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What are super-enhancers?

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Abstract

The term 'super-enhancer' has been used to describe groups of putative enhancers in close genomic proximity with unusually high levels of Mediator binding, as measured by chromatin immunoprecipitation and sequencing (ChIP-seq). Here we review the identification and composition of super-enhancers, describe links between super-enhancers, gene regulation and disease, and discuss the functional significance of enhancer clustering. We also provide our perspective regarding the proposition that super-enhancers are a regulatory entity conceptually distinct from what was known before the introduction of the term. Our opinion is that there is not yet strong evidence that super-enhancers are a novel paradigm in gene regulation and that use of the term in this context is not currently justified. However, the term likely identifies strong enhancers that exhibit behaviors consistent with previous models and concepts of transcriptional regulation. In this respect, the super-enhancer definition is useful in identifying regulatory elements likely to control genes important for cell type specification.

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Figure 1: Defining super-enhancers.
Figure 2: Schematic of an experimental approach to characterizing super-enhancers.

References

  1. 1

    Banerji, J., Rusconi, S. & Schaffner, W. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981).

    CAS  Article  Google Scholar 

  2. 2

    Neuberger, M.S. Expression and regulation of immunoglobulin heavy chain gene transfected into lymphoid cells. EMBO J. 2, 1373–1378 (1983).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3

    Gillies, S.D., Morrison, S.L., Oi, V.T. & Tonegawa, S. A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell 33, 717–728 (1983).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4

    Banerji, J., Olson, L. & Schaffner, W. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell 33, 729–740 (1983).

    CAS  Article  Google Scholar 

  5. 5

    Lelli, K.M., Slattery, M. & Mann, R.S. Disentangling the many layers of eukaryotic transcriptional regulation. Annu. Rev. Genet. 46, 43–68 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Spitz, F. & Furlong, E.E.M. Transcription factors: from enhancer binding to developmental control. Nat. Rev. Genet. 13, 613–626 (2012).

    CAS  Article  Google Scholar 

  7. 7

    Bulger, M. & Groudine, M. Functional and mechanistic diversity of distal transcription enhancers. Cell 144, 327–339 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Shlyueva, D., Stampfel, G. & Stark, A. Transcriptional enhancers: from properties to genome-wide predictions. Nat. Rev. Genet. 15, 272–286 (2014).

    CAS  Google Scholar 

  9. 9

    Deng, W. et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell 149, 1233–1244 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Tolhuis, B., Palstra, R.J., Splinter, E., Grosveld, F. & de Laat, W. Looping and interaction between hypersensitive sites in the active β-globin locus. Mol. Cell 10, 1453–1465 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Thurman, R.E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 488, 57–60 (2012).

  14. 14

    Johnson, D.S., Mortazavi, A., Myers, R.M. & Wold, B. Genome-wide mapping of in vivo protein-DNA interactions. Science 316, 1497–1502 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    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).

    CAS  Article  Google Scholar 

  17. 17

    Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    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).

    CAS  Article  Google Scholar 

  20. 20

    Zhu, J. et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell 152, 642–654 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Nord, A.S. et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155, 1521–1531 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Whyte, W.A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Parker, S.C.J. et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl. Acad. Sci. USA 110, 17921–17926 (2013).

    CAS  Article  Google Scholar 

  26. 26

    Kagey, M.H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Siersbæk, R. et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 7, 1443–1455 (2014).

    Article  CAS  Google Scholar 

  28. 28

    Akhtar-Zaidi, B. et al. Epigenomic enhancer profiling defines a signature of colon cancer. Science 336, 736–739 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Chapuy, B. et al. Discovery and characterization of super-enhancer–associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24, 777–790 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Jang, M.K. et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II–dependent transcription. Mol. Cell 19, 523–534 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Dey, A., Chitsaz, F., Abbasi, A., Misteli, T. & Ozato, K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl. Acad. Sci. USA 100, 8758–8763 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Dawson, M.A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Delmore, J.E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Mertz, J.A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl. Acad. Sci. USA 108, 16669–16674 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Xiang, J.-F. et al. Human colorectal cancer–specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 24, 513–531 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Kwiatkowski, N. et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616–620 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Knoechel, B. et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46, 364–370 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Shi, J. et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648–2662 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Northcott, P.A. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Affer, M. et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28, 1725–1735 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Walker, B.A. et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J. 4, e191 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Gröschel, S. et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157, 369–381 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44

    Hayday, A.C. et al. Activation of a translocated human c-myc gene by an enhancer in the immunoglobulin heavy-chain locus. Nature 307, 334–340 (1984).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46

    Maurano, M.T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Pasquali, L. et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124–130 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Xie, W. et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153, 1134–1148 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Li, Q., Peterson, K.R., Fang, X. & Stamatoyannopoulos, G. Locus control regions. Blood 100, 3077–3086 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Grosveld, F., van Assendelft, G.B., Greaves, D.R. & Kollias, G. Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell 51, 975–985 (1987).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Gaulton, K.J. et al. A map of open chromatin in human pancreatic islets. Nat. Genet. 42, 255–259 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Corradin, O. et al. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res. 24, 1–13 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Perry, M.W., Boettiger, A.N., Bothma, J.P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20, 1562–1567 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Frankel, N. et al. Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466, 490–493 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Biggin, M.D. Animal transcription networks as highly connected, quantitative continua. Dev. Cell 21, 611–626 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58

    Fisher, W.W. et al. DNA regions bound at low occupancy by transcription factors do not drive patterned reporter gene expression in Drosophila. Proc. Natl. Acad. Sci. USA 109, 21330–21335 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59

    Junion, G. et al. A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148, 473–486 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    Carey, M., Lin, Y.S., Green, M.R. & Ptashne, M. A mechanism for synergistic activation of a mammalian gene by GAL4 derivatives. Nature 345, 361–364 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61

    Lewis, E.B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    McGinnis, W., Levine, M.S., Hafen, E., Kuroiwa, A. & Gehring, W.J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308, 428–433 (1984).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63

    Pearson, J.C., Lemons, D. & McGinnis, W. Modulating Hox gene functions during animal body patterning. Nat. Rev. Genet. 6, 893–904 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Park, D., Lee, Y., Bhupindersingh, G. & Iyer, V.R. Widespread misinterpretable ChIP-seq bias in yeast. PLoS ONE 8, e83506 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67

    Teytelman, L., Thurtle, D.M., Rine, J. & van Oudenaarden, A. Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proc. Natl. Acad. Sci. USA 110, 18602–18607 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68

    Fan, X. & Struhl, K. Where does Mediator bind in vivo? PLoS ONE 4, e5029 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69

    Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014).

    CAS  Article  Google Scholar 

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Acknowledgements

S.P. was supported by the German Research Foundation (PO 1724/1-1).

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Correspondence to Jason D Lieb.

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Pott, S., Lieb, J. What are super-enhancers?. Nat Genet 47, 8–12 (2015). https://doi.org/10.1038/ng.3167

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