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Transcriptomic analysis of a gut epithelial cell line after the depletion of selenoprotein Glutathione peroxidase 4

ABSTRACT: GPx4 is an important antioxidant gene that is derived from selenium. A ploymorphism in GPx4 has been associated with increased risk of colorectal and prostate cancer. This experiment decsribes the effect of change in GPx4 expression in human intestinal epithelial cell line (Caco-2).Depletion of GPx4 expression led to changes in mitochondrial pathways including oxidative phosphorylation and ubiquinone biosynthesis pathway and genes involved in apoptosis regulation

ORGANISM(S): Homo sapiens

PROVIDER: GSE40287 | GEO | 2013/01/01

SECONDARY ACCESSION(S): PRJNA173416

REPOSITORIES: GEO

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Project description:Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic mutations in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic mutations in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the underlying mechanisms of SEPSECS mutations, we generated a novel mouse model recapitulating the respective human pathogenic Y334C mutation in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, homozygous mutant pups died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by inactivating mutations of the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active site Sec to Cys in GPX4 surprisingly rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of Sepsecs-mutant mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with mutations in SEPSECS or GPX4 may benefit from treatments partially compensating for impaired GPX4 activity.

Dataset Information

Transcriptomic analysis of a gut epithelial cell line after the depletion of selenoprotein Glutathione peroxidase 4

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