The role of enhancers in cancer (original) (raw)

• Futreal, P. A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).
  Article CAS PubMed Google Scholar
• Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).
  CAS PubMed PubMed Central Google Scholar
• Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Garraway, L. A. & Lander, E. S. Lessons from the cancer genome. Cell 153, 17–37 (2013).
  Article CAS PubMed Google Scholar
• Dalla-Favera, R. et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 79, 7824–7827 (1982).
  Article CAS PubMed PubMed Central Google Scholar
• Taub, R. et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837–7841 (1982).
  Article CAS PubMed PubMed Central Google Scholar
• Ar-Rushdi, A. et al. Differential expression of the translocated and the untranslocated c-myc oncogene in Burkitt lymphoma. Science 222, 390–393 (1983).
  Article CAS PubMed Google Scholar
• Erikson, J., ar-Rushdi, A., Drwinga, H. L., Nowell, P. C. & Croce, C. M. Transcriptional activation of the translocated c-myc oncogene in Burkitt lymphoma. Proc. Natl Acad. Sci. USA 80, 820–824 (1983).
  Article CAS PubMed PubMed Central Google Scholar
• Frohling, S. & Dohner, H. Chromosomal abnormalities in cancer. N. Engl. J. Med. 359, 722–734 (2008).
  Article CAS PubMed Google Scholar
• Dekker, J., Marti-Renom, M. A. & Mirny, L. A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat. Rev. Genet. 14, 390–403 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Schwarzer, W. & Spitz, F. The architecture of gene expression: integrating dispersed _cis_-regulatory modules into coherent regulatory domains. Curr. Opin. Genet. Dev. 27, 74–82 (2014).
  Article CAS PubMed Google Scholar
• Gorkin, D. U., Leung, D. & Ren, B. The 3D genome in transcriptional regulation and pluripotency. Cell Stem Cell 14, 762–775 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159, 374–387 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Zabidi, M. A. et al. Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation. Nature 518, 556–559 (2015).
  Article CAS PubMed Google Scholar
• Goto, T., Macdonald, P. & Maniatis, T. Early and late periodic patterns of even skipped expression are controlled by distinct regulatory elements that respond to different spatial cues. Cell 57, 413–422 (1989).
  Article CAS PubMed Google Scholar
• Harding, K., Hoey, T., Warrior, R. & Levine, M. Autoregulatory and gap gene response elements of the even-skipped promoter of Drosophila. EMBO J. 8, 1205–1212 (1989).
  Article CAS PubMed PubMed Central Google Scholar
• Sharpe, J., Nonchev, S., Gould, A., Whiting, J. & Krumlauf, R. Selectivity, sharing and competitive interactions in the regulation of Hoxb genes. EMBO J. 17, 1788–1798 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Buecker, C. & Wysocka, J. Enhancers as information integration hubs in development: lessons from genomics. Trends Genet. 28, 276–284 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Perry, M. W., Boettiger, A. N., Bothma, J. P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20, 1562–1567 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bell, O., Tiwari, V. K., Thomä, N. H. & Schübeler, D. Determinants and dynamics of genome accessibility. Nat. Rev. Genet. 12, 554–564 (2011).
  Article CAS PubMed Google Scholar
• Schübeler, D. Function and information content of DNA methylation. Nature 517, 321–326 (2015).
  Article CAS PubMed Google Scholar
• Furey, T. S. ChIP-seq and beyond: new and improved methodologies to detect and characterize protein–DNA interactions. Nat. Rev. Genet. 13, 840–852 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stormo, G. D. & Zhao, Y. Determining the specificity of protein–DNA interactions. Nat. Rev. Genet. 11, 751–760 (2010).
  Article CAS PubMed Google Scholar
• Levo, M. & Segal, E. In pursuit of design principles of regulatory sequences. Nat. Rev. Genet. 15, 453–468 (2014).
  Article CAS PubMed Google Scholar
• Laird, P. W. Principles and challenges of genomewide DNA methylation analysis. Nat. Rev. Genet. 11, 191–203 (2010).
  Article CAS PubMed Google Scholar
• Belton, J. M. et al. Hi-C: a comprehensive technique to capture the conformation of genomes. Methods 58, 268–276 (2012).
  Article CAS PubMed Google Scholar
• Pennacchio, L. A. et al. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499–502 (2006).
  Article CAS PubMed Google Scholar
• Segal, E., Raveh-Sadka, T., Schroeder, M., Unnerstall, U. & Gaul, U. Predicting expression patterns from regulatory sequence in Drosophila segmentation. Nature 451, 535–540 (2008).
