Clustered DNA methylation changes in polycomb target genes in early-stage liver cancer.
Clustered DNA methylation changes in polycomb target genes in early-stage liver cancer.
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DOI：
10.1016/j.bbrc.2012.07.084
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发表时间：
2012-08
影响因子：
3.1
通讯作者：
Yao‐Li Chen;C. Ko;P. Lin;Wan-Ling Chuang;Chia-Chen Hsu;P. Chu;Mei-Yu Pai;Chun-Chun Chang-Chun;Ming-Han Kuo;Yi-Ru Chu;Chun-Hsin Tung;T. Huang;Yu‐Wei Leu;S. Hsiao
中科院分区：
文献类型：
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作者：
Yao‐Li Chen;C. Ko;P. Lin;Wan-Ling Chuang;Chia-Chen Hsu;P. Chu;Mei-Yu Pai;Chun-Chun Chang-Chun;Ming-Han Kuo;Yi-Ru Chu;Chun-Hsin Tung;T. Huang;Yu‐Wei Leu;S. Hsiao
Polycomb-group蛋白在胚胎和体细胞干细胞中标记了特定的染色质构象，这对维持干细胞的“干性”至关重要。这些蛋白质也标志着在各种癌症中发现的染色质修饰的改变。在正常分化细胞或晚期癌细胞中，这些多梳相关位点通常与DNA甲基化增加有关。因此，假设polycomb相关基因座内DNA甲基化状态的变化可能决定细胞命运，而这些基因座内异常甲基化可能与肿瘤的发生有关。为了评估这一点，我们检测了肝癌中四个多梳靶位点——trip10、Casp8AP2、ENSA和ZNF484的甲基化状态。选择这四个靶点是因为它们的甲基化水平在间充质干细胞向肝脏分化过程中增加。我们发现这四个基因座在大多数早期肝癌标本中都是低甲基化的。为了比较，我们还检测了两个非多梳肿瘤抑制基因HIC1和RassF1A。而HIC1的甲基化水平在正常和肿瘤样本之间没有显著差异，RassF1A在肝脏肿瘤样本中显著高甲基化。无监督聚类分析将多梳和非多梳靶点的甲基化变化分类为独立的，表明独立的表观遗传进化。因此，体细胞内预沉积的多梳标记可能有助于确定肝脏肿瘤发生过程中的甲基化变化。
Polycomb-group proteins mark specific chromatin conformations in embryonic and somatic stem cells that are critical for maintenance of their “stemness”. These proteins also mark altered chromatin modifications identified in various cancers. In normal differentiated cells or advanced cancerous cells, these polycomb-associated loci are frequently associated with increased DNA methylation. It has thus been hypothesized that changes in DNA methylation status within polycomb-associated loci may dictate cell fate and that abnormal methylation within these loci may be associated with tumor development. To assess this, we examined the methylation states of four polycomb target loci –Trip10, Casp8AP2, ENSA, and ZNF484 – in liver cancer. These four targets were selected because their methylation levels are increased during mesenchymal stem cell-to-liver differentiation. We found that these four loci were hypomethylated in most early-stage liver cancer specimens. For comparison, two non-polycomb tumor suppressor genes, HIC1 and RassF1A, were also examined. Whereas the methylation level of HIC1 did not differ significantly between normal and tumor samples, RassF1A was significantly hypermethylated in liver tumor samples. Unsupervised clustering analysis classified the methylation changes within polycomb and non-polycomb targets to be independent, indicating independent epigenetic evolution. Thus, pre-deposited polycomb marks within somatic stem cells may contribute to the determination of methylation changes during hepatic tumorigenesis.