Dataset Information

The Genetic Architecture of Murine Glutathione Transferases.

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.

SUBMITTER: Lu L

PROVIDER: S-EPMC4734686 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Genetic Architecture of Murine Glutathione Transferases.

Lu Lu L Pandey Ashutosh K AK Houseal M Trevor MT Mulligan Megan K MK

PloS one 20160201 2

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 ...[more]

PMID: 26829228

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Project description:The hepatic glutathione S-transferases (Gsts) are critical phase II enzymes in protecting cellular macromolecules against electrophiles and oxidative stress. Little is known about the ontogeny of Gsts and the underlying regulatory mechanisms during liver development. Therefore, in this study, the ontogeny and the regulatory mechanisms of 19 known Gst isoforms were investigated in mouse liver from 2 days before birth to postnatal day 45. With the exception of Gstm5 and MGst2 that showed a progressive decline in postnatal messenger RNA (mRNA) expression, most other Gst isoforms showed a progressive increase in postnatal mRNA expression. Two-way hierarchical clustering revealed three distinct expression patterns of these Gsts isoforms: perinatal, adolescent, and adult enriched. The expression signatures of certain Gst isoforms showed positive association with the ontogeny of critical xenobiotic-sensing transcription factors, including aryl hydrocarbon receptor, pregnane X receptor (PXR), constitutive androstane receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor-2. Specifically, genome-wide chromatin immunoprecipitation coupled with the next generation sequencing technology (ChIP-Seq) revealed direct PXR-binding sites to the Gsta, Gstm, Gstt, and Gstp polycistron clusters as well as to the Mgst1 gene locus. Chromatin immunoprecipitation-on-chip analysis demonstrated that DNA methylation and histone H3K27-trimethylation (H3K27me3), two-gene expression-suppressing epigenetic marks, were consistently low around the Gstz1 gene locus. In contrast, enrichment of histone H3K4-dimethylation (H3K4me2), a hallmark for gene activation, increased 60% around the Gstz1 gene locus from prenatal to the young adult period. Regression analysis revealed a strong correlation between the enrichment of H3K4me2 and Gstz1 mRNA expression (r = 0.76). In conclusion, this study characterized three distinct ontogenic expression signatures of the 19 Gst isoforms and examined some genetic and epigenetic mechanisms inducing their transcription during liver development.

Dataset Information

The Genetic Architecture of Murine Glutathione Transferases.

Publications

The Genetic Architecture of Murine Glutathione Transferases.

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