Chromosome Research

, Volume 21, Issue 6–7, pp 713–724 | Cite as

Boosting transcription by transcription: enhancer-associated transcripts



Enhancers are traditionally viewed as DNA sequences located some distance from a promoter that act in cis and in an orientation-independent fashion to increase utilization of specific promoters and thereby regulate gene expression. Much progress has been made over the last decade toward understanding how these distant elements interact with target promoters, but how transcription is enhanced remains an object of active inquiry. Recent reports convey the prevalence and diversity of enhancer transcription and transcripts and support both as key factors with mechanistically distinct, but not mutually exclusive roles in enhancer function. Decoupling the causes and effects of transcription on the local chromatin landscape and understanding the role of enhancer transcripts in the context of long-range interactions are challenges that require additional attention. In this review, we focus on the possible functions of enhancer transcription by highlighting several recent enhancer RNA papers and, within the context of other enhancer studies, speculate on the role of enhancer transcription in regulating differential gene expression.


Enhancer Chromatin Noncoding RNA Transcription Mediator Cohesion Histone modifications Enhancer transcripts eRNA 



Androgen receptor


Activity-regulated cytoskeleton-associated protein


CREB-binding protein


Chromatin immunoprecipitation


ChIP coupled with massively paralleled sequencing




Estrogen receptor-α


Enhancer RNA


Global run-on sequencing


Histone H3 acetylated at lysine 9


Histone H3 acetylated at lysine 27


Histone H3 monomethylated at lysine 4


Histone H3 dimethylated at lysine 4


Histone H3 trimethylated at lysine 4


Histone H3 trimethylated at lysine 36


H3 serine-10 phosphorylation


Histone acetyltransferase


Histone deacetylase




Potassium chloride


Kdo2-lipid A


Locked nucleic acids


Long noncoding RNA




Noncoding RNA-activating


Neuronal PAS domain 4

Pol II

RNA polymerase II


Massively parallel RNA sequencing


Serum response factor


Small interfering RNA


Transcription factor


Toll-like receptor 4


Transcription start sites




Chromosome conformation capture


Three-dimensional DNA selection and ligation


Circularized chromosome conformation capture



The authors apologize to those whose work is not cited due to space limitations. This work was supported by the National Institutes of Health [GM073120 and NS080779 to B.P.C].

Conflict of interest

The authors declare they have no conflicts of interest.


