Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity

Nature Cell Biology volume 12, pages 235–246 (2010)Cite this article

Subjects

Abstract

Silencing of individual genes can occur by genetic and epigenetic processes during carcinogenesis, but the underlying mechanisms remain unclear. By creating an integrated prostate cancer epigenome map using tiling arrays, we show that contiguous regions of gene suppression commonly occur through long-range epigenetic silencing (LRES). We identified 47 LRES regions in prostate cancer, typically spanning about 2 Mb and harbouring approximately 12 genes, with a prevalence of tumour suppressor and miRNA genes. Our data reveal that LRES is associated with regional histone deacetylation combined with subdomains of different epigenetic remodelling patterns, which include re-enforcement, gain or exchange of repressive histone, and DNA methylation marks. The transcriptional and epigenetic state of genes in normal prostate epithelial and human embryonic stem cells can play a critical part in defining the mode of cancer-associated epigenetic remodelling. We propose that consolidation or effective reduction of the cancer genome commonly occurs in domains through a combination of LRES and LOH or genomic deletion, resulting in reduced transcriptional plasticity within these regions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sliding window analysis on public expression microarray data.
Figure 2: Expression status of LRES regions in PrEC and LNCaP cells.
Figure 3: Epigenetic landscape of 7q31.1-q31.2 in LNCaP and PrEC cells.
Figure 4: Epigenetic suppression of 7q31.1-q31.2 in clinical prostate cancer samples.
Figure 5: Scatter plots of epigenetic marks in all LRES genes.
Figure 6: Epigenetic changes in LRES regions cluster in domains of consecutive genes.
Figure 7: Consolidation of the cancer epigenome into domains of repressive chromatin by LRES.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).

    Article  CAS  Google Scholar 

  2. Baylin, S. B. et al. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum. Mol. Genet. 10, 687–692 (2001).

    Article  CAS  Google Scholar 

  3. Bird, A. P. & Wolffe, A. P. Methylation-induced repression—belts, braces, and chromatin. Cell 99, 451–454 (1999).

    Article  CAS  Google Scholar 

  4. Jones, P. A. & Laird, P. W. Cancer epigenetics comes of age. Nature Genet. 21, 163–167 (1999).

    Article  CAS  Google Scholar 

  5. Lund, A. H. & van Lohuizen, M. Epigenetics and cancer. Genes Dev. 18, 2315–2335 (2004).

    Article  CAS  Google Scholar 

  6. Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    Article  CAS  Google Scholar 

  7. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nature Rev. Cancer 6, 846–856 (2006).

    Article  CAS  Google Scholar 

  8. Schlesinger, Y. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nature Genet. 39, 232–236 (2007).

    Article  CAS  Google Scholar 

  9. Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nature Genet. 39, 157–158 (2007).

    Article  CAS  Google Scholar 

  10. Santos-Reboucas, C. B. & Pimentel, M. M. Implication of abnormal epigenetic patterns for human diseases. Eur. J. Hum. Genet. 15, 10–17 (2007).

    Article  CAS  Google Scholar 

  11. Ohm, J. E. et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature Genet. 39, 237–242 (2007).

    Article  CAS  Google Scholar 

  12. Ting, A. H., McGarvey, K. M. & Baylin, S. B. The cancer epigenome—components and functional correlates. Genes Dev. 20, 3215–3231 (2006).

    Article  CAS  Google Scholar 

  13. Frigola, J. et al. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nature Genet. 38, 540–549 (2006).

    Article  CAS  Google Scholar 

  14. Smith, J. S. & Costello, J. F. A broad band of silence. Nature Genet. 38, 504–506 (2006).

    Article  CAS  Google Scholar 

  15. Nie, Y. et al. DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas. Carcinogenesis 22, 1615–1623 (2001).

    Article  CAS  Google Scholar 

  16. van Noesel, M. M. et al. Clustering of hypermethylated genes in neuroblastoma. Genes, Chrom. Cancer 38, 226–233 (2003).

    Article  CAS  Google Scholar 

  17. Palmisano, W. A. et al. Aberrant promoter methylation of the transcription factor genes PAX5 alpha and beta in human cancers. Cancer Res. 63, 4620–4625 (2003).

    CAS  PubMed  Google Scholar 

  18. Novak, P. et al. Epigenetic inactivation of the HOXA gene cluster in breast cancer. Cancer Res. 66, 10664–10670 (2006).

    Article  CAS  Google Scholar 

  19. Stransky, N. et al. Regional copy number-independent deregulation of transcription in cancer. Nature Genet. 38, 1386–1396 (2006).

    Article  CAS  Google Scholar 

  20. Hitchins, M. P. et al. Epigenetic inactivation of a cluster of genes flanking MLH1 in microsatellite-unstable colorectal cancer. Cancer Res. 67, 9107–9116 (2007).

    Article  CAS  Google Scholar 

  21. Novak, P. et al. Agglomerative epigenetic aberrations are a common event in human breast cancer. Cancer Res. 68, 8616–8625 (2008).

    Article  CAS  Google Scholar 

  22. Kim, H. et al. The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer. Cancer Res. 65, 8118–8124 (2005).

    Article  CAS  Google Scholar 

  23. Dhanasekaran, S. M. et al. Delineation of prognostic biomarkers in prostate cancer. Nature 412, 822–826 (2001).

    Article  CAS  Google Scholar 

  24. Dhanasekaran, S. M. et al. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEB J. 19, 243–245 (2005).

    Article  CAS  Google Scholar 

  25. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl Acad. Sci. USA 101, 811–816 (2004).

    Article  CAS  Google Scholar 

  26. Luo, J. et al. Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. Cancer Res. 61, 4683–4688 (2001).

    CAS  PubMed  Google Scholar 

  27. Singh, D. et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1, 203–209 (2002).

    Article  CAS  Google Scholar 

  28. Tomlins, S. A. et al. Integrative molecular concept modeling of prostate cancer progression. Nature Genet. 39, 41–51 (2007).

    Article  CAS  Google Scholar 

  29. Vanaja, D. K., Cheville, J. C., Iturria, S. J. & Young, C. Y. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63, 3877–3882 (2003).

    CAS  PubMed  Google Scholar 

  30. Welsh, J. B. et al. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res. 61, 5974–5978 (2001).

    CAS  PubMed  Google Scholar 

  31. Yu, Y. P. et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004).

    Article  CAS  Google Scholar 

  32. Feltus, F. A., Lee, E. K., Costello, J. F., Plass, C. & Vertino, P. M. DNA motifs associated with aberrant CpG island methylation. Genomics 87, 572–579 (2006).

    Article  CAS  Google Scholar 

  33. Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    Article  CAS  Google Scholar 

  34. Engstrom, P. G., Fredman, D. & Lenhard, B. Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes. Genome Biol. 9, R34 (2008).

    Article  Google Scholar 

  35. Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genet. 40, 499–507 (2008).

    Article  CAS  Google Scholar 

  36. Gupta, P. B., Chaffer, C. L. & Weinberg, R. A. Cancer stem cells: mirage or reality? Nature Med. 15, 1010–1012 (2009).

    Article  CAS  Google Scholar 

  37. Cher, M. L. et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 56, 3091–3102 (1996).

    CAS  PubMed  Google Scholar 

  38. Dumur, C. I. et al. Genome-wide detection of LOH in prostate cancer using human SNP microarray technology. Genomics 81, 260–269 (2003).

    Article  CAS  Google Scholar 

  39. Latil, A., Cussenot, O., Fournier, G., Baron, J. C. & Lidereau, R. Loss of heterozygosity at 7q31 is a frequent and early event in prostate cancer. Clin. Cancer Res. 1, 1385–1389 (1995).

    CAS  PubMed  Google Scholar 

  40. Henrique, R. et al. High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients. Clin. Cancer Res. 13, 6122–6129 (2007).

    Article  CAS  Google Scholar 

  41. Kohonen-Corish, M. R. et al. Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer. Oncogene 26, 4435–4441 (2007).

    Article  CAS  Google Scholar 

  42. Guan, M., Zhou, X., Soulitzis, N., Spandidos, D. A. & Popescu, N. C. Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer: potential clinical applications. Clin. Cancer Res. 12, 1412–1419 (2006).

