Selenium regulation of the selenoprotein and nonselenoprotein transcriptomes in rodents

Abstract

This review discusses progress in understanding the hierarchy of selenoprotein expression at the transcriptome level from selenium (Se) deficiency to Se toxicity. Microarray studies of the full selenoproteome have found that 5 of 24 rodent selenoprotein mRNA decrease to <40% of Se adequate levels in Se deficient liver but that the majority of selenoprotein mRNA are not regulated by Se deficiency. These differences match with the hierarchy of selenoprotein expression, helping to explain these differences and also showing that selenoprotein transcripts can be used as molecular biomarkers for assessing Se status. The similarity of the response curves for regulated selenoproteins suggests one underlying mechanism is responsible for the downregulation of selenoprotein mRNA in Se deficiency, but the heterogeneity of the UGA position in regulated and nonregulated selenoprotein transcripts now indicates that current nonsense mediated decay models cannot explain which transcripts are susceptible to mRNA decay. Microarray studies on the full liver transcriptome in rats found only <10 transcripts/treatment were significantly down- or upregulated by Se deficiency or by supernutritional Se up to 2.0 μg Se/g diet (20× requirement), suggesting that cancer prevention associated with supernutritional Se may not be mediated by transcriptional changes. Toxic dietary Se at 50× requirement (5 μg Se/g diet), however, significantly altered ∼4% of the transcriptome, suggesting number of transcriptional changes itself as a biomarker of Se toxicity. Finally, panels of Se regulated selenoprotein plus nonselenoprotein transcripts predict Se status from deficient to toxic better than conventional biomarkers, illustrating potential roles for molecular biomarkers in nutrition.

Figure 1

Liver Se concentration (A) and Gpx1 (B), Gpx4 (C), and Txnrd (D) activities in male weanling rats supplemented with the indicated levels of dietary Se (as Na₂SeO₃) for 28 d. Values are means ± SEM, n = 3–6, and the legends indicate the level of significance by ANOVA. Adapted with permission from (40).

Figure 2

Relative liver selenoprotein transcript levels for Gpx1 (A), Sepw1 (B), Selh (C), and Gpx4 (D) in rats described in Figure 1. Values are means ± SEM, n = 3, and the legends indicate the level of significance by ANOVA. Adapted with permission from (40).

Figure 3

Effect of Se status on total transcript expression and selenoprotein transcript expression. Shown is the number of transcripts of >30,000 total transcripts (left) and the number of selenoprotein transcripts of a total of 24 selenoprotein transcripts (right) altered (P < 0.05) by the indicated level of dietary Se relative to rats fed a 0.24 μg Se/g diet and within an experiment. Data collected using Affymetrix Rat Genome 230 2.0 arrays; transcript data are analyzed using RMA, as described previously (80), and selenoprotein transcript data analyzed as described in Figure 5. The x-axis is nonlinear; arrow indicates the relative position of the minimum dietary requirement for Se (0.1 μg Se/g diet).

Figure 4

RMA generated expression values for the 22 selenoprotein transcripts present on the Rat Genome 230 2.0 array. Columns represent liver expression from individual rats fed a 0, 0.08, 0.24, 0.8, 2, and 5 μg Se/g diet. Rows represent the probe sets. Also shown for comparison are expression values for 2 control transcripts (Gapdh and Rsp14) and for 6 transcripts for cysteine containing paralogs of selenoproteins. RMA gene expression is shown using the indicated pseudo color scale from −2× (green) to +2× (red) relative to values for rats fed 0.24 μg Se/g.

Figure 5

Mean RMA generated expression values for Se regulated selenoprotein transcripts in rats fed 0–5 μg Se/g diet. (A–C) Transcripts that were highly (to <40% of Se adequate levels) and significantly decreased by Se deficiency but not increased by supernutritional or toxic Se supplementation. (D–G) Transcripts that were moderately (41–70% of Se adequate levels) and significantly decreased by Se deficiency but not increased by supernutritional or toxic Se supplementation. (H–K) Transcripts that were not significantly decreased by Se deficiency but were increased significantly toxic Se supplementation. (L–N) Representative transcripts that were not significantly regulated by Se status. Values are expressed relative to levels in Se adequate (0.24 μg Se/g) rats and are means ± SEM (n = 3/treatment). Indicated P-values were determined by ANOVA. Labeled means without a common letter differ, P > 0.05 (Duncan’s multiple range test).

Figure 6

Prediction of liver Se by biomarker panels. Liver Se concentration activity as determined by actual measurement or calculated using biomarker panels based on liver Gpx1 plus liver Gpx4 activities, based on RBC Gpx1 plus plasma Gpx3 activities, based on the 11-transcript molecular biomarker panel identified by multiple regression analysis, as described in the text. Values are means ± SEM, n = 3. Reproduced with permission from (80).