Department of Genetics, Blavatnik Institute at Harvard Medical School, Boston, MA, USA.
College of Agriculture, Nanjing Agricultural University, Nanjing, China.
Nature. 2020 Jun;582(7811):283-288. doi: 10.1038/s41586-020-2323-8. Epub 2020 May 20.
Mobile genetic elements threaten genome integrity in all organisms. RDE-3 (also known as MUT-2) is a ribonucleotidyltransferase that is required for transposon silencing and RNA interference in Caenorhabditis elegans. When tethered to RNAs in heterologous expression systems, RDE-3 can add long stretches of alternating non-templated uridine (U) and guanosine (G) ribonucleotides to the 3' termini of these RNAs (designated poly(UG) or pUG tails). Here we show that, in its natural context in C. elegans, RDE-3 adds pUG tails to targets of RNA interference, as well as to transposon RNAs. RNA fragments attached to pUG tails with more than 16 perfectly alternating 3' U and G nucleotides become gene-silencing agents. pUG tails promote gene silencing by recruiting RNA-dependent RNA polymerases, which use pUG-tailed RNAs (pUG RNAs) as templates to synthesize small interfering RNAs (siRNAs). Our results show that cycles of pUG RNA-templated siRNA synthesis and siRNA-directed pUG RNA biogenesis underlie double-stranded-RNA-directed transgenerational epigenetic inheritance in the C. elegans germline. We speculate that this pUG RNA-siRNA silencing loop enables parents to inoculate progeny against the expression of unwanted or parasitic genetic elements.
移动遗传元件威胁着所有生物体的基因组完整性。RDE-3（也称为 MUT-2）是一种核糖核苷酸转移酶，它是秀丽隐杆线虫中转座子沉默和 RNA 干扰所必需的。当在异源表达系统中与 RNA 连接时，RDE-3 可以在这些 RNA 的 3' 末端添加长串交替的非模板尿嘧啶（U）和鸟嘌呤（G）核糖核苷酸（指定为多（UG）或 pUG 尾巴）。在这里，我们表明，在其在秀丽隐杆线虫中的自然环境中，RDE-3 将 pUG 尾巴添加到 RNA 干扰的靶标上，以及转座子 RNA 上。与具有超过 16 个完美交替的 3' U 和 G 核苷酸的 pUG 尾巴连接的 RNA 片段成为基因沉默剂。pUG 尾巴通过招募 RNA 依赖性 RNA 聚合酶来促进基因沉默，该聚合酶使用 pUG 尾巴 RNA（pUG RNA）作为模板来合成小干扰 RNA（siRNA）。我们的结果表明，pUG RNA 模板 siRNA 合成和 siRNA 指导的 pUG RNA 生物发生的循环是秀丽隐杆线虫生殖系中双链 RNA 指导的跨代表观遗传遗传的基础。我们推测，这种 pUG RNA-siRNA 沉默循环使父母能够为后代接种，防止表达不需要的或寄生的遗传元件。
