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Related Articles Genetic and Epigenetic Regulation and Expression Signatures of Glutathione S-Transferases in Developing Mouse Liver.
Toxicol Sci. 2010 Apr 15;
Authors: Cui JY, Choudhuri S, Knight TR, Klaassen CD
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 the present 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 which showed a progressive decline in postnatal mRNA expression, most other Gst isoforms showed a progressive increase in postnatal mRNA expression. Two-way hierachical 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 AhR, PXR, CAR, PPARalpha, and Nrf2. Specifically, genome-wide ChIP-seq revealed direct PXR-binding sites to the Gsta, Gstm, Gstt, and Gstp polycistron clusters, as well as to the Mgst1 gene locus. ChIP-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, the present 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.
PMID: 20395309 [PubMed - as supplied by publisher]
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Related Articles Genetic and Epigenetic Regulation and Expression Signatures of Glutathione S-Transferases in Developing Mouse Liver.
Toxicol Sci. 2010 Apr 15;
Authors: Cui JY, Choudhuri S, Knight TR, Klaassen CD
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 the present 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 which showed a progressive decline in postnatal mRNA expression, most other Gst isoforms showed a progressive increase in postnatal mRNA expression. Two-way hierachical 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 AhR, PXR, CAR, PPARalpha, and Nrf2. Specifically, genome-wide ChIP-seq revealed direct PXR-binding sites to the Gsta, Gstm, Gstt, and Gstp polycistron clusters, as well as to the Mgst1 gene locus. ChIP-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, the present 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.
PMID: 20395309 [PubMed - as supplied by publisher]
More...