Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.
Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.
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DOI：
10.1038/ncb2023
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发表时间：
2010-03
影响因子：
21.3
通讯作者：
Clark, Susan J.
中科院分区：
文献类型：
--
作者：
Coolen, Marcel W.;Stirzaker, Clare;Song, Jenny Z.;Statham, Aaron L.;Kassir, Zena;Moreno, Carlos S.;Young, Andrew N.;Varma, Vijay;Speed, Terence P.;Cowley, Mark;Lacaze, Paul;Kaplan, Warren;Robinson, Mark D.;Clark, Susan J.
在癌变过程中，单个基因的沉默可以通过遗传和表观遗传过程发生，但潜在的机制尚不清楚。通过使用平片阵列创建一个集成的前列腺癌表观基因组图谱，我们发现由于长范围表观遗传沉默（LRES），基因抑制的连续区域通常发生。我们在前列腺癌中发现了47个新的LRES区域，通常跨越约2 Mb，包含约12个基因，普遍存在肿瘤抑制基因和mirna。我们的数据显示，LRES与区域性组蛋白去乙酰化以及不同表观遗传重塑模式的子结构域相关，包括抑制组蛋白和DNA甲基化标记的再强化、获得或交换。正常前列腺上皮细胞和人胚胎干细胞中基因的转录和表观遗传状态可以在定义癌症相关表观遗传重塑模式中发挥关键作用。我们提出，由于LRES和LOH或基因组缺失的结合，癌症基因组的巩固或有效减少通常发生在这些区域，导致这些区域的转录可塑性降低。
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 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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