Dicer dependent tRNA derived small RNAs promote nascent RNA silencing.
Dicer dependent tRNA derived small RNAs promote nascent RNA silencing.
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DOI：
10.1093/nar/gkac022
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发表时间：
2022-02-22
影响因子：
14.9
通讯作者：
Gullerova M
中科院分区：
文献类型：
--
作者：
Di Fazio A;Schlackow M;Pong SK;Alagia A;Gullerova M
在哺乳动物细胞中，小的非编码RNA （sncRNAs）通过一种被称为RNA干扰（RNAi）的途径负调控基因表达。RNAi可分为转录后基因沉默（PTGS）和转录基因沉默（TGS）两种，前者通过在靶基因座上建立抑制性表观遗传标记来介导，PTGS涉及裂解靶信使RNA （mRNA）或抑制细胞质中的翻译。转运rna （trna）是翻译过程中必不可少的，可以加工成小的非rna，称为trna衍生的小rna （tsrna）。tsRNAs的生物发生机制及其在基因表达调控中的作用尚不完全清楚。在这里，我们发现Dicer依赖的tsRNAs通过不同于PTGS和TGS的机制促进基因沉默。tsrna可以通过细胞核内新生RNA沉默（NRS）靶向内含子，从而导致靶基因的下调。此外，我们表明Ago2切片机活性是该机制所必需的。合成的tsRNAs可以在RNA和蛋白水平上显著降低靶基因的表达。NRS调控的靶基因与多种疾病相关，这进一步支持了其生物学意义。最后，我们表明NRS是进化保守的，并且有潜力作为一种新的基于合成sRNA的治疗方法被探索。
In mammalian cells, small non-coding RNAs (sncRNAs) negatively regulate gene expression in a pathway known as RNA interference (RNAi). RNAi can be categorized into post-transcriptional gene silencing (PTGS), which involves the cleavage of target messenger RNA (mRNA) or inhibition of translation in the cytoplasm, and transcriptional gene silencing (TGS), which is mediated by the establishment of repressive epigenetic marks at target loci. Transfer RNAs (tRNAs), which are essential for translation, can be processed into small ncRNAs, termed tRNA-derived small RNAs (tsRNAs). The biogenesis of tsRNAs and their role in gene expression regulation has not yet been fully understood. Here, we show that Dicer dependent tsRNAs promote gene silencing through a mechanism distinct from PTGS and TGS. tsRNAs can lead to downregulation of target genes by targeting introns via nascent RNA silencing (NRS) in nuclei. Furthermore, we show that Ago2 slicer activity is required for this mechanism. Synthetic tsRNAs can significantly reduce expression of a target gene at both RNA and protein levels. Target genes regulated by NRS are associated with various diseases, which further underpins its biological significance. Finally, we show that NRS is evolutionarily conserved and has the potential to be explored as a novel synthetic sRNA based therapeutic.
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DOI：
10.1038/s41576-019-0135-1
发表时间：
2019-09
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Li X;Fu XD
通讯作者：
Fu XD
DOI：
10.1038/nrg3355
发表时间：
2013-02
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.5
作者：
Babiarz, Joshua E.;Ruby, J. Graham;Blelloch, Robert
通讯作者：
Blelloch, Robert
影响因子：
14.9
作者：
Martinez G;Choudury SG;Slotkin RK
通讯作者：
Slotkin RK
影响因子：
4.4
作者：
Kawaji H;Nakamura M;Takahashi Y;Sandelin A;Katayama S;Fukuda S;Daub CO;Kai C;Kawai J;Yasuda J;Carninci P;Hayashizaki Y
通讯作者：
Hayashizaki Y