Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis
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Evgeniy Stoyanov1, Guy Ludwig2, Lina Mizrahi1, Devorah Olam1, Temima Schnitzer-Perlman1, Elena Tasika3, Gabriele Sass3, Gisa Tiegs3, Yong Jiang4, Ting Nie4, James Kohler4, Raymond F. Schinazi4, Paula M. Vertino5, Howard Cedar2, Eithan Galun1 and Daniel Goldenberg1
1 The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2 Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University, Jerusalem, Israel
3 Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4 Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA, USA
5 Department of Radiation Oncology and the Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
Daniel Goldenberg, email:
Keywords: Mdr2 (Abcb4), hepatocellular carcinoma, DNA methylation, mtDNA deletion, 5-hydroxymethylcytosine
Received: December 09, 2014 Accepted: February 26, 2015 Published: March 14, 2015
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 non-hepatocyte 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.
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