    Article  CAS  Google Scholar 

  43. Chene, L. et al. Extensive analysis of the 7q31 region in human prostate tumors supports TES as the best candidate tumor suppressor gene. Int. J. Cancer 111, 798–804 (2004).

    Article  CAS  Google Scholar 

  44. Bachmann, N. et al. Expression changes of CAV1 and EZH2, located on 7q31 approximately q36, are rarely related to genomic alterations in primary prostate carcinoma. Cancer Genet. Cytogenet. 182, 103–110 (2008).

    Article  CAS  Google Scholar 

  45. Tatarelli, C., Linnenbach, A., Mimori, K. & Croce, C. M. Characterization of the human TESTIN gene localized in the FRA7G region at 7q31.2. Genomics 68, 1–12 (2000).

    Article  CAS  Google Scholar 

  46. Tobias, E. S., Hurlstone, A. F., MacKenzie, E., McFarlane, R. & Black, D. M. The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein. Oncogene 20, 2844–2853 (2001).

    Article  CAS  Google Scholar 

  47. Friedman, J. M. et al. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 69, 2623–2629 (2009).

    Article  CAS  Google Scholar 

  48. Varambally, S. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695–1699 (2008).

    Article  CAS  Google Scholar 

  49. Fabbri, M. et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc. Natl Acad. Sci. USA 104, 15805–15810 (2007).

    Article  CAS  Google Scholar 

  50. Gandellini, P. et al. miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res. 69, 2287–2295 (2009).

    Article  CAS  Google Scholar 

  51. Ke, X. S. et al. Genome-wide profiling of histone h3 lysine 4 and lysine 27 trimethylation reveals an epigenetic signature in prostate carcinogenesis. PLoS ONE 4, e4687 (2009).

    Article  Google Scholar 

  52. O'Hagan, H. M., Mohammad, H. P. & Baylin, S. B. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 4, e1000155 (2008).

    Article  Google Scholar 

  53. Hong, Z. et al. A polycomb group protein, PHF1, is involved in the response to DNA double-strand breaks in human cell. Nucleic Acids Res. 36, 2939–2947 (2008).

    Article  CAS  Google Scholar 

  54. Schotta, G. et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 22, 2048–2061 (2008).

    Article  CAS  Google Scholar 

  55. Gal-Yam, E. N. et al. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc. Natl Acad. Sci. USA 105, 12979–12984 (2008).

    Article  Google Scholar 

  56. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  Google Scholar 

  57. Wen, B., Wu, H., Shinkai, Y., Irizarry, R. A. & Feinberg, A. P. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nature Genet. 41, 246–250 (2009).

    Article  CAS  Google Scholar 

  58. Pauler, F. M. et al. H3K27me3 forms BLOCs over silent genes and intergenic regions and specifies a histone banding pattern on a mouse autosomal chromosome. Genome Res. 19, 221–233 (2009).

    Article  CAS  Google Scholar 

  59. Pajerowski, J. D., Dahl, K. N., Zhong, F. L., Sammak, P. J. & Discher, D. E. Physical plasticity of the nucleus in stem cell differentiation. Proc. Natl Acad. Sci. USA 104, 15619–15624 (2007).

    Article  CAS  Google Scholar 

  60. Spivakov, M. & Fisher, A. G. Epigenetic signatures of stem-cell identity. Nature Rev. Genet. 8, 263–271 (2007).

    Article  CAS  Google Scholar 

  61. Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007).

    Article  CAS  Google Scholar 

  62. Wiblin, A. E., Cui, W., Clark, A. J. & Bickmore, W. A. Distinctive nuclear organisation of centromeres and regions involved in pluripotency in human embryonic stem cells. J. Cell Sci. 118, 3861–3868 (2005).

    Article  CAS  Google Scholar 

  63. Liu, P. et al. Sex-determining region Y Box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res. 66, 4011–4019 (2006).

    Article  CAS  Google Scholar 

  64. Varambally, S. et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 8, 393–406 (2005).

    Article  CAS  Google Scholar 

  65. Song, J. Z., Stirzaker, C., Harrison, J., Melki, J. R. & Clark, S. J. Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. Oncogene 21, 1048–1061 (2002).

