The Tug1 lncRNA locus is essential for male fertility
The Tug1 lncRNA locus is essential for male fertility
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DOI：
10.1186/s13059-020-02081-5
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发表时间：
2020-09-07
期刊：
影响因子：
12.3
通讯作者：
Rinn, John L.
中科院分区：
文献类型：
--
作者：
Lewandowski, Jordan P.;Dumbovic, Gabrijela;Rinn, John L.
研究背景几种长链非编码RNA（lncRNA）已被证明是分子机器的组成部分，在生物学中起着重要作用。虽然哺乳动物基因组中注释的lncRNA的数量大大增加，但由于它们的生物学作用不同，并且lncRNA基因座可能包含多种可能发挥功能的分子模式，因此研究lncRNA功能一直是一个挑战。结果我们先前产生并表征了20个lncRNA基因座敲除小鼠的队列。在这里，我们扩展了这一初步研究，并提供了一个更详细的分析高度保守的lncRNA基因座，牛磺酸上调基因1（Tug 1）。我们报告说，Tug 1基因敲除雄性小鼠是不育的潜在缺陷，包括精子数量少和精子形态异常。由于lncRNA基因座可以包含多种作用模式，因此我们希望确定Tug 1基因组区域中包含的哪些潜在元件（如果有的话）具有任何活性。使用工程小鼠模型和基于细胞的测定，我们提供的证据表明，Tug 1位点具有两种不同的非编码调节活性，作为acis-DNA阻遏物，调节邻近基因和作为lncRNA，可以调节基因的atrans为基础的功能。我们还表明，Tug 1包含一个进化保守的开放阅读框架，当过表达产生一个稳定的蛋白质，影响线粒体膜电位，这表明一个潜在的第三编码功能。结论我们的研究结果揭示了Tug 1基因座在男性生育中的重要作用，并揭示了Tug 1基因座不同分子模式的证据，从而突出了lncRNA基因座的复杂性。
Background Several long noncoding RNAs (lncRNAs) have been shown to function as components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, studying lncRNA function has been a challenge due to their diverse biological roles and because lncRNA loci can contain multiple molecular modes that may exert function. Results We previously generated and characterized a cohort of 20 lncRNA loci knockout mice. Here, we extend this initial study and provide a more detailed analysis of the highly conserved lncRNA locus, taurine-upregulated gene 1 (Tug1). We report that Tug1-knockout male mice are sterile with underlying defects including a low number of sperm and abnormal sperm morphology. Because lncRNA loci can contain multiple modes of action, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region have any activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors two distinct noncoding regulatory activities, as acis-DNA repressor that regulates neighboring genes and as a lncRNA that can regulate genes by atrans-based function. We also show that Tug1 contains an evolutionary conserved open reading frame that when overexpressed produces a stable protein which impacts mitochondrial membrane potential, suggesting a potential third coding function. Conclusions Our results reveal an essential role for the Tug1 locus in male fertility and uncover evidence for distinct molecular modes in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.