title: Epigenetic regulation of ABCG2 gene is associated with susceptibility to xenobiotic exposure.
abstract: A highly conserved defence mechanism has evolved to protect cells from oxidative stress and xenobiotic exposure. A network of coupled xenobiotic metabolizing enzymatic reactions (XMEs) converts free oxidative radicals to less damaging metabolites, while efflux pumps remove toxins and XME derivatives from the cell. These mechanisms have been well studied in the contexts of hypoxia and Multidrug Resistance (MDR). Exposure of ruminants to fungal toxins leads to hepatotoxicosis and subsequent skin eczema (FE) depending upon toxic burden. Using toxin challenge in sheep we have investigated the potential for epigenetic regulation in cellular responses to xenobiotic exposure with a focus on the efflux protein ABCG2 which functions in Phase III of the defence mechanism. We show that 'resistance' to FE disease is positively associated with ABCG2 expression, and inversely correlated with DNA methylation state at CpG sites in the regulatory region of the ABCG2 gene. The analytical sensitivity provided by the Sequenom EpiTyper MS platform allows resolution of individual CpG sites varying significantly with disease progression, informing fine mapping of relevant transcription factor bindings which underpin this epigenetic response. Our findings indicate that epigenetic mechanisms are important to xenobiotic responses, suggest useful diagnostic markers and raise potential opportunities for disease remediation. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry.
authors.affiliation: AgResearch Ltd., New Zealand.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Babu
authors.forename: Jinbi
authors.initials: J
authors.lastname: Zhang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moloney
authors.forename: Tony
authors.initials: T
authors.lastname: Pleasants
authors.forename: Cameron A
authors.initials: CA
authors.lastname: McLean
authors.forename: Sin H
authors.initials: SH
authors.lastname: Phua
authors.forename: Allan M
authors.initials: AM
authors.lastname: Sheppard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D013058:Mass Spectrometry / Q000379:methods*; D008969:Molecular Sequence Data; D009183:Mycotoxins / Q000633:toxicity*; D017422:Sequence Analysis, DNA / Q000379:methods*; D012756:Sheep; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D018528:ATP-Binding Cassette Transporters; D009183:Mycotoxins; D015262:Xenobiotics; D004247:DNA