  Article CAS PubMed Google Scholar
• Markstein, M., Markstein, P., Markstein, V. & Levine, M. S. Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo. Proc. Natl Acad. Sci. USA 99, 763–768 (2002).
  Article CAS PubMed Google Scholar
• Hallikas, O. et al. Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124, 47–59 (2006).This study revealed the presence of multiple enhancers regulating the MYC and MYCN oncogenes.
  Article CAS PubMed Google Scholar
• Fullwood, M. J. et al. An oestrogen receptor α-bound human chromatin interactome. Nature 462, 58–64 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Song, L. et al. Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Res. 21, 1757–1767 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Shlyueva, D., Stampfel, G. & Stark, A. Transcriptional enhancers: from properties to genome-wide predictions. Nat. Rev. Genet. 15, 272–286 (2014).
  Article CAS PubMed Google Scholar
• Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011).
  Article CAS PubMed Google Scholar
• Heyn, H. et al. Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol. 17, 11 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hu, G. et al. H2A. Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation. Cell Stem Cell 12, 180–192 (2013).
  Article CAS PubMed Google Scholar
• Jin, C. et al. H3.3/H2A. Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions. Nat. Genet. 41, 941–945 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Yukawa, M. et al. Genome-wide analysis of the chromatin composition of histone H2A and H3 variants in mouse embryonic stem cells. PLoS ONE 9, e92689 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010).
  Article PubMed PubMed Central Google Scholar
• Roh, T. Y., Cuddapah, S. & Zhao, K. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. Genes Dev. 19, 542–552 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Seumois, G. et al. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. Nat. Immunol. 15, 777–788 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Verzi, M. P. et al. Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2. Dev. Cell 19, 713–726 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Lam, M. T., Li, W., Rosenfeld, M. G. & Glass, C. K. Enhancer RNAs and regulated transcriptional programs. Trends Biochem. Sci. 39, 170–182 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).
  CAS PubMed PubMed Central Google Scholar
• Yan, J. et al. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell 154, 801–813 (2013).
  Article CAS PubMed Google Scholar
• Hnisz, D. et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol. Cell 58, 362–370 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Mansour, M. R. et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377 (2014).This study shows the de novo generation of a super-enhancer in tumour cells through somatic mutations that introduce TF binding sites.
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, H. Y. et al. A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential. Genes Dev. 28, 2699–2711 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Li, Y. et al. CRISPR reveals a distal super-enhancer required for Sox2 expression in mouse embryonic stem cells. PLoS ONE 9, e114485 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Akhtar-Zaidi, B. et al. Epigenomic enhancer profiling defines a signature of colon cancer. Science 336, 736–739 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Aran, D., Sabato, S. & Hellman, A. DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes. Genome Biol. 14, R21 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).This study indicates that super-enhancers generated de novo in tumour cells can be selectively inhibited by the BET-bromodomain inhibitor JQ1.
  Article CAS PubMed PubMed Central Google Scholar
• Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
  Article CAS PubMed Google Scholar
• Jia, L. et al. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 5, e1000597 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wasserman, N. F., Aneas, I. & Nobrega, M. A. An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. Genome Res. 20, 1191–1197 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ahmadiyeh, N. et al. 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc. Natl Acad. Sci. USA 107, 9742–9746 (2010).This study found that multiple tumour type-specific enhancers are found close to the MYC oncogene.
  Article PubMed PubMed Central Google Scholar
• Tuupanen, S. et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat. Genet. 41, 885–890 (2009).
  Article CAS PubMed Google Scholar
• Pomerantz, M. M. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882–884 (2009).References 61 and 62 show that SNPs identified by GWAS can alter the affinity of enhancers for oncogenic TFs.
  Article CAS PubMed PubMed Central Google Scholar
• Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).
  Article CAS PubMed Google Scholar
• Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009).
  Article PubMed PubMed Central Google Scholar
• Manolio, T. A. Genomewide association studies and assessment of the risk of disease. N. Engl. J. Med. 363, 166–176 (2010).
  Article CAS PubMed Google Scholar
• Schaub, M. A., Boyle, A. P., Kundaje, A., Batzoglou, S. & Snyder, M. Linking disease associations with regulatory information in the human genome. Genome Res. 22, 1748–1759 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Nicolae, D. L. et al. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 6, e1000888 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hulur, I. et al. Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC Genomics 16, 138 (2015).
