Super-enhancer explained

In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity.[1] [2] [3] Because super-enhancers are frequently identified near genes important for controlling and defining cell identity, they may thus be used to quickly identify key nodes regulating cell identity.[4]

Enhancers have several quantifiable traits that have a range of values, and these traits are generally elevated at super-enhancers. Super-enhancers are bound by higher levels of transcription-regulating proteins and are associated with genes that are more highly expressed.[1] [5] [6] [7] Expression of genes associated with super-enhancers is particularly sensitive to perturbations, which may facilitate cell state transitions or explain sensitivity of super-enhancer—associated genes to small molecules that target transcription.[1] [8] [9]

History

The regulation of transcription by enhancers has been studied since the 1980s.[10] [11] [12] [13] [14] Large or multi-component transcription regulators with a range of mechanistic properties, including locus control regions, clustered open regulatory elements, and transcription initiation platforms, were observed shortly thereafter.[15] [16] [17] [18] More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer.[19]

In 2013, two labs identified large enhancers near several genes especially important for establishing cell identities. While Richard A. Young and colleagues identified super-enhancers, Francis Collins and colleagues identified stretch enhancers.[1] Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous.[20]

As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse embryonic stem cells (ESCs). These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including Oct-4, Sox2, Nanog, Klf4, and Esrrb. Perturbation of the super-enhancers associated with these genes showed a range of effects on their target genes’ expression. Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues. [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]

Function

The enhancers comprising super-enhancers share the functions of enhancers, including binding transcription factor proteins, looping to target genes, and activating transcription.[1] [3] [19] [20] Three notable traits of enhancers comprising super-enhancers are their clustering in genomic proximity, their exceptional signal of transcription-regulating proteins, and their high frequency of physical interaction with each other. Perturbing the DNA of enhancers comprising super-enhancers showed a range of effects on the expression of cell identity genes, suggesting a complex relationship between the constituent enhancers.[20] Super-enhancers separated by tens of megabases cluster in three-dimensions inside the nucleus of mouse embryonic stem cells.[38] [39]

High levels of many transcription factors and co-factors are seen at super-enhancers (e.g., CDK7, BRD4, and Mediator).[1] [3] [5] [8] [9] [19] This high concentration of transcription-regulating proteins suggests why their target genes tend to be more highly expressed than other classes of genes. However, housekeeping genes tend to be more highly expressed than super-enhancer—associated genes.[1]

Super-enhancers may have evolved at key cell identity genes to render the transcription of these genes responsive to an array of external cues.[20] The enhancers comprising a super-enhancer can each be responsive to different signals, which allows the transcription of a single gene to be regulated by multiple signaling pathways.[20] Pathways seen to regulate their target genes using super-enhancers include Wnt, TGFb, LIF, BDNF, and NOTCH.[20] [40] [41] [42] [43] The constituent enhancers of super-enhancers physically interact with each other and their target genes over a long range sequence-wise.[7] [22] [44] Super-enhancers that control the expression of major cell surface receptors with a crucial role in the function of a given cell lineage have also been defined. This is notably the case for B-lymphocytes, the survival, the activation and the differentiation of which rely on the expression of membrane-form immunoglobulins (Ig). The Ig heavy chain locus super-enhancer is a very large (25kb) cis-regulatory region, including multiple enhancers and controlling several major modifications of the locus (notably somatic hypermutation, class-switch recombination and locus suicide recombination).

Relevance to Disease

Mutations in super-enhancers have been noted in various diseases, including cancers, type 1 diabetes, Alzheimer’s disease, lupus, rheumatoid arthritis, multiple sclerosis, systemic scleroderma, primary biliary cirrhosis, Crohn’s disease, Graves disease, vitiligo, and atrial fibrillation.[45] [46] [47] [48] [49] A similar enrichment in disease-associated sequence variation has also been observed for stretch enhancers.

Super-enhancers may play important roles in the misregulation of gene expression in cancer. During tumor development, tumor cells acquire super-enhancers at key oncogenes, which drive higher levels of transcription of these genes than in healthy cells.[44] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] Altered super-enhancer function is also induced by mutations of chromatin regulators.[60] Acquired super-enhancers may thus be biomarkers that could be useful for diagnosis and therapeutic intervention.

