Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation
Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation
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DOI：
10.4161/epi.20706
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发表时间：
2012-07-01
期刊：
影响因子：
3.7
通讯作者：
Rangasamy, Danny
中科院分区：
文献类型：
--
作者：
Chen, Long;Dahlstrom, Jane E.;Rangasamy, Danny
长穿插核素1(LINE-1)反转录转座子是一种诱变剂，能够通过将自己插入基因并影响人类基因组中的基因功能来产生有害突变。在正常细胞中，LINE-1反转录转座子的活性大多受到抑制，维持了稳定的基因组结构。相比之下，癌细胞的特征是LINE-1反转录转座子的异常表达，原则上，这可能会导致基因组的不稳定。调节LINE-1表达的机制仍不清楚。利用深度测序小RNA分析，我们鉴定了直接调控Line-1表达的差异表达的Endo-siRNAs的子集。详细的分析表明，与正常乳腺细胞相比，人类乳腺癌细胞中这些内切的siRNAs显著减少。这些Endo-siRNAs在癌细胞中的过表达通过增加LINE-1 5‘UTR启动子的DNA甲基化而显著抑制内源性LINE-1的表达。这一发现表明，在人类细胞中，Endo-siRNAs的表达与LINE-1反转录转座子之间存在功能联系。
Long interspersed nuclear element 1 (LINE-1) retrotransposons are mutagens that are capable of generating deleterious mutations by inserting themselves into genes and affecting gene function in the human genome. In normal cells, the activity of LINE-1 retrotransposon is mostly repressed, maintaining a stable genome structure. In contrast, cancer cells are characterized by aberrant expression of LINE-1 retrotransposons, which, in principle, have the potential to contribute to genomic instability. The mechanistic pathways that regulate LINE-1 expression remain unclear. Using deep-sequencing small RNA analysis, we identified a subset of differentially expressed endo-siRNAs that directly regulate LINE-1 expression. Detailed analyses suggest that these endo-siRNAs are significantly depleted in human breast cancer cells compared with normal breast cells. The overexpression of these endo-siRNAs in cancer cells markedly silences endogenous LINE-1 expression through increased DNA methylation of the LINE-1 5'UTR promoter. The finding that endo-siRNAs can silence LINE-1 activity through DNA methylation suggests that a functional link exists between the expression of endo-siRNAs and LINE-1 retrotransposons in human cells.