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首页> 外文期刊>PLoS Genetics >Switching of dominant retrotransposon silencing strategies from posttranscriptional to transcriptional mechanisms during male germ-cell development in mice
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Switching of dominant retrotransposon silencing strategies from posttranscriptional to transcriptional mechanisms during male germ-cell development in mice

机译：小鼠雄性生殖细胞发育过程中主要逆转录转座子沉默策略从转录后机制向转录机制的转换

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Mammalian genomes harbor millions of retrotransposon copies, some of which are transpositionally active. In mouse prospermatogonia, PIWI-interacting small RNAs (piRNAs) combat retrotransposon activity to maintain the genomic integrity. The piRNA system destroys retrotransposon-derived RNAs and guides de novo DNA methylation at some retrotransposon promoters. However, it remains unclear whether DNA methylation contributes to retrotransposon silencing in prospermatogonia. We have performed comprehensive studies of DNA methylation and polyA(+) RNAs (transcriptome) in developing male germ cells from Pld6/Mitopld and Dnmt3l knockout mice, which are defective in piRNA biogenesis and de novo DNA methylation, respectively. The Dnmt3l mutation greatly reduced DNA methylation levels at most retrotransposons, but its impact on their RNA abundance was limited in prospermatogonia. In Pld6 mutant germ cells, although only a few retrotransposons exhibited reduced DNA methylation, many showed increased expression at the RNA level. More detailed analysis of RNA sequencing, nascent RNA quantification, profiling of cleaved RNA ends, and the results obtained from double knockout mice suggest that PLD6 works mainly at the posttranscriptional level. The increase in retrotransposon expression was larger in Pld6 mutants than it was in Dnmt3l mutants, suggesting that RNA degradation by the piRNA system plays a more important role than does DNA methylation in prospermatogonia. However, DNA methylation had a long-term effect: hypomethylation caused by the Pld6 or Dnmt3l mutation resulted in increased retrotransposon expression in meiotic spermatocytes. Thus, posttranscriptional silencing plays an important role in the early stage of germ cell development, then transcriptional silencing becomes important in later stages. In addition, intergenic and intronic retrotransposon sequences, in particular those containing the antisense L1 promoters, drove ectopic expression of nearby genes in both mutant spermatocytes, suggesting that retrotransposon silencing is important for the maintenance of not only genomic integrity but also transcriptomic integrity.
机译：哺乳动物基因组具有数百万个反转录转座子拷贝，其中一些具有转位活性。在小鼠生精症中，与PIWI相互作用的小RNA（piRNA）与反转录转座子活性作斗争，以维持基因组完整性。 piRNA系统破坏了反转录转座子来源的RNA，并指导某些反转录转座子启动子的DNA甲基化。然而，尚不清楚DNA甲基化是否有助于生色菌中逆转录转座子沉默。我们已经对发育中的Pld6 / Mitopld和Dnmt3l敲除小鼠的雄性生殖细胞中的DNA甲基化和polyA（+）RNA（转录组）进行了全面研究，这些小鼠分别在piRNA生物发生和从头DNA甲基化方面存在缺陷。 Dnmt3l突变大大降低了大多数逆转座子的DNA甲基化水平，但是在生精症中，其对RNA丰度的影响受到限制。在Pld6突变生殖细胞中，尽管只有少数逆转录转座子表现出减少的DNA甲基化，但许多表现出在RNA水平表达增加。 RNA测序，新生RNA定量，裂解的RNA末端谱图的更详细分析以及从双敲除小鼠获得的结果表明PLD6主要在转录后水平上起作用。在Pld6突变体中，反转录转座子表达的增加比在Dnmt3l突变体中的表达大，这表明piRNA系统对RNA的降解作用在生精症中比DNA甲基化更重要。但是，DNA甲基化具有长期作用：由Pld6或Dnmt3l突变引起的低甲基化导致减数分裂精细胞中反转录转座子表达的增加。因此，转录后沉默在生殖细胞发育的早期阶段起着重要作用，然后转录沉默在以后的阶段中变得重要。此外，基因间和内含子的反转录转座子序列，特别是那些含有反义L1启动子的序列，在两个突变的精母细胞中驱动附近基因的异位表达，这表明反转录转座子沉默不仅对于维持基因组完整性而且对于转录组完整性都是重要的。

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