Proteins enriched at super-enhancers include the targets of small molecules that target transcription-regulating proteins and have been deployed against cancers.[61] For instance, super-enhancers rely on exceptional amounts of CDK7, and, in cancer, multiple papers report the loss of expression of their target genes when cells are treated with the CDK7 inhibitor THZ1.[62] Similarly, super-enhancers are enriched in the target of the JQ1 small molecule, BRD4, so treatment with JQ1 causes exceptional losses in expression for super-enhancer—associated genes.

Identification

Super-enhancers have been most commonly identified by locating genomic regions that are highly enriched in ChIP-Seq signal. ChIP-Seq experiments targeting master transcription factors and co-factors like Mediator or BRD4 have been used, but the most frequently used is H3K27ac-marked nucleosomes.[63] [64] [65] The program “ROSE” (Rank Ordering of Super-Enhancers) is commonly used to identify super-enhancers from ChIP-Seq data. This program stitches together previously identified enhancer regions and ranks these stitched enhancers by their ChIP-Seq signal. The stitching distance selected to combine multiple individual enhancers into larger domains can vary. Because some markers of enhancer activity also are enriched in promoters, regions within promoters of genes can be disregarded. ROSE separates super-enhancers from typical enhancers by their exceptional enrichment in a mark of enhancer activity. Homer is another tool that can identify super-enhancers.[66]

