title: Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome.
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.
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.forename: Harri
authors.initials: H
authors.lastname: Lempiäinen
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Hackett
authors.forename: Colm E
authors.initials: CE
authors.lastname: Nestor
authors.forename: Arne
authors.initials: A
authors.lastname: Müller
authors.forename: Federico
authors.initials: F
authors.lastname: Bolognani
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
authors.forename: Rémi
authors.initials: R
authors.lastname: Terranova
authors.forename: Diana
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D057890:Epigenomics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010634:Phenobarbital / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects
chemical_list: D006657:Histones; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D010634:Phenobarbital