Differentiated super-enhancers in lung cancer cells

Abstract

Super-enhancers (SEs) are regulatory elements with enriched accumulation of key transcription factors. Few studies were done investigating SEs in lung cancers. Here we analyzed epigenetic profiling data to identify SEs in lung cancer cell lines. Enhancers were classified as SEs and typical enhancers (TEs). Most of the TEs were overlapped between normal cell and cancer cells. A great portion of SEs were differentiated comparing these cells. Analysis of GO terms associated with SEs revealed SE remodeling (lost on some sites while gain on others) between normal and lung cancer cells. By comparing the average number of SEs in each GO term in cancer cells with the number in control cells, surprisingly, no GO terms with significantly increased SE number in cancer condition were observed. On the contrary, in aspects such as “cell-cell adhesion”, “receptor activity” and “negative regulation of canonical Wnt signaling pathway”, the related SEs were significantly reduced in cancer cells. These findings suggest that in lung cancer, cells may not gain decisive gene expression in the related aspect, instead, they may have lost control of the fateful genes. Taken together, our work with the usability of omics data identified SEs in lung cancer cells and further showed cancer-specific features of SE-related terms.

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References

  1. Barriot, R., Sherman, D.J., and Dutour, I. (2007). How to decide which are the most pertinent overly-represented features during gene set enrichment analysis. BMC Bioinf 8, 332.

    Article  CAS  Google Scholar 

  2. Bignell, G.R., Greenman, C.D., Davies, H., Butler, A.P., Edkins, S., Andrews, J.M., Buck, G., Chen, L., Beare, D., Latimer, C., et al. (2010). Signatures of mutation and selection in the cancer genome. Nature 463, 893–898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Christensen, C.L., Kwiatkowski, N., Abraham, B.J., Carretero, J., Al-Shahrour, F., Zhang, T., Chipumuro, E., Herter-Sprie, G.S., Akbay, E.A., Altabef, A., et al. (2014). Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26, 909–922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ding, L., Getz, G., Wheeler, D.A., Mardis, E.R., McLellan, M.D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D.M., Morgan, M.B., et al. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Francis, J.M., Zhang, C.Z., Maire, C.L., Jung, J., Manzo, V.E., Adalsteinsson, V.A., Homer, H., Haidar, S., Blumenstiel, B., Pedamallu, C. S., et al. (2014). EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4, 956–971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gröschel, S., Sanders, M.A., Hoogenboezem, R., de Wit, E., Bouwman, B. A.M., Erpelinck, C., van der Velden, V.H.J., Havermans, M., Avellino, R., van Lom, K., et al. (2014). A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157, 369–381.

    Article  CAS  PubMed  Google Scholar 

  8. Heintzman, N.D., Stuart, R.K., Hon, G., Fu, Y., Ching, C.W., Hawkins, R. D., Barrera, L.O., Van Calcar, S., Qu, C., Ching, K.A., et al. (2007). Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39, 311–318.

    Article  CAS  PubMed  Google Scholar 

  9. Heyn, H., Vidal, E., Ferreira, H.J., Vizoso, M., Sayols, S., Gomez, A., Moran, S., Boque-Sastre, R., Guil, S., Martinez-Cardus, A., et al. (2016). Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol 17, 11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hnisz, D., Abraham, B.J., Lee, T.I., Lau, A., Saint-André, V., Sigova, A.A., Hoke, H.A., and Young, R.A. (2013). Super-enhancers in the control of cell identity and disease. Cell 155, 934–947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hnisz, D., Schuijers, J., Lin, C.Y., Weintraub, A.S., Abraham, B.J., Lee, T. I., Bradner, J.E., and Young, R.A. (2015). Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell 58, 362–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Imielinski, M., Berger, A.H., Hammerman, P.S., Hernandez, B., Pugh, T.J., Hodis, E., Cho, J., Suh, J., Capelletti, M., Sivachenko, A., et al. (2012). Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jiang, R., Wang, X., Jin, Z., and Li, K. (2016). Association of nuclear PIM1 expression with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma and squamous cell carcinoma. J Cancer 7, 324–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kanehisa, M., Araki, M., Goto, S., Hattori, M., Hirakawa, M., Itoh, M., Katayama, T., Kawashima, S., Okuda, S., Tokimatsu, T., et al. (2008). KEGG for linking genomes to life and the environment. Nucleic Acids Res 36, D480–D484.

    Article  CAS  Google Scholar 

  15. Khan, A., and Zhang, X. (2016). dbSUPER: a database of super-enhancers in mouse and human genome. Nucleic Acids Res 44, D164–D171.