Notes and References

  1. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA . Master transcription factors and mediator establish super-enhancers at key cell identity genes . Cell . 153 . 2 . 307–19 . April 2013 . 23582322 . 3653129 . 10.1016/j.cell.2013.03.035 .
  2. Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, van Bueren KL, Chines PS, Narisu N, Black BL, Visel A, Pennacchio LA, Collins FS . Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants . Proceedings of the National Academy of Sciences of the United States of America . 110 . 44 . 17921–6 . October 2013 . 24127591 . 3816444 . 10.1073/pnas.1317023110 . 2013PNAS..11017921P . free .
  3. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA . Super-enhancers in the control of cell identity and disease . Cell . 155 . 4 . 934–47 . November 2013 . 24119843 . 3841062 . 10.1016/j.cell.2013.09.053 .
  4. Saint-André V, Federation AJ, Lin CY, Abraham BJ, Reddy J, Lee TI, Bradner JE, Young RA . Models of human core transcriptional regulatory circuitries . Genome Research . 26 . 3 . 385–96 . March 2016 . 26843070 . 10.1101/gr.197590.115 . 4772020 .
  5. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, Tesar B, Jenkins CE, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND, Look T, Mitsiades CS, Weng AP, Brown JR, Benes CH, Marto JA, Young RA, Gray NS . 6 . Targeting transcription regulation in cancer with a covalent CDK7 inhibitor . Nature . 511 . 7511 . 616–20 . July 2014 . 25043025 . 4244910 . 10.1038/nature13393 . 2014Natur.511..616K .
  6. Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA . Selective inhibition of tumor oncogenes by disruption of super-enhancers . Cell . 153 . 2 . 320–34 . April 2013 . 23582323 . 3760967 . 10.1016/j.cell.2013.03.036 .
  7. Dowen JM, Fan ZP, Hnisz D, Ren G, Abraham BJ, Zhang LN, Weintraub AS, Schuijers J, Lee TI, Zhao K, Young RA . Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes . Cell . 159 . 2 . 374–87 . October 2014 . 25303531 . 4197132 . 10.1016/j.cell.2014.09.030 .
  8. Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, Chipumuro E, Herter-Sprie GS, Akbay EA, Altabef A, Zhang J, Shimamura T, Capelletti M, Reibel JB, Cavanaugh JD, Gao P, Liu Y, Michaelsen SR, Poulsen HS, Aref AR, Barbie DA, Bradner JE, George RE, Gray NS, Young RA, Wong KK . 6 . Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor . Cancer Cell . 26 . 6 . 909–22 . December 2014 . 25490451 . 4261156 . 10.1016/j.ccell.2014.10.019 .
  9. Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, Abraham BJ, Sharma B, Yeung C, Altabef A, Perez-Atayde A, Wong KK, Yuan GC, Gray NS, Young RA, George RE . CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer . Cell . 159 . 5 . 1126–39 . November 2014 . 25416950 . 4243043 . 10.1016/j.cell.2014.10.024 .
  10. Banerji J, Rusconi S, Schaffner W . Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences . Cell . 27 . 2 Pt 1 . 299–308 . December 1981 . 6277502 . 10.1016/0092-8674(81)90413-x . 54234674 .
  11. Benoist C, Chambon P . In vivo sequence requirements of the SV40 early promoter region . Nature . 290 . 5804 . 304–10 . March 1981 . 6259538 . 10.1038/290304a0 . 1981Natur.290..304B . 4263279 .
  12. Gruss P, Dhar R, Khoury G . Simian virus 40 tandem repeated sequences as an element of the early promoter . Proceedings of the National Academy of Sciences of the United States of America . 78 . 2 . 943–7 . February 1981 . 6262784 . 319921 . 10.1073/pnas.78.2.943 . 1981PNAS...78..943G . free .
  13. Evans T, Felsenfeld G, Reitman M . Control of globin gene transcription . Annual Review of Cell Biology . 6 . 95–124 . 1990 . 2275826 . 10.1146/annurev.cb.06.110190.000523 .
  14. Cellier M, Belouchi A, Gros P . Resistance to intracellular infections: comparative genomic analysis of Nramp . Trends in Genetics . 12 . 6 . 201–4 . June 1996 . 8928221 . 10.1016/0168-9525(96)30042-5 .
