Abstract
Glutathione S-transferase (GST) genes play a protective role against oxidative stress and may influence disease risk and drug pharmacokinetics. In this study, massive multiscalar trait profiling across a large population of mice derived from a cross between C57BL/6J (B6) and DBA2/J (D2)—the BXD family—was combined with linkage and bioinformatic analyses to characterize mechanisms controlling GST expression and to identify downstream consequences of this variation. Similar to humans, mice show a wide range in expression of GST family members. Variation in the expression of Gsta4, Gstt2, Gstz1, Gsto1, and Mgst3 is modulated by local expression QTLs (eQTLs) in several tissues. Higher expression of Gsto1 in brain and liver of BXD strains is strongly associated (P < 0.01) with inheritance of the B6 parental allele whereas higher expression of Gsta4 and Mgst3 in brain and liver, and Gstt2 and Gstz1 in brain is strongly associated with inheritance of the D2 parental allele. Allele-specific assays confirmed that expression of Gsto1, Gsta4, and Mgst3 are modulated by sequence variants within or near each gene locus. We exploited this endogenous variation to identify coexpression networks and downstream targets in mouse and human. Through a combined systems genetics approach, we provide new insight into the biological role of naturally occurring variants in GST genes.
Highlights
Cellular life forms, whether autonomous or multicellular, must respond to a constant barrage of environmental and metabolic hazards [1]
Variation in expression of several Glutathione S-tranferase (GST) family members is under genetic control Genome-wide expression profiles are available for ~20 peripheral tissues or cell types and ~10 individual brain regions for the BXD population
Representative data sets are robust for expression quantitative trait loci (QTL) mapping, have been extensively error-checked, and include a large number of BXD strains
Summary
Cellular life forms, whether autonomous or multicellular, must respond to a constant barrage of environmental and metabolic hazards [1]. Glutathione (GSH) transferase activity evolved as a common strategy to combat threats posed by oxidative stress and xenobiotics [2]. GSH is an important cellular antioxidant, signaling molecule, and cofactor [3]. It is essential for the maintenance of a suitable redox state in mitochondria—which constantly produce damaging reactive oxygen species as a by-product of cellular respiration. Glutathione S-tranferase (GST) enzymes catalyze the conjugation of GSH to electrophilic compounds [2,4], enabling the subsequent export of these potentially harmful substances out of the cell [5,6]. GSTs play an important role in detoxification of electrophilic xenobiotics [2,7], including drugs, carcinogens, and pesticides, and in the regulation of key signaling pathways involved in apoptosis, homeostasis, and the cellular stress response [3]
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