Conserved piRNA Expression from a Distinct Set of piRNA Cluster Loci in Eutherian Mammals.
Conserved piRNA Expression from a Distinct Set of piRNA Cluster Loci in Eutherian Mammals.
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DOI：
10.1371/journal.pgen.1005652
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发表时间：
2015-11
期刊：
影响因子：
4.5
通讯作者：
Lau NC
中科院分区：
文献类型：
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作者：
Chirn GW;Rahman R;Sytnikova YA;Matts JA;Zeng M;Gerlach D;Yu M;Berger B;Naramura M;Kile BT;Lau NC
Piwi通路在动物中非常保守，因为它的基本功能之一是抑制转座子。然而，许多piwi相互作用rna （pirna）不与转座子碱基对，其靶向功能仍然是神秘的。动物基因组中大量的piRNA簇（piC）位点和罕见的piRNA序列保护也给确定哪些piC位点对发育最重要带来了挑战。为了解决这个问题，我们在广泛的动物系统发育谱中确定了piC位点的piRNA表达模式，并揭示了大多数基因和基因间piC位点在其产生piRNA的能力上迅速进化，而不管已知的转座子沉默功能。令人惊讶的是，我们还发现了一组独特的piC位点，其piRNA表达在真兽哺乳动物中深度保守。我们将这些位点命名为eutherian - conservative piRNA cluster （ECpiC）位点。为了支持真动物在1亿年的进化过程中piRNA表达的保守性意味着其功能的假设，我们确定了一个ECpiC位点产生大量与STOX1转录物反义的piRNA， STOX1转录物是临床与子痫前期相关的基因。此外，我们证实了现有小鼠ECpiC-Asb1和-Cbl突变中pirna的减少，这些突变也表现出生精缺陷。具有Asb1 pirna强烈降低的Asb1突变睾丸也表现出基因表达谱的上调。这些数据表明，ECpiC位点可能特别适应于支持真兽的繁殖。从果蝇到人类的动物基因组包含数百个称为piwi相互作用rna （piRNAs）簇位点（piC位点）的非编码元件。其中一些元素产生pirna，指导转座因子的沉默，转座因子是普遍存在的遗传寄生虫。然而，我们对其余大部分pirna的靶向功能缺乏了解，因为它们的位点与转座元件不互补。此外，该领域不知道是否所有piC位点都在快速进化，或者是否一些piC位点在piRNA表达中可能是深度保守的，这表明其潜在的功能重要性。我们的研究证实了果蝇和哺乳动物中大多数piC位点的piRNA表达能力的高度快速进化，具有许多进化支和物种特异性的piC位点表达模式。尽管如此，我们还发现了一组piC位点，这些位点在人类到狗的piRNA表达中高度保守，这是真动物哺乳动物中一个非常广泛的系统发育谱。然而，piRNA表达的这种保守性在非动物哺乳动物如有袋动物和单孔动物中终止。这些eutherian -保守piC （ECpiC）位点中的两个存在突变，损害小鼠生殖并取消piRNA的产生。因此，我们认为，由于这些ECpiC位点在真动物生殖中的重要功能，它们对于piRNA的表达是保守的，并且是未来遗传研究的主要候选者。
The Piwi pathway is deeply conserved amongst animals because one of its essential functions is to repress transposons. However, many Piwi-interacting RNAs (piRNAs) do not base-pair to transposons and remain mysterious in their targeting function. The sheer number of piRNA cluster (piC) loci in animal genomes and infrequent piRNA sequence conservation also present challenges in determining which piC loci are most important for development. To address this question, we determined the piRNA expression patterns of piC loci across a wide phylogenetic spectrum of animals, and reveal that most genic and intergenic piC loci evolve rapidly in their capacity to generate piRNAs, regardless of known transposon silencing function. Surprisingly, we also uncovered a distinct set of piC loci with piRNA expression conserved deeply in Eutherian mammals. We name these loci Eutherian-Conserved piRNA cluster (ECpiC) loci. Supporting the hypothesis that conservation of piRNA expression across ~100 million years of Eutherian evolution implies function, we determined that one ECpiC locus generates abundant piRNAs antisense to the STOX1 transcript, a gene clinically associated with preeclampsia. Furthermore, we confirmed reduced piRNAs in existing mouse mutations at ECpiC-Asb1 and -Cbl, which also display spermatogenic defects. The Asb1 mutant testes with strongly reduced Asb1 piRNAs also exhibit up-regulated gene expression profiles. These data indicate ECpiC loci may be specially adapted to support Eutherian reproduction. Animal genomes from flies to humans contain many hundreds of non-coding elements called Piwi-interacting RNAs (piRNAs) cluster loci (piC loci). Some of these elements generate piRNAs that direct the silencing of transposable elements, which are pervasive genetic parasites. However, we lack an understanding of the targeting function for the remaining bulk of piRNAs because their loci are not complementarity to transposable elements. In addition, the field does not know if all piC loci are quickly evolving, or if some piC loci might be deeply conserved in piRNA expression, an indication of its potentially functional importance. Our study confirms the highly rapid evolution in piRNA expression capacity for the majority of piC loci in flies and mammals, with many clade- and species-specific piC loci expression patterns. In spite of this, we also discover a cohort of piC loci that are deeply conserved in piRNA expression from the human to the dog, a significantly broad phylogenetic spectrum of eutherian mammals. However, this conservation in piRNA expression ends at non-eutherian mammals like marsupials and monotremes. Existing mutations in two of these Eutherian-Conserved piC (ECpiC) loci impair mouse reproduction and abrogate piRNA production. Therefore, we suggest these ECpiC loci are conserved for piRNA expression due to their important function in eutherian reproduction and stand out as prime candidates for future genetic studies.