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

Abstract

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.

Long-Range Epigenetic Silencing Associates with Deregulation of Ikaros Targets in Colorectal Cancer Cells

“…It has been proposed that if some CpG island genes are targeted for methylation, neighboring genes may also be affected by default (10). Perhaps, LRES might be initiated by 1 critical gene target that spreads and conscripts "innocent bystanders," analogous to large genetic deletions (18).…”

“…More recently, genome-wide surveys have uncovered other mechanisms. For instance, Frigola and colleagues found coordinated hypermethylation of 12 closely located CpG islands in colorectal cancer (7) and recent data suggest that concurrent hypermethylation of adjacent CpG islands and associated gene repression, also known as long-range epigenetic silencing (LRES), may be a more common phenomenon in cancer than previously recognized (8)(9)(10)(11).…”

“…As mentioned above, recent genome-scale analyses have identified large chromosomal regions containing several CpG island often hypermethylated and transcriptionally repressed termed as LRES (7)(8)(9)(10)(11)18). LRES is frequent in colorectal cancer (7,11).…”

Evaluation of affinity-based genome-wide DNA methylation data: Effects of CpG density, amplification bias, and copy number variation

“…3A; Coolen et al 2010). MeDIP-qPCR experiments, used as a control before hybridization, confirmed a strong affinity of methylated DNA at the GSTP1 locus, both before (77-fold) and after (76-fold) amplification (Supplemental Fig.…”

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

“…Importantly, while transcriptional activation by NF-kB is well appreciated 8,[15][16][17][18][19] , the physiological significance of transcriptional repression by NF-kB in cancer has not been established. While maintenance of pro-tumorigenic repressive chromatin in cancer has been well described [19][20][21] , it is not clear whether NF-kB is essential for maintaining repressive chromatin that facilitates tumour growth. Moreover, while transcriptionally active complexes formed by NF-kB are extensively studied 22 , the molecular nature of transcriptionally repressive NF-kB complexes is not well established.…”