Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.
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.
Coolen
Marcel W
MW
Epigenetics Laboratory, Cancer Program, Garvan Institute of Medical Research, Sydney 2010, New South Wales, Australia.
Stirzaker
Clare
C
Song
Jenny Z
JZ
Statham
Aaron L
AL
Kassir
Zena
Z
Moreno
Carlos S
CS
Young
Andrew N
AN
Varma
Vijay
V
Speed
Terence P
TP
Cowley
Mark
M
Lacaze
Paul
P
Kaplan
Warren
W
Robinson
Mark D
MD
Clark
Susan J
SJ
D000107:Acetylation; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D019295:Computational Biology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D030541:Databases, Genetic; D015536:Down-Regulation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D005796:Genes / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics; D005810:Multigene Family / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D006657:Histones; D035683:MicroRNAs; D012333:RNA, Messenger