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Non-Genotoxic Carcinogen Exposure Induces Defined Changes in the 5-Hydroxymethylome

Published: Friday, October 05, 2012
Last Updated: Friday, October 05, 2012
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In a genome wide study Meehan, Moggs and MARCAR co-authors examined 5mC and 5hmC profiles of liver in control and phenobarbital treated mice. They observe dynamic and reciprocal changes in the 5mC/5hmC patterns over genes promoters that are transcriptionally up-regulated.

Text book DNA biology describes a genetic code comprising of four DNA bases (A,C,T,G ) and a 5th chemically modified (methylated) base 5-methylcytosine (5mC). The field of DNA methylation biology has been in a dynamic flux with the publication of new high resolution mapping studies of the DNA methylome in different tissues contexts and by the discovery of new modifications in mammalian DNA, notably a 6th DNA base 5-hydoxymethylcytosine (5hmC). It was recently discovered that 5-methylcytosine (5mC) can be oxidised to 5-hydroxymethylcytosine (5hmC) by the family of ten-eleven translocation (TET) enzymes, and that genomic 5hmC is abundant in a subset of mammalian tissues.  The 5hmC base has been linked to the enigmatic process of DNA demethylation, where the 5mC base is converted to C either through an active or passive mechanism. In a genome wide study Meehan, Moggs and MARCAR co-authors examine the 5mC and 5hmC profiles in liver of control and phenobarbital (PB) treated mice. Essentially they observe dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter of genes that are transcriptionally up-regulated after exposure to phenobarbital. 5hmC had been hypothesized to function as an intermediate of active demethylation during carcinogenesis; this study now provides support for this view.

Summary:

In a genome wide-multi sample study the authors examine the 5mC and 5hmC profiles in liver of control and phenobarbital (PB) treated mice. They observe dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter of genes that are transcriptionally up-regulated after exposure to phenobarbital. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters. Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.

This study was initiated through funding by the Innovative Medicines Initiative (IMI), a joint initiative (Public-Private Partnership) of the DG Research of the European Commission, representing the European Communities, and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI funded a 5 year program, MARCAR, which aims to identify novel bioMARkers and molecular tumor classification for non-genotoxic CARcinogenesis. IMI is aimed towards removing research bottlenecks in the current drug development process.

The new data also contribute to answering some of the provocative questions raised by the National Cancer Institute (http://provocativequestions.nci.nih.gov/rfa) including: 1) ”As modern measurement technologies improve, are there better ways to objectively ascertain exposure to cancer risk?” and 2) “How does susceptibility of exposure to cancer risk factors change during development?”

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Author list: John P Thomson, Harri Lempiäinen, Jamie A Hackett, Colm E Nestor, Arne Müller, Federico Bolognani, Edward J Oakeley, Dirk Schübeler, Rémi Terranova, Diana Reinhardt, Jonathan G Moggs and Richard R Meehan*

Title : Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome

Journal: Genome Biology

http://genomebiology.com/2012/13/10/R93

Summary

Background

Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital.

Results

Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters.

Conclusions

Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.


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