Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Cell. 2012 Jul 6;150(1):65-77. doi: 10.1016/j.cell.2012.06.015. Epub 2012 Jun 25.
Organisms employ a fascinating array of strategies to silence invasive nucleic acids such as transposons and viruses. Although evidence exists for several pathways that detect foreign sequences, including pathways that sense copy number, unpaired DNA, or aberrant RNA (e.g., dsRNA), in many cases, the mechanisms used to distinguish "self" from "nonself" nucleic acids remain mysterious. Here, we describe an RNA-induced epigenetic silencing pathway that permanently silences single-copy transgenes. We show that the Piwi Argonaute PRG-1 and its genomically encoded piRNA cofactors initiate permanent silencing, and maintenance depends on chromatin factors and the WAGO Argonaute pathway. Our findings support a model in which PRG-1 scans for foreign sequences and two other Argonaute pathways serve as epigenetic memories of "self" and "nonself" RNAs. These findings suggest how organisms can utilize RNAi-related mechanisms to detect foreign sequences not by any molecular signature, but by comparing the foreign sequence to a memory of previous gene expression.
生物采用了一系列令人着迷的策略来沉默入侵性核酸，如转座子和病毒。尽管已经有证据表明存在几种检测外来序列的途径，包括检测拷贝数、未配对 DNA 或异常 RNA（例如 dsRNA）的途径，但在许多情况下，用于区分“自我”和“非自我”核酸的机制仍然是神秘的。在这里，我们描述了一种 RNA 诱导的表观遗传沉默途径，该途径可永久性沉默单拷贝转基因。我们表明，Piwi Argonaute PRG-1 及其基因组编码的 piRNA 共因子启动永久性沉默，维持依赖于染色质因子和 WAGO Argonaute 途径。我们的发现支持这样一种模型，即 PRG-1 扫描外来序列，而另外两种 Argonaute 途径作为“自我”和“非自我”RNA 的表观遗传记忆。这些发现表明，生物如何利用 RNAi 相关机制来检测外来序列，不是通过任何分子特征，而是通过将外来序列与以前基因表达的记忆进行比较。
