Frequent Switching of Polycomb Repressive Marks and DNA Hypermethylation in the PC3 Prostate Cancer Cell Line

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Aug 30

PMID 18753622

Citations 197

Authors

Einav Nili Gal-Yam

Gerda Egger

Leo Iniguez

Heather Holster

Steingrimur Einarsson

Xinmin Zhang

Joy C Lin

Gangning Liang

Peter A Jones

Amos Tanay

Affiliations

Soon will be listed here.

Abstract

Epigenetic reprogramming is commonly observed in cancer, and is hypothesized to involve multiple mechanisms, including DNA methylation and Polycomb repressive complexes (PRCs). Here we devise a new experimental and analytical strategy using customized high-density tiling arrays to investigate coordinated patterns of gene expression, DNA methylation, and Polycomb marks which differentiate prostate cancer cells from their normal counterparts. Three major changes in the epigenomic landscape distinguish the two cell types. Developmentally significant genes containing CpG islands which are silenced by PRCs in the normal cells acquire DNA methylation silencing and lose their PRC marks (epigenetic switching). Because these genes are normally silent this switch does not cause de novo repression but might significantly reduce epigenetic plasticity. Two other groups of genes are silenced by either de novo DNA methylation without PRC occupancy (5mC reprogramming) or by de novo PRC occupancy without DNA methylation (PRC reprogramming). Our data suggest that the two silencing mechanisms act in parallel to reprogram the cancer epigenome and that DNA hypermethylation may replace Polycomb-based repression near key regulatory genes, possibly reducing their regulatory plasticity.

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References

Keshet I, Schlesinger Y, Farkash S, Rand E, Hecht M, Segal E . Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet. 2006; 38(2):149-53. DOI: 10.1038/ng1719. View

Weber M, Davies J, Wittig D, Oakeley E, Haase M, Lam W . Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. 2005; 37(8):853-62. DOI: 10.1038/ng1598. View

McGarvey K, Greene E, Fahrner J, Jenuwein T, Baylin S . DNA methylation and complete transcriptional silencing of cancer genes persist after depletion of EZH2. Cancer Res. 2007; 67(11):5097-102. DOI: 10.1158/0008-5472.CAN-06-2029. View

Lee T, Jenner R, Boyer L, Guenther M, Levine S, Kumar R . Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006; 125(2):301-13. PMC: 3773330. DOI: 10.1016/j.cell.2006.02.043. View

Bracken A, Dietrich N, Pasini D, Hansen K, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006; 20(9):1123-36. PMC: 1472472. DOI: 10.1101/gad.381706. View

Ohm J, McGarvey K, Yu X, Cheng L, Schuebel K, Cope L . A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007; 39(2):237-42. PMC: 2744394. DOI: 10.1038/ng1972. View

Sparmann A, van Lohuizen M . Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006; 6(11):846-56. DOI: 10.1038/nrc1991. View

Guenther M, Levine S, Boyer L, Jaenisch R, Young R . A chromatin landmark and transcription initiation at most promoters in human cells. Cell. 2007; 130(1):77-88. PMC: 3200295. DOI: 10.1016/j.cell.2007.05.042. View

Barski A, Cuddapah S, Cui K, Roh T, Schones D, Wang Z . High-resolution profiling of histone methylations in the human genome. Cell. 2007; 129(4):823-37. DOI: 10.1016/j.cell.2007.05.009. View

10.

Yu Y, Landsittel D, Jing L, Nelson J, Ren B, Liu L . Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol. 2004; 22(14):2790-9. DOI: 10.1200/JCO.2004.05.158. View

11.

Weber M, Hellmann I, Stadler M, Ramos L, Paabo S, Rebhan M . Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007; 39(4):457-66. DOI: 10.1038/ng1990. View

12.

Kondo Y, Shen L, Cheng A, Ahmed S, Boumber Y, Charo C . Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet. 2008; 40(6):741-50. DOI: 10.1038/ng.159. View

13.

Mikkelsen T, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P . Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008; 454(7200):49-55. PMC: 2754827. DOI: 10.1038/nature07056. View

14.

Tanay A, ODonnell A, Damelin M, Bestor T . Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci U S A. 2007; 104(13):5521-6. PMC: 1838490. DOI: 10.1073/pnas.0609746104. View

15.

Markl I, Cheng J, Liang G, Shibata D, Laird P, Jones P . Global and gene-specific epigenetic patterns in human bladder cancer genomes are relatively stable in vivo and in vitro over time. Cancer Res. 2001; 61(15):5875-84. View

16.

Jones P, Baylin S . The epigenomics of cancer. Cell. 2007; 128(4):683-92. PMC: 3894624. DOI: 10.1016/j.cell.2007.01.029. View

17.

Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C . The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2005; 439(7078):871-4. DOI: 10.1038/nature04431. View

18.

Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J . Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007; 39(2):232-6. DOI: 10.1038/ng1950. View

19.

Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C . Epigenetic stem cell signature in cancer. Nat Genet. 2007; 39(2):157-8. DOI: 10.1038/ng1941. View

20.

Bernstein B, Meissner A, Lander E . The mammalian epigenome. Cell. 2007; 128(4):669-81. DOI: 10.1016/j.cell.2007.01.033. View