  15. George Stamatoyannopoulos. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G . Locus control regions . Blood . 100 . 9 . 3077–86 . November 2002 . 12384402 . 2811695 . 10.1182/blood-2002-04-1104 .
  16. Grosveld F, van Assendelft GB, Greaves DR, Kollias G . Position-independent, high-level expression of the human beta-globin gene in transgenic mice . Cell . 51 . 6 . 975–85 . December 1987 . 3690667 . 10.1016/0092-8674(87)90584-8 . 1765/2425 . 1150699 . free .
  17. Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D, Berney T, Montanya E, Mohlke KL, Lieb JD, Ferrer J . 6 . A map of open chromatin in human pancreatic islets . Nature Genetics . 42 . 3 . 255–9 . March 2010 . 20118932 . 2828505 . 10.1038/ng.530 .
  18. Koch F, Fenouil R, Gut M, Cauchy P, Albert TK, Zacarias-Cabeza J, Spicuglia S, de la Chapelle AL, Heidemann M, Hintermair C, Eick D, Gut I, Ferrier P, Andrau JC . Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters . Nature Structural & Molecular Biology . 18 . 8 . 956–63 . August 2011 . 21765417 . 10.1038/nsmb.2085 . 12778976 .
  19. Pott S, Lieb JD . What are super-enhancers? . Nature Genetics . 47 . 1 . 8–12 . January 2015 . 25547603 . 10.1038/ng.3167 . 205349376 .
  20. Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, Bradner JE, Young RA . Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers . Molecular Cell . 58 . 2 . 362–70 . April 2015 . 25801169 . 4402134 . 10.1016/j.molcel.2015.02.014 .
  21. Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, Dolgalev I, Yonekubo Y, Zhang G, Rusinova E, Gerona-Navarro G, Cañamero M, Ohlmeyer M, Aifantis I, Zhou MM, Tsirigos A, Hernando E . 6 . Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes . Cell Reports . 9 . 1 . 234–47 . October 2014 . 25263550 . 4317728 . 10.1016/j.celrep.2014.08.055 .
  22. Ji X, Dadon DB, Powell BE, Fan ZP, Borges-Rivera D, Shachar S, Weintraub AS, Hnisz D, Pegoraro G, Lee TI, Misteli T, Jaenisch R, Young RA . 3D Chromosome Regulatory Landscape of Human Pluripotent Cells . Cell Stem Cell . 18 . 2 . 262–75 . February 2016 . 26686465 . 10.1016/j.stem.2015.11.007 . 4848748 .
  23. Tsankov AM, Gu H, Akopian V, Ziller MJ, Donaghey J, Amit I, Gnirke A, Meissner A . Transcription factor binding dynamics during human ES cell differentiation . Nature . 518 . 7539 . 344–9 . February 2015 . 25693565 . 4499331 . 10.1038/nature14233 . 2015Natur.518..344T .
  24. Fang Z, Hecklau K, Gross F, Bachmann I, Venzke M, Karl M, Schuchhardt J, Radbruch A, Herzel H, Baumgrass R . Transcription factor co-occupied regions in the murine genome constitute T-helper-cell subtype-specific enhancers . European Journal of Immunology . 45 . 11 . 3150–7 . November 2015 . 26300430 . 10.1002/eji.201545713 . free .
  25. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ . Super-enhancers delineate disease-associated regulatory nodes in T cells . Nature . 520 . 7548 . 558–62 . April 2015 . 25686607 . 4409450 . 10.1038/nature14154 . 2015Natur.520..558V .
  26. Koues OI, Kowalewski RA, Chang LW, Pyfrom SC, Schmidt JA, Luo H, Sandoval LE, Hughes TB, Bednarski JJ, Cashen AF, Payton JE, Oltz EM . Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma . Immunity . 42 . 1 . 186–98 . January 2015 . 25607463 . 4302272 . 10.1016/j.immuni.2014.12.021 .
  27. Adam RC, Yang H, Rockowitz S, Larsen SB, Nikolova M, Oristian DS, Polak L, Kadaja M, Asare A, Zheng D, Fuchs E . Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice . Nature . 521 . 7552 . 366–70 . May 2015 . 25799994 . 4482136 . 10.1038/nature14289 . 2015Natur.521..366A .
  28. Siersbæk R, Baek S, Rabiee A, Nielsen R, Traynor S, Clark N, Sandelin A, Jensen ON, Sung MH, Hager GL, Mandrup S . Molecular architecture of transcription factor hotspots in early adipogenesis . Cell Reports . 7 . 5 . 1434–42 . June 2014 . 24857666 . 10.1016/j.celrep.2014.04.043 . 6360525 .
  29. Siersbæk R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, La Cour Poulsen L, Rogowska-Wrzesinska A, Jensen ON, Mandrup S . Transcription factor cooperativity in early adipogenic hotspots and super-enhancers . Cell Reports . 7 . 5 . 1443–55 . June 2014 . 24857652 . 10.1016/j.celrep.2014.04.042 . free .
