Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Biology, The University of Texas at San Antonio, Texas, USA.
Biol Reprod. 2017 Aug 1;97(2):313-323. doi: 10.1093/biolre/iox084.
Mammalian reproduction requires that males and females produce functional haploid germ cells through complex cellular differentiation processes known as spermatogenesis and oogenesis, respectively. While numerous studies have functionally characterized protein-coding genes and small noncoding RNAs (microRNAs and piRNAs) that are essential for gametogenesis, the roles of regulatory long noncoding RNAs (lncRNAs) are yet to be fully characterized. Previously, we and others have demonstrated that intergenic regions of the mammalian genome encode thousands of long noncoding RNAs, and many studies have now demonstrated their critical roles in key biological processes. Thus, we postulated that some lncRNAs may also impact mammalian spermatogenesis and fertility. In this study, we identified a dynamic expression pattern of lncRNAs during murine spermatogenesis. Importantly, we identified a subset of lncRNAs and very few mRNAs that appear to escape meiotic sex chromosome inactivation, an epigenetic process that leads to the silencing of the X- and Y-chromosomes at the pachytene stage of meiosis. Further, some of these lncRNAs and mRNAs show a strong testis expression pattern suggesting that they may play key roles in spermatogenesis. Lastly, we generated a mouse knockout of one X-linked lncRNA, Tslrn1 (testis-specific long noncoding RNA 1), and found that males carrying a Tslrn1 deletion displayed normal fertility but a significant reduction in spermatozoa. Our findings demonstrate that dysregulation of specific mammalian lncRNAs is a novel mechanism of low sperm count or infertility, thus potentially providing new biomarkers and therapeutic strategies.
哺乳动物的繁殖需要雄性和雌性分别通过复杂的细胞分化过程产生功能上的单倍体生殖细胞，这一过程分别称为精子发生和卵子发生。虽然有许多研究已经对参与配子发生的蛋白编码基因和小非编码 RNA（microRNAs 和 piRNAs）进行了功能特征分析，但调控长非编码 RNA（lncRNA）的作用尚未得到充分的描述。此前，我们和其他人已经证明了哺乳动物基因组的基因间区编码了数千种长非编码 RNA，现在许多研究已经证明了它们在关键生物学过程中的关键作用。因此，我们推测一些 lncRNA 也可能影响哺乳动物的精子发生和生育能力。在这项研究中，我们鉴定了 lncRNA 在小鼠精子发生过程中的动态表达模式。重要的是，我们鉴定了一小部分 lncRNA 和极少数的 mRNAs 似乎逃避了减数分裂性染色体失活，这是一种导致 X 和 Y 染色体在减数分裂的粗线期沉默的表观遗传过程。此外，其中一些 lncRNA 和 mRNAs 表现出强烈的睾丸表达模式，这表明它们可能在精子发生中发挥关键作用。最后，我们生成了一个 X 连锁 lncRNA Tslrn1（睾丸特异性长非编码 RNA 1）的小鼠敲除品系，发现携带 Tslrn1 缺失的雄性表现出正常的生育能力，但精子数量显著减少。我们的研究结果表明，特定哺乳动物 lncRNA 的失调是精子数量低或不育的一种新机制，因此可能为提供新的生物标志物和治疗策略提供了依据。
