Global analysis of DNA methylation in early-stage liver fibrosis.
Global analysis of DNA methylation in early-stage liver fibrosis.
复制标题
早期肝纤维化中DNA甲基化的全球分析。
DOI：
10.1186/1755-8794-5-5
复制
发表时间：
2012-01-27
影响因子：
2.7
通讯作者：
Yanagisawa J
中科院分区：
文献类型：
--
作者：
Komatsu Y;Waku T;Iwasaki N;Ono W;Yamaguchi C;Yanagisawa J
肝纤维化是由化学物质或病毒感染引起的。肝纤维化的进展导致晚期肝细胞癌的发生。近年来的研究表明，DNA甲基化在肝纤维化向肝细胞癌（HCC）发展过程中的重要性。然而，DNA甲基化在早期肝纤维化中的重要性尚不清楚。为了解决这个问题，我们使用了一种早期肝纤维化的病理小鼠模型，该模型通过四氯化碳（CCl 4）治疗2周诱导，并对DNA甲基化状态进行了全基因组分析。DNA甲基化的这种全局分析使用基于甲基结合蛋白（MBP）的高通量测序（MBP-seq）和生物信息学工具IPA和Oncomine的组合进行。为了确认MBP-seq数据的功能方面，我们补充使用了生物化学方法，例如亚硫酸氢盐修饰和体外甲基化测定。全基因组分析显示，在早期肝纤维化中，由于CCl 4治疗，DNA甲基化状态在整个基因组中降低。生物信息学和生化分析显示，与纤维化相关的基因，分泌磷蛋白1（Spp 1），诱导炎症，是低甲基化，其表达上调。这些结果表明，负责纤维化的基因的DNA低甲基化可能先于肝纤维化的发病。此外，Spp 1也被认为可以促进肿瘤的发展。使用基于网络的数据库，我们发现Spp 1的表达在HCC中增加。我们的研究表明，低甲基化对于肝纤维化向HCC的发生和进展至关重要。阐明从纤维化发作到随后进展为HCC的甲基化状态的这种变化可能导致新的临床诊断。
Liver fibrosis is caused by chemicals or viral infection. The progression of liver fibrosis results in hepatocellular carcinogenesis in later stages. Recent studies have revealed the importance of DNA hypermethylation in the progression of liver fibrosis to hepatocellular carcinoma (HCC). However, the importance of DNA methylation in the early-stage liver fibrosis remains unclear. To address this issue, we used a pathological mouse model of early-stage liver fibrosis that was induced by treatment with carbon tetrachloride (CCl4) for 2 weeks and performed a genome-wide analysis of DNA methylation status. This global analysis of DNA methylation was performed using a combination of methyl-binding protein (MBP)-based high throughput sequencing (MBP-seq) and bioinformatic tools, IPA and Oncomine. To confirm functional aspect of MBP-seq data, we complementary used biochemical methods, such as bisulfite modification and in-vitro-methylation assays. The genome-wide analysis revealed that DNA methylation status was reduced throughout the genome because of CCl4 treatment in the early-stage liver fibrosis. Bioinformatic and biochemical analyses revealed that a gene associated with fibrosis, secreted phosphoprotein 1 (Spp1), which induces inflammation, was hypomethylated and its expression was up-regulated. These results suggest that DNA hypomethylation of the genes responsible for fibrosis may precede the onset of liver fibrosis. Moreover, Spp1 is also known to enhance tumor development. Using the web-based database, we revealed that Spp1 expression is increased in HCC. Our study suggests that hypomethylation is crucial for the onset of and in the progression of liver fibrosis to HCC. The elucidation of this change in methylation status from the onset of fibrosis and subsequent progression to HCC may lead to a new clinical diagnosis.
登录
查看更多内容
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
25.7
作者：
Lorena, D;Darby, IA;Desmoulière, A
通讯作者：
Desmoulière, A
影响因子：
3.3
作者：
Chen, X;Cheung, ST;Brown, PO
通讯作者：
Brown, PO
影响因子：
64.5
作者：
Murayama, Akiko;Ohmori, Kazuji;Yanagisawa, Junn
通讯作者：
Yanagisawa, Junn
影响因子：
2.7
作者：
Bulger, Michael;Groudine, Mark
通讯作者：
Groudine, Mark