    Article  CAS  PubMed  Google Scholar 

  16. Kim, W., Youn, H.S., Kwon, T.W., Kang, J.H., Kim, E.G., Son, B., Yang, H.J., Jung, Y., and Youn, B.H. (2013). PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells. Pharmacol Res 70, 90–101.

    Article  CAS  PubMed  Google Scholar 

  17. Levine, M., Cattoglio, C., and Tjian, R. (2014). Looping back to leap forward: transcription enters a new era. Cell 157, 13–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lovén, J., Hoke, H.A., Lin, C.Y., Lau, A., Orlando, D.A., Vakoc, C.R., Bradner, J.E., Lee, T.I., and Young, R.A. (2013). Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Northcott, P.A., Lee, C., Zichner, T., Stütz, A.M., Erkek, S., Kawauchi, D., Shih, D.J.H., Hovestadt, V., Zapatka, M., Sturm, D., et al. (2014). Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ong, C.T., and Corces, V.G. (2011). Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12, 283–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pott, S., and Lieb, J.D. (2015). What are super-enhancers? Nat Genet 47, 8–12.

    Article  CAS  PubMed  Google Scholar 

  23. Siersbæk, R., Rabiee, A., Nielsen, R., Sidoli, S., Traynor, S., Loft, A., Poulsen, L.L.C., Rogowska-Wrzesinska, A., Jensen, O.N., and Mandrup, S. (2014). Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep 7, 1443–1455.

    Article  CAS  PubMed  Google Scholar 

  24. Stratton, M.R., Campbell, P.J., and Futreal, P.A. (2009). The cancer genome. Nature 458, 719–724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Suzuki, A., Makinoshima, H., Wakaguri, H., Esumi, H., Sugano, S., Kohno, T., Tsuchihara, K., and Suzuki, Y. (2014). Aberrant transcriptional regulations in cancers: genome, transcriptome and epigenome analysis of lung adenocarcinoma cell lines. Nucleic Acids Res 42, 13557–13572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wei, Y., Zhang, S., Shang, S., Zhang, B., Li, S., Wang, X., Wang, F., Su, J., Wu, Q., Liu, H., et al. (2016). SEA: a super-enhancer archive. Nucleic Acids Res 44, D172–D179.

    Article  CAS  PubMed  Google Scholar 

  27. Weischenfeldt, J., Dubash, T., Drainas, A.P., Mardin, B.R., Chen, Y., Stütz, A.M., Waszak, S.M., Bosco, G., Halvorsen, A.R., Raeder, B., et al. (2017). Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat Genet 49, 65–74.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Young, M.D., Wakefield, M.J., Smyth, G.K., and Oshlack, A. (2010). Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol 11, R14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yuan, C., Hu, H., Kuang, M., Chen, Z., Tao, X., Fang, S., Sun, Y., Zhang, Y., and Chen, H. (2017). Super enhancer associated RAI14 is a new potential biomarker in lung adenocarcinoma. Oncotarget 8, 105251–105261.

    PubMed  PubMed Central  Google Scholar 

  31. Zhang, H., Qi, J., Reyes, J.M., Li, L., Rao, P.K., Li, F., Lin, C.Y., Perry, J. A., Lawlor, M.A., Federation, A., et al. (2016a). Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discov 6, 1006–1021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang, X., Choi, P.S., Francis, J.M., Imielinski, M., Watanabe, H., Cherniack, A.D., and Meyerson, M. (2016b). Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet 48, 176–182.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang, Y., Liu, T., Meyer, C.A., Eeckhoute, J., Johnson, D.S., Bernstein, B. E., Nussbaum, C., Myers, R.M., Brown, M., Li, W., et al. (2008). Model-based analysis of ChIP-Seq (MACS). Genome Biol 9, R137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhu, H.X., Shi, L., Zhang, Y., Zhu, Y.C., Bai, C.X., Wang, X.D., and Zhou, J.B. (2017). Myocyte enhancer factor 2D provides a cross-talk between chronic inflammation and lung cancer. J Transl Med 15, 65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81600307) to Xin Li and National Key Investigation Program (2016YFC1100900).

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Correspondence to Hezhong Chen or Hai Jin.

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Compliance and ethics The author(s) declare that they have no conflict of interest.

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Li, X., Lu, C., Lu, Q. et al. Differentiated super-enhancers in lung cancer cells. Sci. China Life Sci. 62, 1218–1228 (2019). https://doi.org/10.1007/s11427-018-9319-4

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Keywords

  • super-enhancer
  • lung cancer
  • genomics