  30. Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, Kurokawa M, Won KJ, Seale P . 6 . Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice . Cell Metabolism . 19 . 4 . 593–604 . April 2014 . 24703692 . 4012340 . 10.1016/j.cmet.2014.03.007 .
  31. Loft A, Forss I, Siersbæk MS, Schmidt SF, Larsen AS, Madsen JG, Pisani DF, Nielsen R, Aagaard MM, Mathison A, Neville MJ, Urrutia R, Karpe F, Amri EZ, Mandrup S . Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers . Genes & Development . 29 . 1 . 7–22 . January 2015 . 25504365 . 4281566 . 10.1101/gad.250829.114 .
  32. Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Morán I, Gómez-Marín C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, García-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Gómez-Skarmeta JL, Müller F, McCarthy MI, Ferrer J . 6 . Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants . Nature Genetics . 46 . 2 . 136–43 . February 2014 . 24413736 . 3935450 . 10.1038/ng.2870 .
  33. Liu CF, Lefebvre V . The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis . Nucleic Acids Research . 43 . 17 . 8183–203 . September 2015 . 26150426 . 4787819 . 10.1093/nar/gkv688 .
  34. Ohba S, He X, Hojo H, McMahon AP . Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte . Cell Reports . 12 . 2 . 229–43 . July 2015 . 26146088 . 4504750 . 10.1016/j.celrep.2015.06.013 .
  35. Kaikkonen MU, Niskanen H, Romanoski CE, Kansanen E, Kivelä AM, Laitalainen J, Heinz S, Benner C, Glass CK, Ylä-Herttuala S . Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization . Nucleic Acids Research . 42 . 20 . 12570–84 . November 2014 . 25352550 . 4227755 . 10.1093/nar/gku1036 .
  36. Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK . Environment drives selection and function of enhancers controlling tissue-specific macrophage identities . Cell . 159 . 6 . 1327–40 . December 2014 . 25480297 . 4364385 . 10.1016/j.cell.2014.11.023 .
  37. Sun J, Rockowitz S, Xie Q, Ashery-Padan R, Zheng D, Cvekl A . Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development . Nucleic Acids Research . 43 . 14 . 6827–46 . August 2015 . 26138486 . 4538810 . 10.1093/nar/gkv589 .
  38. Beagrie RA, Scialdone A, Schueler M, Kraemer DC, Chotalia M, Xie SQ, Barbieri M, de Santiago I, Lavitas LM, Branco MR, Fraser J, Dostie J, Game L, Dillon N, Edwards PA, Nicodemi M, Pombo A . Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM). Nature . 543 . 519–524 . March 2017 . 7646. 28273065 . 5366070 . 10.1038/nature21411 .
  39. Quinodoz SA, Ollikainen N, Tabak B, Palla A, Schmidt JM, Detmar E, Lai MM, Shishkin AA, Bhat P, Takei Y, Trinh V, Aznauryan E, Russell P, Cheng C, Jovanovic M, Chow A, Cai L, McDonel P, Garber M, Guttman M . Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus. Cell . 174 . 744–757 . June 2018 . 3. 29887377 . 10.1016/j.cell.2018.05.024 . 6548320.
  40. Joo JY, Schaukowitch K, Farbiak L, Kilaru G, Kim TK . Stimulus-specific combinatorial functionality of neuronal c-fos enhancers . Nature Neuroscience . 19 . 1 . 75–83 . January 2016 . 26595656 . 4696896 . 10.1038/nn.4170 .
  41. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, Xu L, Castillo-Martin M, Llobet-Navás D, Cordon-Cardo C, Clappier E, Soulier J, Ferrando AA . A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia . Nature Medicine . 20 . 10 . 1130–7 . October 2014 . 25194570 . 4192073 . 10.1038/nm.3665 .
  42. Wang H, Zang C, Taing L, Arnett KL, Wong YJ, Pear WS, Blacklow SC, Liu XS, Aster JC . NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers . Proceedings of the National Academy of Sciences of the United States of America . 111 . 2 . 705–10 . January 2014 . 24374627 . 3896193 . 10.1073/pnas.1315023111 . 2014PNAS..111..705W . free .
