CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer.
CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer.
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DOI：
10.1038/onc.2010.361
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发表时间：
2010-12-02
期刊：
影响因子：
8
通讯作者：
Esteller, M.
中科院分区：
文献类型：
--
作者：
Lujambio, A.;Portela, A.;Liz, J.;Melo, S. A.;Rossi, S.;Spizzo, R.;Croce, C. M.;Calin, G. A.;Esteller, M.
虽然只有1.5%的人类基因组似乎编码蛋白质，但癌症研究的许多努力都致力于我们DNA的这一小部分。然而，近几年来，人们认识到一类称为microRNA的非编码RNA（ncRNA）通过充当癌基因或肿瘤抑制基因而促进癌症的发生和发展。最近的研究还表明，通过CpG岛超甲基化使具有肿瘤抑制特征的microRNA的表观遗传沉默是人类肿瘤的共同标志。因此，我们想知道在转化细胞中是否有其他ncRNA经历异常DNA甲基化相关的沉默。我们专注于转录超保守区（T-UCRs），这是一个绝对保守的DNA序列子集，位于人类，大鼠和小鼠基因组的正向区域之间，位于基因内和基因间区域。我们使用了药理学和基因组学的方法来揭示T-UCRs的异常表观遗传沉默模式的可能存在，通过用DNA去甲基化剂处理癌细胞，然后与含有这些序列的表达微阵列杂交。我们观察到DNA低甲基化诱导癌细胞中T-UCR沉默的释放。在药物治疗后重新激活的T-UCR中，发现Uc.160+、Uc 283 +A和Uc.346+在癌细胞中与正常组织相比经历特异性CpG岛高甲基化相关沉默。对大量原发性人类肿瘤（n=283）的分析表明，所述T-UCR CpG岛的超甲基化是各种肿瘤类型中的常见事件。我们的发现，除了microRNA，另一类ncRNA（T-UCRs）在转化细胞中经历DNA甲基化相关的失活支持了一个模型，其中编码和非编码序列的表观遗传和遗传改变在人类肿瘤发生中合作。
Although only 1.5% of the human genome appears to code for proteins, much effort in cancer research has been devoted to this minimal fraction of our DNA. However, the last few years have witnessed the realization that a large class of non-coding RNAs (ncRNAs), named microRNAs, contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also shown that epigenetic silencing of microRNAs with tumor suppressor features by CpG island hypermethylation is a common hallmark of human tumors. Thus, we wondered whether there were other ncRNAs undergoing aberrant DNA methylation-associated silencing in transformed cells. We focused on the transcribed-ultraconserved regions (T-UCRs), a subset of DNA sequences that are absolutely conserved between orthologous regions of the human, rat and mouse genomes and that are located in both intra- and intergenic regions. We used a pharmacological and genomic approach to reveal the possible existence of an aberrant epigenetic silencing pattern of T-UCRs by treating cancer cells with a DNA-demethylating agent followed by hybridization to an expression microarray containing these sequences. We observed that DNA hypomethylation induces release of T-UCR silencing in cancer cells. Among the T-UCRs that were reactivated upon drug treatment, Uc.160+, Uc283+A and Uc.346+ were found to undergo specific CpG island hypermethylation-associated silencing in cancer cells compared with normal tissues. The analysis of a large set of primary human tumors (n=283) demonstrated that hypermethylation of the described T-UCR CpG islands was a common event among the various tumor types. Our finding that, in addition to microRNAs, another class of ncRNAs (T-UCRs) undergoes DNA methylation-associated inactivation in transformed cells supports a model in which epigenetic and genetic alterations in coding and non-coding sequences cooperate in human tumorigenesis.
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影响因子：
11.2
作者：
Huang YW;Liu JC;Deatherage DE;Luo J;Mutch DG;Goodfellow PJ;Miller DS;Huang TH
通讯作者：
Huang TH
影响因子：
8
作者：
Jacinto, F. V.;Ballestar, E.;Esteller, M.
通讯作者：
Esteller, M.
DOI：
10.1126/science.1174334
发表时间：
2009-08-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hill DA;Ivanovich J;Priest JR;Gurnett CA;Dehner LP;Desruisseau D;Jarzembowski JA;Wikenheiser-Brokamp KA;Suarez BK;Whelan AJ;Williams G;Bracamontes D;Messinger Y;Goodfellow PJ
通讯作者：
Goodfellow PJ
影响因子：
3.5
作者：
Iwama, Hisakazu;Masaki, Tsutomu;Kuriyama, Shigeki
通讯作者：
Kuriyama, Shigeki
DOI：
10.1073/pnas.0404432101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Calin, GA;Liu, CG;Croce, CM
通讯作者：
Croce, CM