Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis

Evgeniy Stoyanov, Guy Ludwig, Lina Mizrahi, Devorah Olam, Temima Schnitzer-Perlman, Elena Tasika, Gabriele Sass, Gisa Tiegs, Yong Jiang, Ting Nie, James Kohler, Raymond F. Schinazi, Paula M. Vertino, Howard Cedar, Eithan Galun, Daniel Goldenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2-/- (Mdr2/Abcb4-knockout) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation followed by hybridization with "CpG islands" (CGIs) microarrays, we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-/- liver compared to age-matched healthy controls. The observed hypermethylation resulted mainly from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-/- liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-/- livers affected either hepatocyte, or non-hepatocyte, or both fractions without a correlation between changes of gene methylation and expression. Our findings demonstrate that chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and nonhepatocyte liver cells. These changes may serve as useful markers of an increased regenerative activity and of a late precancerous stage in the chronically inflamed liver.

Original languageAmerican English
Pages (from-to)11047-11060
Number of pages14
JournalOncotarget
Volume6
Issue number13
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • 5-hydroxymethylcytosine
  • DNA methylation
  • Hepatocellular carcinoma
  • Mdr2 (Abcb4)
  • mtDNA deletion

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