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Logo of bmcmedgenoBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Medical Genomics
 
BMC Med Genomics. 2012; 5: 5.
Published online Jan 27, 2012. doi:  10.1186/1755-8794-5-5
PMCID: PMC3295686
Global analysis of DNA methylation in early-stage liver fibrosis
Yoko Komatsu,#1 Tsuyoshi Waku,#2 Naoya Iwasaki,#1 Wakana Ono,1 Chie Yamaguchi,1 and Junn Yanagisawacorresponding author1,2
1Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan
2Center for Tsukuba Advanced Research Alliance (TARA), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan
corresponding authorCorresponding author.
#Contributed equally.
Yoko Komatsu: s0930264/at/u.tsukuba.ac.jp; Tsuyoshi Waku: twaku/at/tara.tsukuba.ac.jp; Naoya Iwasaki: s1121118/at/u.tsukuba.ac.jp; Wakana Ono: s1121135/at/u.tsukuba.ac.jp; Chie Yamaguchi: s1121218/at/u.tsukuba.ac.jp; Junn Yanagisawa: junny/at/agbi.tsukuba.ac.jp
Received October 11, 2011; Accepted January 27, 2012.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
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