  43. Yashiro-Ohtani Y, Wang H, Zang C, Arnett KL, Bailis W, Ho Y, Knoechel B, Lanauze C, Louis L, Forsyth KS, Chen S, Chung Y, Schug J, Blobel GA, Liebhaber SA, Bernstein BE, Blacklow SC, Liu XS, Aster JC, Pear WS . 6 . Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia . Proceedings of the National Academy of Sciences of the United States of America . 111 . 46 . E4946-53 . November 2014 . 25369933 . 4246292 . 10.1073/pnas.1407079111 . 2014PNAS..111E4946Y . free .
  44. 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, Dekker J, Young RA . Activation of proto-oncogenes by disruption of chromosome neighborhoods . Science . 351 . 6280 . 1454–8 . March 2016 . 26940867 . 10.1126/science.aad9024 . 4884612. 2016Sci...351.1454H .
  45. Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, Etchin J, Lawton L, Sallan SE, Silverman LB, Loh ML, Hunger SP, Sanda T, Young RA, Look AT . Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element . Science . 346 . 6215 . 1373–7 . December 2014 . 25394790 . 4720521 . 10.1126/science.1259037 .
  46. Cavalli G, Hayashi M, Jin Y, Yorgov D, Santorico SA, Holcomb C, Rastrou M, Erlich H, Tengesdal IW, Dagna L, Neff CP, Palmer BE, Spritz RA, Dinarello CA . MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo . Proceedings of the National Academy of Sciences of the United States of America . 113 . 5 . 1363–8 . February 2016 . 26787888 . 10.1073/pnas.1523482113 . 4747741 . 2016PNAS..113.1363C . free .
  47. 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 . Genetic and epigenetic fine mapping of causal autoimmune disease variants . Nature . 518 . 7539 . 337–43 . February 2015 . 25363779 . 4336207 . 10.1038/nature13835 . 2015Natur.518..337F .
  48. Weinstein JS, Lezon-Geyda K, Maksimova Y, Craft S, Zhang Y, Su M, Schulz VP, Craft J, Gallagher PG . Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes . Blood . 124 . 25 . 3719–29 . December 2014 . 25331115 . 4263981 . 10.1182/blood-2014-06-582700 .
  49. Oldridge DA, Wood AC, Weichert-Leahey N, Crimmins I, Sussman R, Winter C, McDaniel LD, Diamond M, Hart LS, Zhu S, Durbin AD, Abraham BJ, Anders L, Tian L, Zhang S, Wei JS, Khan J, Bramlett K, Rahman N, Capasso M, Iolascon A, Gerhard DS, Guidry Auvil JM, Young RA, Hakonarson H, Diskin SJ, Look AT, Maris JM . 6 . Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism . Nature . 528 . 7582 . 418–21 . December 2015 . 26560027 . 4775078 . 10.1038/nature15540 . 2015Natur.528..418O .
  50. Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, Garbitt VM, Riggs DL, Brents LA, Roschke AV, Van Wier S, Fonseca R, Bergsagel PL, Kuehl WM . Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma . Leukemia . 28 . 8 . 1725–35 . August 2014 . 24518206 . 4126852 . 10.1038/leu.2014.70 .
  51. Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ, Kluk MJ, Carey CD, Rodig SJ, Sholl LM, Afrogheh AH, Faquin WC, Queimado L, Qi J, Wick MJ, El-Naggar AK, Bradner JE, Moskaluk CA, Aster JC, Knoechel B, Bernstein BE . 6 . An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma . Nature Genetics . 48 . 3 . 265–72 . March 2016 . 26829750 . 10.1038/ng.3502 . 4767593 .
  52. Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, Shih DJ, Hovestadt V, Zapatka M, Sturm D, Jones DT, Kool M, Remke M, Cavalli FM, Zuyderduyn S, Bader GD, VandenBerg S, Esparza LA, Ryzhova M, Wang W, Wittmann A, Stark S, Sieber L, Seker-Cin H, Linke L, Kratochwil F, Jäger N, Buchhalter I, Imbusch CD, Zipprich G, Raeder B, Schmidt S, Diessl N, Wolf S, Wiemann S, Brors B, Lawerenz C, Eils J, Warnatz HJ, Risch T, Yaspo ML, Weber UD, Bartholomae CC, von Kalle C, Turányi E, Hauser P, Sanden E, Darabi A, Siesjö P, Sterba J, Zitterbart K, Sumerauer D, van Sluis P, Versteeg R, Volckmann R, Koster J, Schuhmann MU, Ebinger M, Grimes HL, Robinson GW, Gajjar A, Mynarek M, von Hoff K, Rutkowski S, Pietsch T, Scheurlen W, Felsberg J, Reifenberger G, Kulozik AE, von Deimling A, Witt O, Eils R, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Korbel JO, Wechsler-Reya RJ, Pfizer SM . 6 . Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma . Nature . 511 . 7510 . 428–34 . July 2014 . 25043047 . 4201514 . 10.1038/nature13379 . 2014Natur.511..428N .
