A DNA hypermethylation module for the stem/progenitor cell signature of cancer
A DNA hypermethylation module for the stem/progenitor cell signature of cancer
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DOI：
10.1101/gr.131169.111
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发表时间：
2012-05-01
期刊：
影响因子：
7
通讯作者：
Baylin, Stephen B.
中科院分区：
文献类型：
--
作者：
Easwaran, Hariharan;Johnstone, Sarah E.;Baylin, Stephen B.
在胚胎干细胞（ESCs）中，许多DNA高甲基化的癌基因被Polycomb（PcG）阻遏复合物占据。它们在所有癌症中的普遍性、涉及的染色质的确切背景以及它们在成人细胞更新系统中的地位尚不清楚。使用全基因组分析，我们表明，类似于75%的高甲基化基因标记的PcG的背景下，在胚胎干细胞和成人干/祖细胞的二价染色质。这些基因中的大量基因是关键的发育调节因子，我们称之为“DNA超甲基化模块”的一个子集包括在癌症中下调的PcG靶基因的一部分。具有二价染色质的基因具有低的、稳定的基因转录状态，其已被证明在正常干细胞中维持干细胞性和自我更新。然而，当肿瘤中DNA高甲基化时，我们发现这些基因被进一步抑制。我们还表明，这些基因的甲基化状态可以聚集结肠癌和乳腺癌的重要亚型。通过评估在不同癌症中甲基化的基因子集，并考虑它们在ESC中的染色质状态，我们提供了DNA超甲基化优先靶向PcG基因子集的证据，PcG基因是发育调节因子，这可能有助于癌症的干细胞样状态。此外，通过表型对肿瘤进行聚类的全局甲基化分析的能力可能对进一步细化肿瘤行为模式具有重要意义，这可能最终有助于治疗干预。
Many DNA-hypermethylated cancer genes are occupied by the Polycomb (PcG) repressor complex in embryonic stem cells (ESCs). Their prevalence in the full spectrum of cancers, the exact context of chromatin involved, and their status in adult cell renewal systems are unknown. Using a genome-wide analysis, we demonstrate that similar to 75% of hypermethylated genes are marked by PcG in the context of bivalent chromatin in both ESCs and adult stem / progenitor cells. A large number of these genes are key developmental regulators, and a subset, which we call the "DNA hypermethylation module," comprises a portion of the PcG target genes that are down-regulated in cancer. Genes with bivalent chromatin have a low, poised gene transcription state that has been shown to maintain stemness and self-renewal in normal stem cells. However, when DNA-hypermethylated in tumors, we find that these genes are further repressed. We also show that the methylation status of these genes can cluster important subtypes of colon and breast cancers. By evaluating the subsets of genes that are methylated in different cancers with consideration of their chromatin status in ESCs, we provide evidence that DNA hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer. Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions.