SUMMARYSilencing 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 due to Long Range Epigenetic Silencing (LRES). We identified 47 novel LRES regions in prostate cancer, typically spanning ~2 Mb and harbouring ~12 genes, with a prevalence of tumour suppressor genes and miRNAs. Our data reveal that LRES is associated with regional histone deacetylation combined with sub-domains of different epigenetic remodelling patterns, that 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 role in defining the mode of cancer-associated epigenetic remodelling. We propose that a consolidation or effective reduction of the cancer genome commonly occurs in domains, due to a combination of LRES and LOH or genomic deletion, resulting in reduced transcriptional plasticity within these regions.

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