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1. J Proteomics. 2012 May 10. [Epub ahead of print]

Epigenetic regulation of ABCG2 gene is associated with susceptibility to
xenobiotic exposure.

Babu K, Zhang J, Moloney S, Pleasants T, McLean CA, Phua SH, Sheppard AM.

AgResearch Ltd., New Zealand.

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 Issue entitled: Genome
regulation.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID: 22580025 [PubMed - as supplied by publisher]