Decrease of 5‐hydroxymethylcytosine in rat liver with subchronic exposure to genotoxic carcinogens riddelliine and aristolochic acid

Lian, Christine G.; Xu, Shuyun; Guo, Weimin; Yan, Jun; Frank, Maximilian Y.M.; Liu, Robert; Liu, Cynthia; Chen, Ying; Murphy, Gëorge F.; Chen, Tao

doi:10.1002/mc.22201

Cited by 8 publications

(9 citation statements)

References 19 publications

(35 reference statements)

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“…DNA methylation reprogramming has been previously noted for a host of tumour types including HCC (2,14,16,37). In addition, changes to the normal 5hmC patterns have also been reported in both mouse and rat livers following exposure to either non-genotoxic or genotoxic agents (13,19,38). In this present study we build on these early observations to show for the first time in mouse models of liver cancer that early perturbations in the epigenetic landscape over transcriptionally silent CGIs that are marked by low levels of 5hmC and H3K27me3.predicate hyper-methylation that occurs in tumours.…”

Section: Discussionmentioning

confidence: 94%

Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

et al. 2016

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Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations that occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, selected CGIs underwent hypo-hydroxymethylation prior to hypermethylation, while retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumorspecific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprograming of DNA methylation at silent CGI during progression. Cancer Res; 76(10); 3097-108. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 94%

Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

et al. 2016

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“…The reduced 5hmC level in the Mdr2-KO liver may reflect, in part, the reduced active demethylation of multiple CpG sites; the total number of such sites in the genome could be significantly higher than the number of the specific CGIs detected in our study. The level of 5hmC in the liver is known to be decreased in cancer and at the pre-cancerous stage [ 35 ], including human liver cancer [ 36 ] and chemically induced hepatocarcinogenesis in mice [ 37 ], as well as in rodent liver subjected to chronic [ 38 ] or sub-chronic [ 39 ] genotoxic treatments. We are not aware of studies exploring the 5hmC dynamics during liver regeneration; however, the recent finding of the reduced 5hmC level during regeneration of zebrafish fin [ 40 ] supports the negative correlation between cell proliferation and 5hmC level.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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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“…We have previously reported that in the mouse liver that promoter 5hmC patterns can reflect both acute and chronic exposure to carcinogenic agents in a model of nongenotoxic carcinogenesis [84][85][86]. In addition, a global decrease in the level of 5hmC was noted following subchronic exposures to the genotoxic carcinogens riddelliine and aristolochic acid in rat liver [87]. Thus, 5hmC can be regarded as an 'identifier of cell type or disease state,' with specific 5hmC patterns dependant on the length of time of exposure to a carcinogenic agent.…”

Section: Hmc 'Barcoding' To Identify Carcinogenic Compoundsmentioning

confidence: 95%

The Application of Genome-Wide 5-Hydroxymethylcytosine Studies in Cancer Research

Thomson

Meehan

2016

Epigenomics

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Early detection and characterization of molecular events associated with tumorgenesis remain high priorities. Genome-wide epigenetic assays are promising diagnostic tools, as aberrant epigenetic events are frequent and often cancer specific. The deposition and analysis of multiple patient-derived cancer epigenomic profiles contributes to our appreciation of the underlying biology; aiding the detection of novel identifiers for cancer subtypes. Modifying enzymes and co-factors regulating these epigenetic marks are frequently mutated in cancers, and as epigenetic modifications themselves are reversible, this makes their study very attractive with respect to pharmaceutical intervention. Here we focus on the novel modified base, 5-hydoxymethylcytosine, and discuss how genome-wide 5-hydoxymethylcytosine profiling expedites our molecular understanding of cancer, serves as a lineage tracer, classifies the mode of action of potentially carcinogenic agents and clarifies the roles of potential novel cancer drug targets; thus assisting the development of new diagnostic/prognostic tools.

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Decrease of 5‐hydroxymethylcytosine in rat liver with subchronic exposure to genotoxic carcinogens riddelliine and aristolochic acid

Cited by 8 publications

References 19 publications

Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

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

The Application of Genome-Wide 5-Hydroxymethylcytosine Studies in Cancer Research

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