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Title: Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis

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. Hypermethylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. Finally, 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.

Authors:
 [1];  [2];  [3];  [2];  [4];  [1];  [5];  [6];  [7];  [8];  [9];  [1];  [10]
  1. Korea Research Inst. of Bioscience and Biotechnology (KRIBB), Daejeon (Korea). Personalized Genomic Medicine Research Center; Univ. of Science and Technology, Daejeon (Korea). Dept. of Functional Genomics
  2. National Cancer Center, Goyang-si (Korea). Rare Cancer Branch, Research Inst.
  3. Yonsei Univ. College of Medicine, Seoul (Korea)
  4. Kyung Hee Univ., Seoul (Korea). Dept. of Life and Nanopharmaceutical Sciences and Dept. of Oriental Pharmacy
  5. National Cancer Center, Goyang-si (Korea). Immunotherapeutics Branch, Research Inst.
  6. National Cancer Center, Goyang-si (Korea). Immunotherapeutics Branch, Research Inst.
  7. Univ. of Texas Medical Branch, Galveston, TX (United States)
  8. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  9. Yonsei Univ. College of Medicine, Seoul (Korea). Inst. of Tropical Medicine; Yonsei Univ. College of Medicine, Seoul (Korea). Brain Korea 21 Plus Project for Medical Science
  10. Univ. of Texas Medical Branch, Galveston, TX (United States); National Cancer Center, Goyang (Republic of Korea)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Research Foundation of Korea (NRF)
OSTI Identifier:
1532258
Grant/Contract Number:  
AC02-05CH11231; RSG-12-187-01—RMC; RF-2012M3A9D1054670; 2016R1A2B4014183; 2017M3C9A5029978
Resource Type:
Accepted Manuscript
Journal Name:
Oncogene
Additional Journal Information:
Journal Volume: 36; Journal Issue: 49; Journal ID: ISSN 0950-9232
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Park, J-L, Lee, Y-S, Song, M-J, Hong, S-H, Ahn, J-H, Seo, E-H, Shin, S-P, Lee, S-J, Johnson, B. H., Stampfer, M. R., Kim, H-P, Kim, S-Y, and Lee, Y. S. Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis. United States: N. p., 2017. Web. doi:10.1038/onc.2017.285.
Park, J-L, Lee, Y-S, Song, M-J, Hong, S-H, Ahn, J-H, Seo, E-H, Shin, S-P, Lee, S-J, Johnson, B. H., Stampfer, M. R., Kim, H-P, Kim, S-Y, & Lee, Y. S. Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis. United States. doi:https://doi.org/10.1038/onc.2017.285
Park, J-L, Lee, Y-S, Song, M-J, Hong, S-H, Ahn, J-H, Seo, E-H, Shin, S-P, Lee, S-J, Johnson, B. H., Stampfer, M. R., Kim, H-P, Kim, S-Y, and Lee, Y. S. Mon . "Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis". United States. doi:https://doi.org/10.1038/onc.2017.285. https://www.osti.gov/servlets/purl/1532258.
@article{osti_1532258,
title = {Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis},
author = {Park, J-L and Lee, Y-S and Song, M-J and Hong, S-H and Ahn, J-H and Seo, E-H and Shin, S-P and Lee, S-J and Johnson, B. H. and Stampfer, M. R. and Kim, H-P and Kim, S-Y and Lee, Y. S.},
abstractNote = {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. Hypermethylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. Finally, 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.},
doi = {10.1038/onc.2017.285},
journal = {Oncogene},
number = 49,
volume = 36,
place = {United States},
year = {2017},
month = {8}
}

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Figures / Tables:

Figure 1 Figure 1: Figure 1. Pol III transcriptome in nine HMEC cultures. (a) Diagram illustrating the HMEC progression series derived from reduction mammoplasty specimen 184. (b) A pie chart of 4553 candidate Pol III genes (left panel) and 924 that were occupied by Pol III in at least one HMEC culturemore » in our POLR3A ChIP-seq data (right panel). The full information on individual Pol III genes is in Supplementary Table S1 and S2. (c) Number of POR3A-occupied Pol III loci in the nine HMEC cultures derived from specimen 184. (d) A bar chart illustrating fractions of ‘genuine Pol III genes’ and ‘pseudogenes and repeats’. See Supplementary Table S1 and S2 for full information. (e) A box plot of normalized Pol III occupancy per each locus in the nine 184-derived cultures. 10 000 000 of tags were used for normalization among cultures during the calculation of relative Pol III signal from POLR3A ChIP-seq reads. The analysis of variance (ANOVA) test was used to calculate a P-value. (f) A bar chart illustrating fractions of Pol III-occupied tRNA genes in a total of 608 tRNA loci (see Supplementary Table S3 for full information).« less

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