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

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; Richard Meehan

doi:10.1186/gb-2012-13-10-r93

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

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, Richard Meehan

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

ABSTRACT: 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.

Original language	English
Article number	R93
Journal	Genome Biology
Volume	13
Issue number	10
DOIs	https://doi.org/10.1186/gb-2012-13-10-r93
Publication status	Published - 3 Oct 2012

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10.1186/gb-2012-13-10-r93

Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome
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title = "Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome",

abstract = "ABSTRACT: 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.",

author = "Thomson, {John P} and Harri Lempi{\"a}inen and Hackett, {Jamie A} and Nestor, {Colm E} and Arne M{\"u}ller and Federico Bolognani and Oakeley, {Edward J} and Dirk Sch{\"u}beler and R{\'e}mi Terranova and Diana Reinhardt and Moggs, {Jonathan G} and Richard Meehan",

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doi = "10.1186/gb-2012-13-10-r93",

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AU - Thomson, John P

AU - Lempiäinen, Harri

AU - Hackett, Jamie A

AU - Nestor, Colm E

AU - Müller, Arne

AU - Bolognani, Federico

AU - Oakeley, Edward J

AU - Schübeler, Dirk

AU - Terranova, Rémi

AU - Reinhardt, Diana

AU - Moggs, Jonathan G

AU - Meehan, Richard

PY - 2012/10/3

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N2 - ABSTRACT: 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.

AB - ABSTRACT: 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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DO - 10.1186/gb-2012-13-10-r93

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JO - Genome Biology

JF - Genome Biology

IS - 10

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

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