  53. Walker BA, Wardell CP, Brioli A, Boyle E, Kaiser MF, Begum DB, Dahir NB, Johnson DC, Ross FM, Davies FE, Morgan GJ . Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients . Blood Cancer Journal . 4 . e191 . 14 March 2014 . 3 . 24632883 . 3972699 . 10.1038/bcj.2014.13 .
  54. 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 . 6 . A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia . Cell . 157 . 2 . 369–81 . April 2014 . 24703711 . 10.1016/j.cell.2014.02.019 . free .
  55. Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, Minder JL, Mercan F, Wang E, Eckersley-Maslin MA, Campbell AE, Kawaoka S, Shareef S, Zhu Z, Kendall J, Muhar M, Haslinger C, Yu M, Roeder RG, Wigler MH, Blobel GA, Zuber J, Spector DL, Young RA, Vakoc CR . 6 . Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation . Genes & Development . 27 . 24 . 2648–62 . December 2013 . 24285714 . 3877755 . 10.1101/gad.232710.113 .
  56. Kennedy AL, Vallurupalli M, Chen L, Crompton B, Cowley G, Vazquez F, Weir BA, Tsherniak A, Parasuraman S, Kim S, Alexe G, Stegmaier K . Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma . Oncotarget . 6 . 30 . 30178–93 . October 2015 . 26337082 . 4745789 . 10.18632/oncotarget.4903 .
  57. Tomazou EM, Sheffield NC, Schmidl C, Schuster M, Schönegger A, Datlinger P, Kubicek S, Bock C, Kovar H . Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1 . Cell Reports . 10 . 7 . 1082–95 . February 2015 . 25704812 . 4542316 . 10.1016/j.celrep.2015.01.042 .
  58. Nabet B, Ó Broin P, Reyes JM, Shieh K, Lin CY, Will CM, Popovic R, Ezponda T, Bradner JE, Golden AA, Licht JD . Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape . Cell Reports . 12 . 8 . 1300–13 . August 2015 . 26279576 . 10.1016/j.celrep.2015.06.078 . 4551578 . free .
  59. Zhang X, Choi PS, Francis JM, Imielinski M, Watanabe H, Cherniack AD, Meyerson M . Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers . Nature Genetics . 48 . 2 . 176–82 . February 2016 . 26656844 . 4857881 . 10.1038/ng.3470 .
  60. Hodges HC, Stanton BZ, Cermakova K, Chang CY, Miller EL, Kirkland JG, Ku WL, Veverka V, Zhao K, Crabtree GR . Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers . Nature Structural & Molecular Biology . 25 . 1 . 61–72 . January 2018 . 29323272 . 10.1038/s41594-017-0007-3 . 5909405 .
  61. Porcher C . Toward a BETter grasp of acetyl-lysine readers . Blood . 125 . 18 . 2739–41 . April 2015 . 25931578 . 10.1182/blood-2015-03-630830 . free .
  62. Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI, Xie S, Yuzugullu H, Von T, Li H, Lin Z, Stover DG, Lim E, Wang ZC, Iglehart JD, Young RA, Gray NS, Zhao JJ . CDK7-dependent transcriptional addiction in triple-negative breast cancer . Cell . 163 . 1 . 174–86 . September 2015 . 26406377 . 10.1016/j.cell.2015.08.063 . 4583659 . free .
  63. Wei Y, Zhang S, Shang S, Zhang B, Li S, Wang X, Wang F, Su J, Wu Q, Liu H, Zhang Y . SEA: a super-enhancer archive . Nucleic Acids Research . 44 . D1 . D172-9 . January 2016 . 26578594 . 4702879 . 10.1093/nar/gkv1243 .
  64. Khan A, Zhang X . dbSUPER: a database of super-enhancers in mouse and human genome . Nucleic Acids Research . 44 . D1 . D164-71 . January 2016 . 26438538 . 4702767 . 10.1093/nar/gkv1002 .
  65. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna J, Lodato MA, Frampton GM, Sharp PA, Boyer LA, Young RA, Jaenisch R . Histone H3K27ac separates active from poised enhancers and predicts developmental state . Proceedings of the National Academy of Sciences of the United States of America . 107 . 50 . 21931–6 . December 2010 . 21106759 . 3003124 . 10.1073/pnas.1016071107 . free .
  66. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities . Molecular Cell . 38 . 4 . 576–89 . May 2010 . 20513432 . 2898526 . 10.1016/j.molcel.2010.05.004 .

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