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

TY - JOUR

T1 - Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis

AU - Stoyanov, Evgeniy

AU - Ludwig, Guy

AU - Mizrahi, Lina

AU - Olam, Devorah

AU - Schnitzer-Perlman, Temima

AU - Tasika, Elena

AU - Sass, Gabriele

AU - Tiegs, Gisa

AU - Jiang, Yong

AU - Nie, Ting

AU - Kohler, James

AU - Schinazi, Raymond F

AU - Vertino, Paula M

AU - Cedar, Howard

AU - Galun, Eithan

AU - Goldenberg, Daniel

PY - 2015/5/10

Y1 - 2015/5/10

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.3567

DO - 10.18632/oncotarget.3567

M3 - SCORING: Journal article

C2 - 25918251

VL - 6

SP - 11047

EP - 11060

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 13

ER -