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 highdensity 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.spatial clustering ͉ DNA methylation ͉ MeDIP normalization ͉ Polycomb B iochemical processes including DNA cytosine methylation and histone modifications interact with each other to ensure the stability of epigenetic states. These processes are clearly altered in cancer and contribute to the establishment and maintenance of the malignant phenotype (1). Recent discoveries and technological developments have greatly expanded our understanding of the cell's epigenetic makeup, revealing a rich repertoire of histone modifications and protein complexes that regulate them (2, 3). Chromatin regulating complexes, and most notably the family of Polycomb repressive complexes (PRCs), which mediate trimethylation at H3K27, are highly active in cancer cells (4). Studies of Polycomb activity in pluripotent embryonic stem cells (ESC) (5-7) revealed broad patterns of Polycomb-based repression near key developmental regulators, many of which are known DNA hypermethylation targets in cancer (8). It is therefore pertinent to take an integrated look at both DNA methylation and histone modifications simultaneously in a coherent cell set in which the appropriate presumed normal cell counterpart is compared to its malignant state.The evidence on interaction between PRCs and the DNA methylation machinery is partial and sometimes conflicting. The correlations between ESC PRC targets and cancer hypermethylation (8), or the reported enrichment of H3K27me3 marks at specific hypermethylated CpG islands (9), have led to multiple mechanistic hypotheses on the underlying process. The lack of DNA hypermethylation at PRC occupied regions in embryonic carcinoma cells (10) and of DNA hypomethylation after knockdown of a PRC2 component (EZH2) in cancer cells (11) further demonstrate that the i...

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