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Enhancer RNAs: a missing regulatory layer in gene transcription

  • Renfang Mao
  • Yuanyuan Wu
  • Yue Ming
  • Yuanpei Xu
  • Shouyan Wang
  • Xia Chen
  • Xiaoying Wang
  • Yihui FanEmail author
Open Access
Review
  • 159 Downloads

Abstract

Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Meanwhile, active enhancers and super-enhancers also produce transcripts termed enhancer RNAs (eRNAs) from their DNA elements. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription. RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac, and enriched with transcription regulatory factors such as LDTFs, P300, CBP, BRD4 and MED1. Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers. Compared to mRNAs, eRNAs are quite unstable and play roles at local. Functionally, it has been shown that eRNAs promote formation of enhancer-promoter loops. Several studies also demonstrated that eRNAs help the binding of RNA polymerase II (RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor (NELF) complex. Nevertheless, these proposed mechanisms are not universally accepted and still under controversy. Here, we comprehensively summarize the reported findings and make perspectives for future exploration. We also believe that super-enhancer derived RNAs (seRNAs) might be informative to understand the nature of super-enhancers.

Keywords

enhancer RNAs (eRNAs) enhancers super-enhancers super-enhancer RNAs (seRNAs) gene transcription 

Notes

Acknowledgements

This work was supported by the Distinguished Professorship Program of Jiangsu Province to Y.F, the National Natural Science Foundation of China (31770935, 81641164, 81600386, 81471539, 30801350), the Natural Science Foundation of Nantong University (14Z022), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17_1933), Undergraduate Training Program for Innovation (201710304030Z). We apologize to the many scientists who made contributions to the field, but were not cited due to space limitations.

References

  1. Altshuler, D.L., Durbin, R.M., Abecasis, G.R., Bentley, D.R., Chakravarti, A., Clark, A.G., Collins, F.S., De La Vega, F.M., Donnelly, P., et al. (2010). A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073.CrossRefGoogle Scholar
  2. Abraham, B.J., Hnisz, D., Weintraub, A.S., Kwiatkowski, N., Li, C.H., Li, Z., Weichert-Leahey, N., Rahman, S., Liu, Y., Etchin, J., et al. (2017). Small genomic insertions form enhancers that misregulate oncogenes. Nat Commun 8, 14385.CrossRefGoogle Scholar
  3. Akhtar-Zaidi, B., Cowper-Sallari, R., Corradin, O., Saiakhova, A., Bartels, C.F., Balasubramanian, D., Myeroff, L., Lutterbaugh, J., Jarrar, A., Kalady, M.F., et al. (2012). Epigenomic enhancer profiling defines a signature of colon cancer. Science 336, 736–739.CrossRefGoogle Scholar
  4. Allen, M.A., Andrysik, Z., Dengler, V.L., Mellert, H.S., Guarnieri, A., Freeman, J.A., Sullivan, K.D., Galbraith, M.D., Luo, X., Kraus, W.L., et al. (2014). Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms. eLife 3, e02200.CrossRefGoogle Scholar
  5. Alvarez-Dominguez, J.R., Knoll, M., Gromatzky, A.A., and Lodish, H.F. (2017). The super-enhancer-derived alncRNA-EC7/bloodlinc potentiates red blood cell development in trans. Cell Rep 19, 2503–2514.CrossRefGoogle Scholar
  6. Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., Suzuki, T., et al. (2014). An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461.CrossRefGoogle Scholar
  7. Arner, E., Daub, C.O., Vitting-Seerup, K., Andersson, R., Lilje, B., Drabløs, F., Lennartsson, A., Rönnerblad, M., Hrydziuszko, O., Vitezic, M., et al. (2015). Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010–1014.CrossRefGoogle Scholar
  8. Bales, D.J. (1990). On predicting the future of dentistry. Oper Dent 15, 121.Google Scholar
  9. Banerji, J., Rusconi, S., and Schaffner, W. (1981). Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308.CrossRefGoogle Scholar
  10. Blackwood, E.M., and Kadonaga, J.T. (1998). Going the distance: a current view of enhancer action. Science 281, 60–63.CrossRefGoogle Scholar
  11. Chapuy, B., McKeown, M.R., Lin, C.Y., Monti, S., Roemer, M.G.M., Qi, J., Rahl, P.B., Sun, H.H., Yeda, K.T., Doench, J.G., et al. (2013). Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24, 777–790.CrossRefGoogle Scholar
  12. Cheng, H., Dou, X., and Han, J.D.J. (2016). Understanding superenhancers. Sci China Life Sci 59, 277–280.CrossRefGoogle Scholar
  13. Cheng, J.H., Pan, D.Z.C., Tsai, Z.T.Y., and Tsai, H.K. (2015). Genomewide analysis of enhancer RNA in gene regulation across 12 mouse tissues. Sci Rep 5, 12648.CrossRefGoogle Scholar
  14. Chokas, A.L., Bickford, J.S., Barilovits, S.J., Rogers, R.J., Qiu, X., Newsom, K.J., Beachy, D.E., and Nick, H.S. (2014). A TEAD1/p65 complex regulates the eutherian-conserved MnSOD intronic enhancer, eRNA transcription and the innate immune response. Biochim Biophys Acta 1839, 1205–1216.CrossRefGoogle Scholar
  15. Collis, P., Antoniou, M., and Grosveld, F. (1990). Definition of the minimal requirements within the human beta-globin gene and the dominant control region for high level expression.. EMBO J 9, 233–240.CrossRefGoogle Scholar
  16. Corradin, O., Saiakhova, A., Akhtar-Zaidi, B., Myeroff, L., Willis, J., Cowper-Sal{middle dot}lari, R., Lupien, M., Markowitz, S., and Scacheri, P.C. (2014). 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.CrossRefGoogle Scholar
  17. De Santa, F., Barozzi, I., Mietton, F., Ghisletti, S., Polletti, S., Tusi, B.K., Muller, H., Ragoussis, J., Wei, C.L., and Natoli, G. (2010). A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol 8, e1000384.CrossRefGoogle Scholar
  18. Djebali, S., Davis, C.A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., et al. (2012). Landscape of transcription in human cells. Nature 489, 101–108.CrossRefGoogle Scholar
  19. Dorighi, K.M., Swigut, T., Henriques, T., Bhanu, N.V., Scruggs, B.S., Nady, N., Still Ii, C.D., Garcia, B.A., Adelman, K., and Wysocka, J. (2017). Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promotersin dependently of H3K4 monomethylation. Mol Cell 66, 568–576.e4.CrossRefGoogle Scholar
  20. Dukler, N., Gulko, B., Huang, Y.F., and Siepel, A. (2017). Is a superenhancer greater than the sum of its parts? Nat Genet 49, 2–3.CrossRefGoogle Scholar
  21. ENCODE Project Consortium. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74.Google Scholar
  22. Ernst, J., Kheradpour, P., Mikkelsen, T.S., Shoresh, N., Ward, L.D., Epstein, C.B., Zhang, X., Wang, L., Issner, R., Coyne, M., et al. (2011). Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49.CrossRefGoogle Scholar
  23. Feng, J., Bi, C., Clark, B.S., Mady, R., Shah, P., and Kohtz, J.D. (2006). The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev 20, 1470–1484.CrossRefGoogle Scholar
  24. Flynn, R.A., Do, B.T., Rubin, A.J., Calo, E., Lee, B., Kuchelmeister, H., Rale, M., Chu, C., Kool, E.T., Wysocka, J., et al. (2016). 7SK-BAF axis controls pervasive transcription at enhancers. Nat Struct Mol Biol 23, 231–238.CrossRefGoogle Scholar
  25. Hah, N., Benner, C., Chong, L.W., Yu, R.T., Downes, M., and Evans, R.M. (2015). Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs. Proc Natl Acad Sci USA 112, E297–E302.CrossRefGoogle Scholar
  26. Hah, N., Murakami, S., Nagari, A., Danko, C.G., and Kraus, W.L. (2013). Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23, 1210–1223.CrossRefGoogle Scholar
  27. Harris, H. (1959). Turnover of nuclear and cytoplasmic ribonucleic acid in two types of animal cell, with some further observations on the nucleolus. Biochem J 73, 362–369.CrossRefGoogle Scholar
  28. He, H., Li, W., Wu, D., Nagy, R., Liyanarachchi, S., Akagi, K., Jendrzejewski, J., Jiao, H., Hoag, K., Wen, B., et al. (2013). Ultrarare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance. PLoS ONE 8, e61920.CrossRefGoogle Scholar
  29. Heintzman, N.D., Hon, G.C., Hawkins, R.D., Kheradpour, P., Stark, A., Harp, L.F., Ye, Z., Lee, L.K., Stuart, R.K., Ching, C.W., et al. (2009). Histone modifications at human enhancers reflect global cell-typespecific gene expression. Nature 459, 108–112.CrossRefGoogle Scholar
  30. Henley, C.M. Iii, Owings, M.H., Stagner, B.B., Martin, G.K., and Lonsbury-Martin, B.L. (1990). Postnatal development of 2ƒ1-ƒ2 otoacoustic emissions in pigmented rat. Hear Res 43, 141–148.CrossRefGoogle Scholar
  31. Hsieh, C.L., Fei, T., Chen, Y., Li, T., Gao, Y., Wang, X., Sun, T., Sweeney, C.J., Lee, G.S.M., Chen, S., et al. (2014). Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci USA 111, 7319–7324.CrossRefGoogle Scholar
  32. Isoda, T., Moore, A.J., He, Z., Chandra, V., Aida, M., Denholtz, M., Piet van Hamburg, J., Fisch, K.M., Chang, A.N., Fahl, S.P., et al. (2017). Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate. Cell 171, 103–119.e18.CrossRefGoogle Scholar
  33. Jeong, M., and Goodell, M.A. (2016). Noncoding regulatory RNAs in hematopoiesis. Curr Top Dev Biol 118, 245–270.CrossRefGoogle Scholar
  34. Kaikkonen, M.U., Spann, N.J., Heinz, S., Romanoski, C.E., Allison, K.A., Stender, J.D., Chun, H.B., Tough, D.F., Prinjha, R.K., Benner, C., et al. (2013). Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51, 310–325.CrossRefGoogle Scholar
  35. Kim, T.K., Hemberg, M., Gray, J.M., Costa, A.M., Bear, D.M., Wu, J., Harmin, D.A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., et al. (2010). Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187.CrossRefGoogle Scholar
  36. Koch, F., Fenouil, R., Gut, M., Cauchy, P., Albert, T.K., Zacarias-Cabeza, J., Spicuglia, S., de la Chapelle, A.L., Heidemann, M., Hintermair, C., et al. (2011). Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat Struct Mol Biol 18, 956–963.CrossRefGoogle Scholar
  37. Kowalczyk, M.S., Hughes, J.R., Garrick, D., Lynch, M.D., Sharpe, J.A., Sloane-Stanley, J.A., McGowan, S.J., De Gobbi, M., Hosseini, M., Vernimmen, D., et al. (2012). Intragenic enhancers act as alternative promoters. Mol Cell 45, 447–458.CrossRefGoogle Scholar
  38. Lam, M.T.Y., Li, W., Rosenfeld, M.G., and Glass, C.K. (2014). Enhancer RNAs and regulated transcriptional programs. Trends Biochem Sci 39, 170–182.CrossRefGoogle Scholar
  39. Le Gras, S., Keime, C., Anthony, A., Lotz, C., De Longprez, L., Brouillet, E., Cassel, J.C., Boutillier, A.L., and Merienne, K. (2017). Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature. Sci Rep 7, 42875.CrossRefGoogle Scholar
  40. Léveillé, N., Melo, C.A., Rooijers, K., Díaz-Lagares, A., Melo, S.A., Korkmaz, G., Lopes, R., Akbari Moqadam, F., Maia, A.R., Wijchers, P. J., et al. (2015). Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA. Nat Commun 6, 6520.CrossRefGoogle Scholar
  41. Levine, M., Cattoglio, C., and Tjian, R. (2014). Looping back to leap forward: transcription enters a new era. Cell 157, 13–25.CrossRefGoogle Scholar
  42. Li, W., Hu, Y., Oh, S., Ma, Q., Merkurjev, D., Song, X., Zhou, X., Liu, Z., Tanasa, B., He, X., et al. (2015). Condensin I and II complexes license full estrogen receptor a-dependent enhancer activation. Mol Cell 59, 188–202.CrossRefGoogle Scholar
  43. Li, W., Notani, D., Ma, Q., Tanasa, B., Nunez, E., Chen, A.Y., Merkurjev, D., Zhang, J., Ohgi, K., Song, X., et al. (2013). Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520.CrossRefGoogle Scholar
  44. Li, X., Lu, C., Lu, Q., Li, C., Zhu, J., Zhao, T., Chen, H., and Jin H. (2018). Differentiated super-enhancers in lung cancer cells. Sci China Life Sci., http://doi.org/10.1007/s11427-018-9319-4. Google Scholar
  45. Liang, J., Zhou, H., Gerdt, C., Tan, M., Colson, T., Kaye, K.M., Kieff, E., and Zhao, B. (2016). Epstein-Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation. Proc Natl Acad Sci USA 113, 14121–14126.CrossRefGoogle Scholar
  46. Liu, F. (2017). Enhancer-derived RNA: a primer. Genom Proteom Bioinf 15, 196–200.CrossRefGoogle Scholar
  47. Liu, Z., Merkurjev, D., Yang, F., Li, W., Oh, S., Friedman, M.J., Song, X., Zhang, F., Ma, Q., Ohgi, K.A., et al. (2014). Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell 159, 358–373.CrossRefGoogle Scholar
  48. Mansour, M.R., Abraham, B.J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A.D., Etchin, J., Lawton, L., Sallan, S.E., Silverman, L.B., et al. (2014). An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377.CrossRefGoogle Scholar
  49. Maruyama, A., Mimura, J., and Itoh, K. (2014). Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding. Nucl Acids Res 42, 13599–13614.CrossRefGoogle Scholar
  50. Maurano, M.T., Humbert, R., Rynes, E., Thurman, R.E., Haugen, E., Wang, H., Reynolds, A.P., Sandstrom, R., Qu, H., Brody, J., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195.CrossRefGoogle Scholar
  51. Melo, C.A., Drost, J., Wijchers, P.J., van de Werken, H., de Wit, E., Oude Vrielink, J.A.F., Elkon, R., Melo, S.A., Léveillé, N., Kalluri, R., et al. (2013). eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49, 524–535.CrossRefGoogle Scholar
  52. Micheletti, R., Plaisance, I., Abraham, B.J., Sarre, A., Ting, C.C., Alexanian, M., Maric, D., Maison, D., Nemir, M., Young, R.A., et al. (2017). The long noncoding RNA Wisper controls cardiac fibrosis and remodeling. Sci Transl Med 9, eaai9118–295.CrossRefGoogle Scholar
  53. Mousavi, K., Zare, H., Dell’orso, S., Grontved, L., Gutierrez-Cruz, G., Derfoul, A., Hager, G.L., and Sartorelli, V. (2013). eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci. Mol Cell 51, 606–617.CrossRefGoogle Scholar
  54. Natoli, G., and Andrau, J.C. (2012). Noncoding transcription at enhancers: general principles and functional models. Annu Rev Genet 46, 1–19.CrossRefGoogle Scholar
  55. Pennacchio, L.A., Bickmore, W., Dean, A., Nobrega, M.A., and Bejerano, G. (2013). Enhancers: five essential questions. Nat Rev Genet 14, 288–295.CrossRefGoogle Scholar
  56. Plank, J.L., and Dean, A. (2014). Enhancer function: mechanistic and genome-wide insights come together. Mol Cell 55, 5–14.CrossRefGoogle Scholar
  57. Pnueli, L., Rudnizky, S., Yosefzon, Y., and Melamed, P. (2015). RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin a-subunit gene. Proc Natl Acad Sci USA 112, 4369–4374.CrossRefGoogle Scholar
  58. Pott, S., and Lieb, J.D. (2015). What are super-enhancers? Nat Genet 47, 8–12.CrossRefGoogle Scholar
  59. Puc, J., Kozbial, P., Li, W., Tan, Y., Liu, Z., Suter, T., Ohgi, K.A., Zhang, J., Aggarwal, A.K., and Rosenfeld, M.G. (2015). Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160, 367–380.CrossRefGoogle Scholar
  60. Pulakanti, K., Pinello, L., Stelloh, C., Blinka, S., Allred, J., Milanovich, S., Kiblawi, S., Peterson, J., Wang, A., Yuan, G.C., et al. (2013). Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions. Epigenetics 8, 1303–1320.CrossRefGoogle Scholar
  61. Rahman, S., Zorca, C.E., Traboulsi, T., Noutahi, E., Krause, M.R., Mader, S., and Zenklusen, D. (2017). Single-cell profiling reveals that eRNA accumulation at enhancer-promoter loops is not required to sustain transcription. Nucl Acids Res 45, 3017–3030.CrossRefGoogle Scholar
  62. Schaukowitch, K., Joo, J.Y., Liu, X., Watts, J.K., Martinez, C., and Kim, T. K. (2014). Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell 56, 29–42.CrossRefGoogle Scholar
  63. Smith, E., and Shilatifard, A. (2014). Enhancer biology and enhanceropathies. Nat Struct Mol Biol 21, 210–219.CrossRefGoogle Scholar
  64. Wang, D., Garcia-Bassets, I., Benner, C., Li, W., Su, X., Zhou, Y., Qiu, J., Liu, W., Kaikkonen, M.U., Ohgi, K.A., et al. (2011). Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394.CrossRefGoogle Scholar
  65. Whyte, W.A., Orlando, D.A., Hnisz, D., Abraham, B.J., Lin, C.Y., Kagey, M.H., Rahl, P.B., Lee, T.I., and Young, R.A. (2013). Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319.CrossRefGoogle Scholar
  66. Wu, H., Nord, A.S., Akiyama, J.A., Shoukry, M., Afzal, V., Rubin, E.M., Pennacchio, L.A., and Visel, A. (2014). Tissue-specific RNA expression marks distant-acting developmental enhancers. PLoS Genet 10, e1004610.CrossRefGoogle Scholar
  67. Yang, Y., Su, Z., Song, X., Liang, B., Zeng, F., Chang, X., and Huang, D. (2016). Enhancer RNA-driven looping enhances the transcription of the long noncoding RNA DHRS4-AS1, a controller of the DHRS4 gene cluster. Sci Rep 6, 20961.CrossRefGoogle Scholar
  68. Yao, P., Lin, P., Gokoolparsadh, A., Assareh, A., Thang, M.W.C., and Voineagu, I. (2015). Coexpression networks identify brain regionspecific enhancer RNAs in the human brain. Nat Neurosci 18, 1168–1174.CrossRefGoogle Scholar
  69. Zabidi, M.A., and Stark, A. (2016). Regulatory enhancer-core-promoter communication via transcription factors and cofactors. Trends Genets 32, 801–814.CrossRefGoogle Scholar
  70. Zhao, Y., Wang, L., Ren, S., Wang, L., Blackburn, P.R., McNulty, M.S., Gao, X., Qiao, M., Vessella, R.L., Kohli, M., et al. (2016). Activation of P-TEFb by androgen receptor-regulated enhancer RNAs in castrationresistant prostate cancer. Cell Rep 15, 599–610.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Renfang Mao
    • 1
  • Yuanyuan Wu
    • 2
  • Yue Ming
    • 3
  • Yuanpei Xu
    • 3
  • Shouyan Wang
    • 2
  • Xia Chen
    • 2
  • Xiaoying Wang
    • 3
  • Yihui Fan
    • 2
    • 3
    Email author
  1. 1.Department of Pathophysiology, School of MedicineNantong UniversityNantongChina
  2. 2.Basic Medical Research Center, School of MedicineNantong UniversityNantongChina
  3. 3.Department of Immunology, School of MedicineNantong UniversityNantongChina

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