The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes.
The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes.
复制标题
DOI：
10.1186/s12885-018-4221-0
复制
发表时间：
2018-03-22
期刊：
影响因子：
3.8
通讯作者：
Nohara K
中科院分区：
文献类型：
--
作者：
Matsushita J;Okamura K;Nakabayashi K;Suzuki T;Horibe Y;Kawai T;Sakurai T;Yamashita S;Higami Y;Ichihara G;Hata K;Nohara K
C3H小鼠经常被用于癌症研究，作为自发性肝癌和化学诱导的肝细胞癌的动物模型。表观遗传修饰，包括DNA甲基化，是导致癌症发生的基因表达的关键控制机制之一。虽然关于C3H小鼠肝脏肿瘤的体细胞突变的信息是可用的，但表观遗传学方面仍有待澄清。我们进行了基于下一代测序的DNA甲基化分析和基因表达微阵列分析，以探索DNA甲基化在C3H小鼠自发肝癌中调控的基因。覆盖这些数据，我们选择了癌症相关基因，其表达与位于转录起始点(TSS)(启动子DMRS)附近的相关差异甲基化区域(DMRS)中的DNA甲基化水平呈负相关。我们使用癌症基因组图谱(TCGA)数据库进一步评估了所选基因在人类肝癌中表达和DNA甲基化的相互关系。我们获得了C3H小鼠正常和肿瘤肝脏全基因组DNA甲基化图谱的数据。我们鉴定了与癌症相关的基因的启动子DMRS，这些基因的表达与DNA甲基化呈负相关，包括Mst1r、SLPI和Extl1。用DNA甲基化抑制剂5-氮杂-2‘-脱氧胞苷(5-aza-2’-deoxcytidine，5-aza-DC)证实了DNA甲基化与Hepa1-6细胞基因表达的相关性。Mst1r在Hepa1c1c7细胞中的过表达为IL-33上调提供了一条新的下游途径。数据库检索表明，在人肝细胞癌中，Mst1r和SLPI基因表达上调，TSS上游区域也发生低甲基化。这些结果表明，包括Mst1r和SLPI在内的DMR参与了C3H小鼠的肝脏肿瘤的发生，也可能参与了人类肝癌的发生。我们的研究阐明了C3H小鼠全基因组DNA甲基化的图景。这些数据为进一步研究肝癌小鼠模型的表观遗传学提供了有用的信息。本研究特别针对Mst1r和SLPI提出了新的DNA甲基化调控途径，不仅可应用于小鼠肝癌，也可应用于人肝癌。本文的在线版本(10.1186/s12885-0184221-0)包含向授权用户提供的补充材料。
C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified. We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation in spontaneous liver tumors of C3H mice. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database. We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including Mst1r, Slpi and Extl1. The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of Mst1r in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of Mst1r and Slpi are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of Mst1r and Slpi, are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC. Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for Mst1r and Slpi, which may be applied not only to mouse HCC but also to human HCC. The online version of this article (10.1186/s12885-018-4221-0) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
5.7
作者：
Honda S;Minato M;Suzuki H;Fujiyoshi M;Miyagi H;Haruta M;Kaneko Y;Hatanaka KC;Hiyama E;Kamijo T;Okada T;Taketomi A
通讯作者：
Taketomi A
影响因子：
12.3
作者：
Akalin A;Kormaksson M;Li S;Garrett-Bakelman FE;Figueroa ME;Melnick A;Mason CE
通讯作者：
Mason CE
影响因子：
--
作者：
He L;Tian DA;Li PY;He XX
通讯作者：
He XX
DOI：
10.1073/pnas.1404267111
发表时间：
2014-08-05
影响因子：
11.1
作者：
Hartwell, Hadley J.;Petrosky, Keiko Y.;Rogers, Arlin B.
通讯作者：
Rogers, Arlin B.
影响因子：
5.7
作者：
De Souza AP;Planello AC;Marques MR;De Carvalho DD;Line SR
通讯作者：
Line SR