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A Panel of Differentially Methylated Putative Imprinting Control Regions Associated with Hepatocellular Carcinoma

ABSTRACT: Site-specific 5-methylcytosine levels measured in mixed blood leukocytes have been used as surrogate for inaccessible tissues and associated with hepatocellular carcinoma (HCC) risk. However, findings are difficult to replicate as methylation patterns at many of these sites do not always correlate with those in liver tissue. An exception is methylation at imprinting control regions (ICRs), which regulate the monoallelic expression of imprinted genes, a developmentally critical process requiring parental allele-specific DNA methylation that is consistent across cell types. Aberrant methylation of several ICRs have been linked to advanced liver disease or HCC. We aim to create a DNA methylation-based risk stratification panel to improve early detection and triaging of patients before the onset of HCC in those at increased risk. From whole genome bisulfite sequencing (WGBS) of mixed leukocyte-derived DNA of HCC cases and controls, 1,519 regions were significantly differentially methylated. This list was augmented with a compendium of 3,275 HCC-, cirrhosis-, and fibrosis-associated differentially methylated regions (DMRs) identified from primary literature on PubMed, for a total of 4794 unique DMRs. Filtering these DMRs with a published list of ICRs revealed 97 ICRs within these liver disease-associated DMRs, 21 of them previously characterized and 76 novel. Of these ICRs, 46 replicated in an independent case-control comparison using the novel Illumina custom Imprintome Methylation array. Limited sample sizes notwithstanding, this comprehensive analysis supports the use of altered DNA methylation of ICRs for HCC risk stratification from readily accessible tissue, blood.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302608 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Background: C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified. Methods: We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database. Results: We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including Mst1r, Slpi and Extl1. The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5- aza-2'-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of Mst1r in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of Mstr1 and Slpi are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of Mst1r and Slpi, are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC. Conclusions: Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for Mst1r and Slpi, which may be applied not only to mouse HCC but also to human HCC.

Project description:To further our understanding of the role of DNA methylation in development, Methylated DNA Immunoprecipitation (MeDIP) was used in conjunction with a NimbleGen promoter plus CpG island array to identify Tissue and Developmental Stage specific Differentially Methylated DNA Regions (T-DMRs and DS-DMRs) on a genome-wide basis. Four tissues (brain, heart, liver, and testis) from C57BL/6J mice were analyzed at three developmental stages (15 day embryo, E15; new born, NB; 12 week adult, AD). Almost 5,000 adult T-DMRs and 10,000 DS-DMRs were identified. Surprisingly, almost all DS-DMRs were tissue specific (i.e., methylated and ummenthylated in one or more non-overlapping tissues), indicating that the vast majority of unique sequence DNA methylation has tissue specificity. Also, many DS-DMRs were methylated at early development stages (E15 and NB) but unmethylated in adult, indicating “demethylation” has a prominent role in tissue differentiation. The pattern of DNA methylation in adult testis was dramatically different from somatic tissues in many aspects, mostly notably with a very strong bias of methylation in non-CpGi (CpG island) promoter regions (94%). Although the majority of T-DMRs and DS-DMRs tended to be in non-CpGi promoter regions, a relatively large number were also located in CpGi in promoter, intra-genic and inter-genic regions (>15% of all CpGi). Gene Ontology analysis of genes with methylation in non-CpGi promoters indicates enrichment of genes related to membrane proteins and G-protein coupled receptors. Our data also suggest regulatory roles of DNA methylation outside of promoter regions and in alternative promoter selection. Overall, our studies indicate that change in DNA methylation during development is a dynamic, widespread and tissue-specific process involving both DNA methylation and demethylation. Comparison of DNA methylation across 3 developmental stages (15 day embryo, newborn, and adult) for four tissues (brain, heart, liver and testis)

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A Panel of Differentially Methylated Putative Imprinting Control Regions Associated with Hepatocellular Carcinoma

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