  Article PubMed PubMed Central Google Scholar
• Li, Q. et al. Integrative eQTL-based analyses reveal the biology of breast cancer risk loci. Cell 152, 633–641 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Q.-R., Hu, Y., Yan, C., Buetow, K. & Meerzaman, D. Systematic genetic analysis identifies cis-eQTL target genes associated with glioblastoma patient survival. PLoS ONE 9, e105393 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Albert, F. W. & Kruglyak, L. The role of regulatory variation in complex traits and disease. Nat. Rev. Genet. 16, 197–212 (2015).
  Article CAS PubMed Google Scholar
• Fortini, B. K. et al. Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. PLoS ONE 9, e111914 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Oldridge, D. A. et al. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528, 418–421 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, Q. et al. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nat. Genet. 46, 126–135 (2014).
  Article CAS PubMed Google Scholar
• He, H. et al. Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. Proc. Natl Acad. Sci. USA 112, 6128–6133 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Dunning, A. M. et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1. RMND1 and CCDC170. Nat. Genet. 48, 374–386 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Amundadottir, L. T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).
  Article CAS PubMed Google Scholar
• Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).
  Article CAS PubMed Google Scholar
• Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).
  Article CAS PubMed Google Scholar
• Yeager, M. et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41, 1055–1057 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ghoussaini, M. et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl Cancer Inst. 100, 962–966 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Crowther-Swanepoel, D. et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).
  Article CAS PubMed Google Scholar
• Zanke, B. W. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat. Genet. 39, 989–994 (2007).
  Article CAS PubMed Google Scholar
• Varghese, J. S. & Easton, D. F. Genome-wide association studies in common cancers–what have we learnt? Curr. Opin. Genet. Dev. 20, 201–209 (2010).
  Article CAS PubMed Google Scholar
• Pomerantz, M. M. & Freedman, M. L. The genetics of cancer risk. Cancer J. 17, 416–422 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sur, I., Tuupanen, S., Whitington, T., Aaltonen, L. A. & Taipale, J. Lessons from functional analysis of genome-wide association studies. Cancer Res. 73, 4180–4184 (2013).
  Article CAS PubMed Google Scholar
• Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hsu, P.-Y. et al. Amplification of distant estrogen response elements deregulates target genes associated with tamoxifen resistance in breast cancer. Cancer Cell 24, 197–212 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Tuupanen, S. et al. Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution. Cancer Res. 68, 14–17 (2008).The first study to show that a chromosomal region carrying a cancer-risk allele identified by GWAS is preferentially somatically amplified in cancer cells.
  Article CAS PubMed Google Scholar
• Sur, I. K. et al. Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science 338, 1360–1363 (2012).This study showed that deletion of an enhancer element carrying a cancer-risk allele has a marked effect on tumour development.
  Article CAS PubMed Google Scholar
• Zhang, X. et al. Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat. Genet. 48, 176–182 (2016).
  Article CAS PubMed Google Scholar
• Herranz, D. et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20, 1130–1137 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Cauwelier, B. et al. Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRβ locus rearrangements and putative new T-cell oncogenes. Leukemia 20, 1238–1244 (2006).
  Article CAS PubMed Google Scholar
• Northcott, P. A. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Katainen, R. et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat. Genet. 47, 818–821 (2015).
  Article CAS PubMed Google Scholar
• Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).
  Article CAS PubMed Google Scholar
• Schuster-Böckler, B. & Lehner, B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012).
  Article CAS PubMed Google Scholar
• Polak, P. et al. Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair. Nat. Biotechnol. 32, 71–75 (2014).
  Article CAS PubMed Google Scholar
• Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).
  Article CAS PubMed Google Scholar
• Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013).References 105 and 106 show how somatic mutations in the non-coding regulatory genome alter TF binding sites and cause deregulated expression of TERT in cancer.
  Article CAS PubMed PubMed Central Google Scholar
• Melton, C., Reuter, J. A., Spacek, D. V. & Snyder, M. Recurrent somatic mutations in regulatory regions of human cancer genomes. Nat. Genet. 47, 710–716 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Weinhold, N., Jacobsen, A., Schultz, N., Sander, C. & Lee, W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat. Genet. 46, 1160–1165 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Kinde, I. et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 73, 7162–7167 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Nault, J. C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 4, 2218 (2013).
  Article CAS PubMed Google Scholar
• Mertens, F., Johansson, B., Fioretos, T. & Mitelman, F. The emerging complexity of gene fusions in cancer. Nat. Rev. Cancer 15, 371–381 (2015).
  Article CAS PubMed Google Scholar
• Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245 (2007).
  Article CAS PubMed Google Scholar
• Pomerantz, M. M. et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat. Genet. 47, 1346–1351 (2015).A hallmark study showing how aberrant expression of a lineage-specific TF alters the binding landscape of an oncogenic TF.
