genomic Proteomic 3: 267-279.
  • Miele A, Dekker J (2009) Mapping cis- and trans- chromatin interaction networks using chromosome conformation capture (3C). Methods Mol Biol 464: 105-121.
  • Ott CJ, Blackledge NP, Kerschner JL, Leir SH, Crawford GE, Cotton CU, Harris A (2009a) Intronic enhancers coordinate epithelial-specific looping of the active CFTR locus. Proc Natl Acad Sci U S A 106: 19934-19939.
  • Ott CJ, Blackledge NP, Leir SH, Harris A (2009b) Novel regulatory mechanisms for the CFTR gene. Biochem Soc Trans 37: 843-848.
  • Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W (2003) The beta-globin nuclear compartment in development and erythroid differentiation. Nature Genet 35: 190-194.
  • Pecorino L (2012) Epigenomic and histonomic drugs. In Molecular Biology of cancer Mechnisms, Targets and Therapeutics, pp 70-72. Oxford University Press, Oxford.
  • Rodriguez A, Bjerling P (2013) The links between chromatin spatial organization and biological function. Biochem Soc Trans 41: 1634-1639.
  • Rousseau M, Ferraiuolo MA, Crutchley JL, Wang XQ, Miura H, Blanchette M, Dostie J (2014) Classifying leukemia types with chromatin conformation data. Genome Biol 15: R60.
  • Salem T, Gomard T, Court F, Moquet-Torcy G, Brockly F, Forne T, Piechaczyk M (2013) Chromatin loop organization of the junb locus in mouse dendritic cells. Nucleic Acids Res 41: 8908-8925.
  • Sexton T, Bantignies F, Cavalli G (2009) Genomic interactions: Chromatin loops and gene meeting points in transcriptional regulation. Semin Cell Dev Biol 20: 849-855.
  • Simonis M, Klous P, Splinter E, Moshkin Y, Willemsen R, de Wit E, van Steensel B, de Laat W (2006) Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nature Genet 38: 1348-1354.
  • Smyk M, Szafranski P, Startek M, Gambin A, Stankiewicz P (2013) Chromosome conformation capture-on-chip analysis of long-range cis-interactions of the SOX9 promoter. Chromosome Res. 21: 781-788.
  • Splinter E, de Laat W (2011) The complex transcription regulatory landscape of our genome: control in three dimensions. EMBO J 30: 4345-4355.
  • Splinter E, Heath H, Kooren J, Palstra RJ, Klous P, Grosveld F, Galjart N, de Laat W (2006) CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Develop 20: 2349-2354.
  • Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W (2002) Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol Cell 10: 1453-1465.
  • Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472: 120-124.
  • Wang S, Wen F, Wiley GB, Kinter MT, Gaffney PM (2013) An enhancer element harboring variants associated with systemic lupus erythematosus engages the TNFAIP3 promoter to influence A20 expression. PLoS Genetics 9: e1003750.
  • Wolffe AP, Hayes JJ (1999) Chromatin disruption and modification. Nucleic Acids Res 27: 711-720.
  • Yokota H, van den Engh G, Hearst JE, Sachs RK, Trask BJ (1995) Evidence for the organization of chromatin in megabase pair-sized loops arranged along a random walk path in the human G0/G1 interphase nucleus. J Cell Biol 130: 1239-1249.
  • Zeitz MJ, Ay F, Heidmann JD, Lerner PL, Noble WS, Steelman BN, Hoffman AR (2013) Genomic interaction profiles in breast cancer reveal altered chromatin architecture. PloS One 8: e73974.
  • Zhang Z, Ott CJ, Lewandowska MA, Leir SH, Harris A (2012) Molecular mechanisms controlling CFTR gene expression in the airway. J Cell Mol Med 16: 1321-3130.
  • Zhao Z, Tavoosidana G, Sjolinder M, Gondor A, Mariano P, Wang S, Kanduri C, Lezcano M, Sandhu KS, Singh U, Pant V, Tiwari V, Kurukuti S, Ohlsson R (2006) Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nature Genet 38: 1341-1347.
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