Methylation of polycomb target genes in intestinal cancer is mediated by inflammation.
Methylation of polycomb target genes in intestinal cancer is mediated by inflammation.
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DOI：
10.1158/0008-5472.can-08-1957
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Pfeifer GP
中科院分区：
文献类型：
--
作者：
Hahn MA;Hahn T;Lee DH;Esworthy RS;Kim BW;Riggs AD;Chu FF;Pfeifer GP
表观遗传变化与癌症发展密切相关。DNA超甲基化与基因沉默相关，并且经常在CpG岛中观察到。最近研究表明肿瘤中CpG岛甲基化的异常是由Polycomb蛋白介导的。然而，负责癌症中Polycomb靶基因甲基化的具体机制尚不清楚。慢性感染和炎症占全球所有癌症的25%。我们使用谷胱甘肽过氧化物酶Gpx 1和Gpx 2双敲除（Gpx 1/2-KO）小鼠作为易患肠癌的炎症性肠道疾病模型，分析了慢性炎症、衰老和癌症期间小鼠回肠全基因组DNA甲基化。我们发现，炎症导致Polycomb（PcG）靶基因的异常DNA甲基化，在炎症组织中甲基化的约250个基因中，70%是胚胎干细胞中的PcG靶基因，59%的甲基化基因在成年野生型小鼠的回肠中被H3 K27三甲基化标记。Gpx-1/2-KO小鼠回肠中CpG岛DNA甲基化的获得通常与相同基因座处H3 K27三甲基化的丧失相关。炎症相关的DNA甲基化优先发生在组织特异性沉默基因中，重要的是，它在肿瘤中比年龄依赖性DNA甲基化更常见。在肿瘤中发现的60%的异常甲基化也存在于发炎组织中。总之，炎症产生了异常DNA甲基化的特征，这是后来在恶性组织中观察到的，并由PcG复合物指导。
Epigenetic changes are strongly associated with cancer development. DNA hypermethylation is associated with gene silencing and is often observed in CpG islands. Recently it was suggested that aberrant CpG island methylation in tumors is directed by Polycomb proteins. However, specific mechanisms responsible for methylation of Polycomb target genes in cancer are not known. Chronic infection and inflammation contribute to up to 25% of all cancers worldwide. Using glutathione peroxidase, Gpx1 and Gpx2, double knockout (Gpx1/2-KO) mice as a model of inflammatory bowel disease predisposing to intestinal cancer, we analyzed genome-wide DNA methylation in the mouse ileum during chronic inflammation, aging and cancer. We found that inflammation leads to aberrant DNA methylation in Polycomb (PcG) target genes, with 70% of the ~250 genes methylated in the inflamed tissue being PcG targets in embryonic stem cells and 59% of the methylated genes being marked by H3K27 trimethylation in the ileum of adult wildtype mice. Acquisition of DNA methylation at CpG islands in the ileum of Gpx-1/2-KO mice frequently correlates with loss of H3K27 trimethylation at the same loci. Inflammation-associated DNA methylation occurs preferentially in tissue-specific silent genes and, importantly, is much more frequently represented in tumors than is age-dependent DNA methylation. 60% of aberrant methylation found in tumors is also present in the inflamed tissue. In summary, inflammation creates a signature of aberrant DNA methylation, which is observed later in the malignant tissue and is directed by the PcG complex.