  Article CAS PubMed PubMed Central Google Scholar
• Solomon, D. A., Kim, J. S. & Waldman, T. Cohesin gene mutations in tumorigenesis: from discovery to clinical significance. BMB Rep. 47, 299–310 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Plass, C. et al. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat. Rev. Genet. 14, 765–780 (2013).
  Article CAS PubMed Google Scholar
• Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bhaskara, S. et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436–447 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, H. et al. _Rad21_-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice. PLoS ONE 5, e12112 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, L., Rau, R. & Goodell, M. A. DNMT3A in haematological malignancies. Nat. Rev. Cancer 15, 152–165 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, Y. & Rao, A. Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet. 30, 464–474 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Witte, T., Plass, C. & Gerhauser, C. Pan-cancer patterns of DNA methylation. Genome Med. 6, 66 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
  CAS PubMed PubMed Central Google Scholar
• Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Herman, J. G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA 91, 9700–9704 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Esteller, M. et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564–569 (2000).
  Article CAS PubMed Google Scholar
• Blattler, A. & Farnham, P. J. Cross-talk between site-specific transcription factors and DNA methylation states. J. Biol. Chem. 288, 34287–34294 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).
  Article CAS PubMed Google Scholar
• Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Webster, D. E. et al. Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition. Genome Res. 24, 751–760 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Tak, Y. G. et al. Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells. Nucleic Acids Res. 44, 4123–4133 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Diffner, E. et al. Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia. Blood 121, 2289–2300 (2013).
  Article CAS PubMed Google Scholar
• Lehmann-Werman, R. et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc. Natl Acad. Sci. USA 113, E1826–E1834 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, K. et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc. Natl Acad. Sci. USA 112, E5503–E5512 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Snyder, M. W., Kircher, M., Hill, A. J., Daza, R. M. & Shendure, J. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 164, 57–68 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Chipumuro, E. et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159, 1126–1139 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).This report showed the efficacy of JQ1 in inhibiting MYC transcription.
  Article CAS PubMed PubMed Central Google Scholar
• Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• West, A. C. & Johnstone, R. W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124, 30–39 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Richon, V. M., Sandhoff, T. W., Rifkind, R. A. & Marks, P. A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl Acad. Sci. USA 97, 10014–10019 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Insinga, A. et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat. Med. 11, 71–76 (2005).
  Article CAS PubMed Google Scholar
• Rhodes, J. M. et al. Positive regulation of c-Myc by cohesin is direct, and evolutionarily conserved. Dev. Biol. 344, 637–649 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• McEwan, M. V., Eccles, M. R. & Horsfield, J. A. Cohesin is required for activation of MYC by estradiol. PLoS ONE 7, e49160 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Pelish, H. E. et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526, 273–276 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Nebbioso, A. et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat. Med. 11, 77–84 (2005).
  Article CAS PubMed Google Scholar
• Xu, W. S., Perez, G., Ngo, L., Gui, C. Y. & Marks, P. A. Induction of polyploidy by histone deacetylase inhibitor: a pathway for antitumor effects. Cancer Res. 65, 7832–7839 (2005).
  Article CAS PubMed Google Scholar
• Gui, C. Y., Ngo, L., Xu, W. S., Richon, V. M. & Marks, P. A. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc. Natl Acad. Sci. USA 101, 1241–1246 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Rathert, P. et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525, 543–547 (2015).This paper shows that changes in enhancer usage can cause resistance to JQ1-mediated inhibition of MYC expression.
  Article CAS PubMed PubMed Central Google Scholar
• Kumar, K. et al. GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. Sci. Rep. 5, 9489 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Fong, C. Y. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538–542 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714–726 (2013).
  Article CAS PubMed Google Scholar
• Huang, M., Shen, A., Ding, J. & Geng, M. Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol. Sci. 35, 41–50 (2014).
  Article CAS PubMed Google Scholar
• Kress, T. R., Sabo, A. & Amati, B. MYC: connecting selective transcriptional control to global RNA production. Nat. Rev. Cancer 15, 593–607 (2015).
  Article CAS PubMed Google Scholar
• Bolden, J. E. et al. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell Rep. 8, 1919–1929 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Lettice, L. A. et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12, 1725–1735 (2003).
  Article CAS PubMed Google Scholar
• ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
• Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).
  Article CAS PubMed Google Scholar
• Ong, C.-T. & Corces, V. G. CTCF: an architectural protein bridging genome topology and function. Nat. Rev. Genet. 15, 234–246 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).
  Article CAS PubMed PubMed Central Google Scholar