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Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis

Oncogene volume 36, pages 6793–6804 (2017)Cite this article

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Abstract

RNA polymerase III (Pol III) transcribes medium-sized non-coding RNAs (collectively termed Pol III genes). Emerging diverse roles of Pol III genes suggest that individual Pol III genes are exquisitely regulated by transcription and epigenetic factors. Here we report global Pol III expression/methylation profiles and molecular mechanisms of Pol III regulation that have not been as extensively studied, using nc886 as a representative Pol III gene. In a human mammary epithelial cell system that recapitulates early breast tumorigenesis, the fraction of actively transcribed Pol III genes increases reaching a plateau during immortalization. Hyper-methylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. When Pol III genes are hypo-methylated, MYC amplifies their transcription, regardless of its recognition DNA motif. Thus, Pol III expression during tumorigenesis is delineated by methylation and magnified by MYC.

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Acknowledgements

This work was supported by a Research Scholar Grant, RSG-12-187-01—RMC from the American Cancer Society to YSL; grants NRF-2012M3A9D1054670 and NRF-2014M3C9A3068554 funded by the Ministry of Science, ICT and Future Planning and KRIBB Research Initiative to S-YK; a grant 2016R1A2B4014183 and 2017M3C9A5029978 funded by National Research Foundation of Korea to H-PK; National Cancer Center (Korea) intramural project # 1610090 to Y-SL; and US Department of Energy under Contract No. DE-AC02-05CH11231 to MRS.

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  1. J-L Park and Y-S Lee: Co-first authors.

Authors and Affiliations

  1. Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea

    J-L Park, E-H Seo & S-Y Kim

  2. Department of Functional Genomics, University of Science and Technology, Daejeon, Korea

    J-L Park, E-H Seo & S-Y Kim

  3. Rare Cancer Branch, Research Institute, National Cancer Center, Goyang-si, Korea

    Y-S Lee & S-H Hong

  4. Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul, Korea

    M-J Song & H-P Kim

  5. Department of Life and Nanopharmaceutical Sciences and Department of Oriental Pharmacy, Kyung Hee University, Seoul, Korea

    J-H Ahn

  6. Immunotherapeutics Branch, Research Institute, National Cancer Center, Goyang-si, Korea

    S-P Shin & S-J Lee

  7. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, USA

    B H Johnson & Y S Lee

  8. Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    M R Stampfer

  9. Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea

    H-P Kim

  10. Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

    H-P Kim

  11. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea

    Y S Lee

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Correspondence to H-P Kim, S-Y Kim or Y S Lee.

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Park, JL., Lee, YS., Song, MJ. et al. Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis. Oncogene 36, 6793–6804 (2017). https://doi.org/10.1038/onc.2017.285

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