Epigenetics Laboratory, Cancer Program, Garvan Institute of Medical Research, Sydney 2010, New South Wales, Australia.
Nat Cell Biol. 2010 Mar;12(3):235-46. doi: 10.1038/ncb2023. Epub 2010 Feb 21.
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.
个体基因的沉默可能是在癌变过程中通过遗传和表观遗传过程发生的，但潜在机制尚不清楚。通过使用平铺阵列创建综合前列腺癌表观基因组图谱，我们表明，通过长程表观遗传沉默（LRES）经常发生连续的基因抑制区域。我们在前列腺癌中鉴定出 47 个 LRES 区域，通常跨越约 2 Mb 并包含约 12 个基因，其中包含肿瘤抑制基因和 miRNA 基因。我们的数据表明，LRES 与区域性组蛋白去乙酰化有关，同时伴有不同的表观遗传重塑模式的亚域，包括强化、获得或交换抑制性组蛋白以及 DNA 甲基化标记。正常前列腺上皮细胞和人类胚胎干细胞中基因的转录和表观遗传状态可能在确定与癌症相关的表观遗传重塑模式方面起着关键作用。我们提出，通过 LRES 和 LOH 或基因组缺失的组合，癌症基因组在域中通常会发生整合或有效减少，从而导致这些区域内的转录可塑性降低。
