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DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations

ABSTRACT: Hepatoblastomas carry few genetic alterations, and we hypothesize that epigenetic changes could be relevant to their onset. DNA methylation profile of hepatoblastomas was explored in relation to liver development using the HM450K platform. Seven paired samples of hepatoblastomas and adjacent non-tumoral livers were studied, with biologicaland results validation validated in an independent group (12 hepatoblastomas) that confirmed 1,359 differentiated methylated CpG sites (DMSs) in hepatoblastomas compared to controls, associated with 979 genes. Hepatoblastomas also exhibited a global low-level hypomethylation when compared with differentiated livers, especially at non-repetitive intergenic DNA (~55% of the hypomethylated CpGs); conversely, most of the hypermethylated CpGs were located in CpG islands. Functional analyses revealed an enrichment in signaling pathways involved in metabolism, negative regulation of cell differentiation, liver development, cancer, and the WNT pathway. Strikingly, an important overlap was observed between hepatoblastomas DMSs and the CpG sites reported to exhibit methylation changes through liver development. Genes with differential methylation were related to maintenance of undifferentiated cell state, cell transformation and tumor progression, and the methylation profile of tumors resembled that of fetal livers. Altogether, our results suggest an arrest at early stages of liver cell differentiation, in line with the hypothesis that hepatoblastoma ontogeny involves the disruption of liver development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE78732 | GEO | 2017/04/03

SECONDARY ACCESSION(S): PRJNA313415

REPOSITORIES: GEO

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Project description: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/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted 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-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver. Two-condition experiment, Mdr2-KO vs Mdr2-/+ liver tissue from 12m-old male FVB strain mice. Biological replicates: 3 control replicates, 3 knockout replicates.

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DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations

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