    Article  CAS  Google Scholar 

  66. Frigola, J. et al. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nature Genet. 38, 540–549 (2006).

    Article  CAS  Google Scholar 

  67. Johnson, W. E. et al. Model-based analysis of tiling-arrays for ChIP-chip. Proc. Natl Acad. Sci. USA 103, 12457–12462 (2006).

    Article  CAS  Google Scholar 

  68. Liu, P. et al. Sex-determining region Y Box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res. 66, 4011–4019 (2006).

    Article  CAS  Google Scholar 

  69. Clark, S. J., Harrison, J., Paul, C. L. & Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 22, 2990–2997 (1994).

    Article  CAS  Google Scholar 

  70. Coolen, M. W., Statham, A. L., Gardiner-Garden, M. & Clark, S. J. Genomic profiling of CpG methylation and allelic specificity using quantitative high-throughput mass spectrometry: critical evaluation and improvements. Nucleic Acids Res. 35, e119 (2007).

    Article  Google Scholar 

  71. Varambally, S. et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 8, 393–406 (2005).

    Article  CAS  Google Scholar 

  72. Khalili, A. et al. γ-Normal-γ mixture model for dtecting differentially methylated loci in three breast cancer cell lines. Cancer Informatics 3, 43–54 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

We thank K. Patterson, P. Molloy and T. Hulf for reviewing the manuscript. We thank the Ramaciotti Centre, University of NSW (Sydney, Australia) for array hybridizations. This work is supported by Cancer Institute NSW (CINSW) program (S.J.C.), CINSW Fellowship (M.W.C.) and CINSW Student (A.L.S.) grants and National Health and Medical Research Council (NH&MRC) project (427614, 481347) and Fellowship grants (S.J.C. and T.S.) and NBCF program grant.

Author information

Author notes

  1. Marcel W. Coolen and Clare Stirzaker: These authors contributed equally to this work

  2. Jenny Z. Song and Aaron L. Statham: These authors contributed equally to this work

Authors and Affiliations

  1. Epigenetics Laboratory, Cancer Program, Garvan Institute of Medical Research, Sydney, 2010, New South Wales, Australia

    Marcel W. Coolen, Clare Stirzaker, Jenny Z. Song, Aaron L. Statham, Zena Kassir, Mark D. Robinson & Susan J. Clark

  2. Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Carlos S. Moreno, Andrew N. Young & Vijay Varma

  3. Atlanta VA Medical Center, Atlanta, GA, USA

    Vijay Varma

  4. Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, 3052, Victoria, Australia

    Terence P. Speed & Mark D. Robinson

  5. Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Sydney, 2010, New South Wales, Australia

    Mark Cowley, Paul Lacaze & Warren Kaplan

  6. St Vincent's Clinical School, University of NSW, Sydney, Australia, NSW

    Susan J. Clark

Authors
  1. Marcel W. Coolen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clare Stirzaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jenny Z. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aaron L. Statham
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zena Kassir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos S. Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrew N. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vijay Varma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Terence P. Speed
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark Cowley
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Paul Lacaze
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Warren Kaplan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mark D. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Susan J. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.J.C. initiated and supervised the study, and with M.W.C. and C.S., designed the experiments and wrote the paper; M.W.C., C.S., J.Z.S. and A.L.S. performed experiments and helped with data analysis; Z.K. helped with the experiments; M.D.R., T.P.S., P.L, M.C. and W.K. helped with the data analysis; C.S.M., A.N.Y and V.V. prepared the clinical samples.

Corresponding author

Correspondence to Susan J. Clark.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 989 kb)

Supplementary Information

Additional File 1 (PDF 626 kb)

Supplementary Information

Additional File 2 (PDF 350 kb)

Supplementary Information

Additional File 3 (PDF 1012 kb)

Supplementary Information

Additional File 4 (PDF 2773 kb)

Supplementary Information

Additional Bioinformatics Data (PDF 1235 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coolen, M., Stirzaker, C., Song, J. et al. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat Cell Biol 12, 235–246 (2010). https://doi.org/10.1038/ncb2023

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2023

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing