Selenium regulation of selenoprotein enzyme activity and transcripts in a pilot study with Founder strains from the Collaborative Cross

Rodents and humans have 24–25 selenoproteins, and these proteins contain the 21st amino acid, selenocysteine, incorporated co-translationally into the peptide backbone in a series of reactions dependent on at least 6 unique gene products. In selenium (Se) deficiency, there is differential regulation of selenoprotein expression, whereby levels of some selenoproteins and their transcripts decrease dramatically in Se deficiency, but other selenoprotein transcripts are spared this decrease; the underlying mechanism, however, is not fully understood. To begin explore the genetic basis for this variation in regulation by Se status in a pilot study, we fed Se-deficient or Se-adequate diets (0.005 or 0.2 μg Se/g, respectively) for eight weeks to the eight Founder strains of the Collaborative Cross. We found rather uniform expression of selenoenzyme activity for glutathione peroxidase (Gpx) 3 in plasma, Gpx1 in red blood cells, and Gpx1, Gpx4, and thioredoxin reductase in liver. In Founder mice, Se deficiency decreased each of these activities to a similar extent. Regulation of selenoprotein transcript expression by Se status was also globally retained intact, with dramatic down-regulation of Gpx1, Selenow, and Selenoh transcripts in all 8 strains of Founder mice. These results indicate that differential regulation of selenoprotein expression by Se status is an essential aspect of Se metabolism and selenoprotein function. A few lone differences in Se regulation were observed for individual selenoproteins in this pilot study, but these differences did not single-out one strain or one selenoprotein that consistently had unique Se regulation of selenoprotein expression. These differences should be affirmed in larger studies; use of the Diversity Outbred and Collaborative Cross strains may help to better define the functions of these selenoproteins.

啮齿类动物与人类均拥有24至25种硒蛋白（selenoprotein），这类蛋白含有第21种氨基酸——硒代半胱氨酸（selenocysteine），其在共翻译过程中通过一系列依赖至少6种独特基因产物的反应被整合进入肽链骨架。在硒（Se）缺乏状态下，硒蛋白的表达呈现差异化调控：部分硒蛋白及其转录本水平在硒缺乏时会显著下降，而另一些硒蛋白的转录本则不受此影响；但其背后的分子机制尚未完全阐明。

为了在一项先导研究中探索硒状态对这种表达调控差异的遗传基础，我们为协作杂交（Collaborative Cross）的8个创始人品系小鼠饲喂了为期8周的硒缺乏日粮或硒充足日粮（分别含0.005或0.2 μg硒/克）。我们观察到，血浆中谷胱甘肽过氧化物酶（glutathione peroxidase, Gpx）3、红细胞中Gpx1，以及肝脏中Gpx1、Gpx4和硫氧还蛋白还原酶的硒酶活性表达较为一致。在创始人品系小鼠中，硒缺乏会将这些活性均降低至相近的水平。

硒状态对硒蛋白转录本表达的全局调控也基本保持完整，所有8个创始人品系小鼠的Gpx1、Selenow及Selenoh转录本均出现显著下调。上述结果表明，硒状态介导的硒蛋白表达差异化调控是硒代谢与硒蛋白功能的核心特征之一。本项先导研究中仅观察到少数个体硒蛋白的硒调控存在零星差异，但并未发现某一品系或某一硒蛋白始终呈现独特的硒蛋白表达调控模式。这些差异有待在更大规模的研究中验证；利用多样性远交（Diversity Outbred）与协作杂交品系，或可助力进一步明确这些硒蛋白的生物学功能。