Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells
Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells
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DOI：
10.7554/elife.26152
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发表时间：
2017-08-14
期刊：
影响因子：
7.7
通讯作者：
Adams, Ian R.
中科院分区：
文献类型：
--
作者：
MacLennan, Marie;Garcia-Canadas, Marta;Adams, Ian R.
反转录转座子迁移到新的基因组位置是哺乳动物基因组进化的重要驱动力，但这些诱变事件也可能导致遗传疾病。在人类中，逆转录转座子的动员主要是由LINE-1 （L1）逆转录转座子编码的蛋白质介导的，它在发育早期在多能细胞中动员。本研究表明，由发育程序性DNA低甲基化诱导的TEX19.1可以直接与L1编码的蛋白L1- orf1p相互作用，刺激其多泛素化和降解，并限制L1的动员。我们还发现，TEX19.1可能至少在一定程度上通过促进E3泛素连接酶UBR2对L1- orf1p的活性起作用。此外，TEX19.1的缺失增加了多能小鼠胚胎干细胞中L1- orf1p的水平和L1的动员，这意味着TEX19.1阻止了种系周期多能期的新生逆转录。这些数据表明，L1反转录转座子的翻译后调控在维持哺乳动物跨代基因组稳定性中起着关键作用。
Mobilization of retrotransposons to new genomic locations is a significant driver of mammalian genome evolution, but these mutagenic events can also cause genetic disorders. In humans, retrotransposon mobilization is mediated primarily by proteins encoded by LINE-1 (L1) retrotransposons, which mobilize in pluripotent cells early in development. Here we show that TEX19.1, which is induced by developmentally programmed DNA hypomethylation, can directly interact with the L1-encoded protein L1-ORF1p, stimulate its polyubiquitylation and degradation, and restrict L1 mobilization. We also show that TEX19.1 likely acts, at least in part, through promoting the activity of the E3 ubiquitin ligase UBR2 towards L1-ORF1 p. Moreover, loss of Tex19.1 increases L1-ORF1p levels and L1 mobilization in pluripotent mouse embryonic stem cells, implying that Tex19.1 prevents de novo retrotransposition in the pluripotent phase of the germline cycle. These data show that post-translational regulation of L1 retrotransposons plays a key role in maintaining trans-generational genome stability in mammals.