  1. Barski A, Cuddapah S, Cui K et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837PubMedCrossRefGoogle Scholar
  2. Bonn S, Zinzen RP, Girardot C et al (2012) Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nat Genet 44:148–156PubMedCrossRefGoogle Scholar
  3. Calo E, Wysocka J (2013) Modification of enhancer chromatin: what, how, and why? Mol Cell 49:825–837PubMedCrossRefGoogle Scholar
  4. Consortium EP, Birney E, Stamatoyannopoulos JA et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816CrossRefGoogle Scholar
  5. Core LJ, Waterfall JJ, Lis JT (2008) Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:1845–1848PubMedCrossRefGoogle Scholar
  6. Creyghton MP, Cheng AW, Welstead GG et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A 107:21931–21936PubMedCrossRefGoogle Scholar
  7. De Santa F, Barozzi I, Mietton F et al (2010) A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol 8:e1000384PubMedCrossRefGoogle Scholar
  8. Djebali S, Davis CA, Merkel A et al (2012) Landscape of transcription in human cells. Nature 489:101–108PubMedCrossRefGoogle Scholar
  9. Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ (2001) MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Mol Cell Biol 21:2249–2258PubMedCrossRefGoogle Scholar
  10. Ernst J, Kheradpour P, Mikkelsen TS et al (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473:43–49PubMedCrossRefGoogle Scholar
  11. Fullwood MJ, Liu MH, Pan YF et al (2009) An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462:58–64PubMedCrossRefGoogle Scholar
  12. Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE (2002) Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP)—the mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain. J Biol Chem 277:43168–43174PubMedCrossRefGoogle Scholar
  13. Guttman M, Amit I, Garber M et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227PubMedCrossRefGoogle Scholar
  14. Hah N, Murakami S, Nagari A, Danko CG, Kraus WL (2013) Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23:1210–1223PubMedCrossRefGoogle Scholar
  15. He HH, Meyer CA, Shin H et al (2010) Nucleosome dynamics define transcriptional enhancers. Nat Genet 42:343–347PubMedCrossRefGoogle Scholar
  16. Heintzman ND, Stuart RK, Hon G et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318PubMedCrossRefGoogle Scholar
  17. Heintzman ND, Hon GC, Hawkins RD et al (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459:108–112PubMedCrossRefGoogle Scholar
  18. Heinz S, Benner C, Spann N et al (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576–589PubMedCrossRefGoogle Scholar
  19. Ho Y, Elefant F, Liebhaber SA, Cooke NE (2006) Locus control region transcription plays an active role in long-range gene activation. Mol Cell 23:365–375PubMedCrossRefGoogle Scholar
  20. Hwang YC, Zheng Q, Gregory BD, Wang LS (2013) High-throughput identification of long-range regulatory elements and their target promoters in the human genome. Nucleic Acids Res 41:4835–4846PubMedCrossRefGoogle Scholar
  21. John S, Sabo PJ, Thurman RE et al (2011) Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet 43:264–U116PubMedCrossRefGoogle Scholar
  22. Kagey MH, Newman JJ, Bilodeau S et al (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467:430–435PubMedCrossRefGoogle Scholar
  23. Kaikkonen MU, Spann NJ, Heinz S et al (2013) Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51:310–325PubMedCrossRefGoogle Scholar
  24. Kim A, Zhao H, Ifrim I, Dean A (2007) Beta-globin intergenic transcription and histone acetylation dependent on an enhancer. Mol Cell Biol 27:2980–2986PubMedCrossRefGoogle Scholar
  25. Kim TK, Hemberg M, Gray JM et al (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182–187PubMedCrossRefGoogle Scholar
  26. Koch CM, Andrews RM, Flicek P et al (2007) The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res 17:691–707PubMedCrossRefGoogle Scholar
  27. Koch F, Fenouil R, Gut M et al (2011) Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat Struct Mol Biol 18:956–963PubMedCrossRefGoogle Scholar
  28. Kornienko AE, Guenzl PM, Barlow DP, Pauler FM (2013) Gene regulation by the act of long non-coding RNA transcription. BMC Biol 11:59PubMedCrossRefGoogle Scholar
  29. Kowalczyk MS, Hughes JR, Garrick D et al (2012) Intragenic enhancers act as alternative promoters. Mol Cell 45:447–458PubMedCrossRefGoogle Scholar
  30. Lai F, Orom UA, Cesaroni M et al (2013) Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494:497–501PubMedCrossRefGoogle Scholar
  31. Lam MT, Cho H, Lesch HP et al (2013) Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498:511–515PubMedCrossRefGoogle Scholar
  32. Li G, Ruan X, Auerbach RK et al (2012) Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148:84–98PubMedCrossRefGoogle Scholar
  33. Li W, Notani D, Ma Q et al (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498:516–520PubMedCrossRefGoogle Scholar
  34. Lupien M, Eeckhoute J, Meyer CA et al (2008) FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132:958–970PubMedCrossRefGoogle Scholar
  35. Melo CA, Drost J, Wijchers PJ et al (2013) eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49:524–535PubMedCrossRefGoogle Scholar
  36. Mikkelsen TS, Ku MC, Jaffe DB et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–U552PubMedCrossRefGoogle Scholar
  37. Orom UA, Derrien T, Beringer M et al (2010) Long noncoding RNAs with enhancer-like function in human cells. Cell 143:46–58PubMedCrossRefGoogle Scholar
  38. Ostuni R, Piccolo V, Barozzi I et al (2013) Latent enhancers activated by stimulation in differentiated cells. Cell 152:157–171PubMedCrossRefGoogle Scholar
  39. Petesch SJ, Lis JT (2012) Overcoming the nucleosome barrier during transcript elongation. Trends Genet 28:285–294PubMedCrossRefGoogle Scholar
  40. Rada-Iglesias A, Bajpai R, Swigut T et al (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470:279–283PubMedCrossRefGoogle Scholar
  41. Sandhu KS, Li GL, Poh HM et al (2012) Large-scale functional organization of long-range chromatin interaction networks. Cell Rep 2:1207–1219PubMedCrossRefGoogle Scholar
  42. Sanyal A, Lajoie BR, Jain G, Dekker J (2012) The long-range interaction landscape of gene promoters. Nature 489:109–113PubMedCrossRefGoogle Scholar
  43. Schmidt D, Schwalie PC, Ross-Innes CS et al (2010) A CTCF-independent role for cohesin in tissue-specific transcription. Genome Res 20:578–588PubMedCrossRefGoogle Scholar
  44. Thurman RE, Rynes E, Humbert R et al (2012) The accessible chromatin landscape of the human genome. Nature 489:75–82PubMedCrossRefGoogle Scholar
  45. Tsai MC, Manor O, Wan Y et al (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329:689–693PubMedCrossRefGoogle Scholar
  46. Tuan D, Kong SM, Hu K (1992) Transcription of the hypersensitive site Hs2 enhancer in erythroid-cells. Proc Natl Acad Sci U S A 89:11219–11223PubMedCrossRefGoogle Scholar
  47. Visel A, Blow MJ, Li Z et al (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457:854–858PubMedCrossRefGoogle Scholar
  48. Wang Q, Carroll JS, Brown M (2005) Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 19:631–642PubMedCrossRefGoogle Scholar
  49. Wang Z, Zang C, Rosenfeld JA et al (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40:897–903PubMedCrossRefGoogle Scholar
  50. Wang D, Garcia-Bassets I, Benner C et al (2011) Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474:390-+PubMedCrossRefGoogle Scholar
  51. Wang J, Zhuang JL, Iyer S et al (2012) Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res 22:1798–1812PubMedCrossRefGoogle Scholar
  52. Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227–2241PubMedCrossRefGoogle Scholar
  53. Zentner GE, Tesar PJ, Scacheri PC (2011) Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions. Genome Res 21:1273–1283PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Biological ScienceFlorida State UniversityTallahasseeUSA

Personalised recommendations