DNA-methylome analysis of mouse intestinal adenoma identifies a tumour-specific signature that is partly conserved in human colon cancer.
DNA-methylome analysis of mouse intestinal adenoma identifies a tumour-specific signature that is partly conserved in human colon cancer.
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DOI：
10.1371/journal.pgen.1003250
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Morkel M
中科院分区：
文献类型：
--
作者：
Grimm C;Chavez L;Vilardell M;Farrall AL;Tierling S;Böhm JW;Grote P;Lienhard M;Dietrich J;Timmermann B;Walter J;Schweiger MR;Lehrach H;Herwig R;Herrmann BG;Morkel M
异常CpG甲基化是癌细胞基因组的普遍表观遗传特征。然而，人类癌症样品或细胞系排除了对肿瘤发展早期发生的表观遗传变化的研究。在这里，我们使用MeDIP-seq来分析APCMin腺瘤的DNA甲基化组作为肠癌起始的模型，并且我们列出了超过13，000个重复的差异甲基化区域（DMR），其特征在于小鼠的肠腺瘤。我们发现Polycomb抑制复合物（PRC）靶点在高甲基化DMR中高度富集，并且几种PRC 2组分和DNA甲基转移酶在腺瘤中上调。我们进一步证明，通过亚硫酸氢盐焦磷酸测序纯化的细胞群，DMR签名从头出现在腺瘤细胞，而不是通过扩大肠干细胞或未分化的隐窝细胞中的预先存在的模式。我们发现，肿瘤抑制基因的表观遗传沉默，这经常发生在结肠癌，是罕见的腺瘤。非常引人注目的是，我们确定了一组核心DMR，这些DMR在小鼠腺瘤和人类结肠癌之间是保守的，因此可能揭示了一组全球性的肠道肿瘤表观遗传修饰基因。我们的数据可以区分早期保守的表观遗传改变发生在肠腺瘤和晚期随机事件促进结肠癌的进展，并可能有助于选择更具体的临床表观遗传生物标志物。肿瘤的形成和发展到转移性疾病是由两种主要机制驱动的，即激活致癌基因或抑癌基因的遗传改变，以及引起遗传信息表达变化的表观基因组变化。深入了解遗传和表观遗传机制之间的相互作用对于肿瘤生物标志物的选择和未来治疗的发展至关重要。人类肿瘤标本和细胞系包含大量的遗传和表观遗传变化，这使数据分析复杂化。相比之下，小鼠肿瘤模型，如本研究中使用的APCMin小鼠，是由一个单一的起始基因突变引起的，但与人类癌症有着共同的关键特征。在这里，我们表明，小鼠腺瘤获得了大量的表观遗传改变，这是反复出现在小鼠腺瘤和人类结肠癌，分别代表早期和晚期肿瘤。因此，使用小鼠模型使我们能够揭示肿瘤中发生的表观遗传变化序列，这可能有助于识别新的临床结肠癌生物标志物。
Aberrant CpG methylation is a universal epigenetic trait of cancer cell genomes. However, human cancer samples or cell lines preclude the investigation of epigenetic changes occurring early during tumour development. Here, we have used MeDIP-seq to analyse the DNA methylome of APCMin adenoma as a model for intestinal cancer initiation, and we present a list of more than 13,000 recurring differentially methylated regions (DMRs) characterizing intestinal adenoma of the mouse. We show that Polycomb Repressive Complex (PRC) targets are strongly enriched among hypermethylated DMRs, and several PRC2 components and DNA methyltransferases were up-regulated in adenoma. We further demonstrate by bisulfite pyrosequencing of purified cell populations that the DMR signature arises de novo in adenoma cells rather than by expansion of a pre-existing pattern in intestinal stem cells or undifferentiated crypt cells. We found that epigenetic silencing of tumour suppressors, which occurs frequently in colon cancer, was rare in adenoma. Quite strikingly, we identified a core set of DMRs, which is conserved between mouse adenoma and human colon cancer, thus possibly revealing a global panel of epigenetically modified genes for intestinal tumours. Our data allow a distinction between early conserved epigenetic alterations occurring in intestinal adenoma and late stochastic events promoting colon cancer progression, and may facilitate the selection of more specific clinical epigenetic biomarkers. The formation and progression of tumours to metastatic disease is driven by two major mechanisms, i.e. genetic alterations that activate oncogenes or inactivate tumour suppressor genes, and changes in the epigenome that cause variations in the expression of the genetic information. A deeper understanding of the interaction between the genetic and epigenetic mechanisms is critical for the selection of tumour biomarkers and for the future development of therapies. Human tumour specimens and cell lines contain a plethora of genetic and epigenetic changes, which complicate data analysis. In contrast, mouse tumour models such as the APCMin mouse used in this study arise by a single initiating genetic mutation, yet share key traits with human cancer. Here we show that mouse adenomas acquire a multitude of epigenetic alterations, which are recurring in mouse adenoma and in human colon cancer, representing early and advanced tumours, respectively. The use of a mouse model thus allowed us to uncover a sequence of epigenetic changes occurring in tumours, which may facilitate the identification of novel clinical colon cancer biomarkers.
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影响因子：
11.2
作者：
Fackler MJ;Umbricht CB;Williams D;Argani P;Cruz LA;Merino VF;Teo WW;Zhang Z;Huang P;Visvananthan K;Marks J;Ethier S;Gray JW;Wolff AC;Cope LM;Sukumar S
通讯作者：
Sukumar S
影响因子：
7
作者：
Easwaran, Hariharan;Johnstone, Sarah E.;Baylin, Stephen B.
通讯作者：
Baylin, Stephen B.
影响因子：
3.7
作者：
Estecio, Marcos R. H.;Gharibyan, Vazganush;Shen, Lanlan;Ibrahim, Ashraf E. K.;Doshi, Ketan;He, Rong;Jelinek, Jaroslav;Yang, Allen S.;Yan, Pearlly S.;Huang, Tim H-M.;Tajara, Eloiza H.;Issa, Jean-Pierre J.
通讯作者：
Issa, Jean-Pierre J.
影响因子：
6.4
作者：
Farrall, Alexandra L.;Riemer, Pamela;Morkel, Markus
通讯作者：
Morkel, Markus
影响因子：
6
作者：
Gaspar, Claudia;Cardoso, Joana;Fodde, Riccardo
通讯作者：
Fodde, Riccardo