Lewis Alexandra, Berkyurek Ahmet C, Greiner Andre, Sawh Ahilya N, Vashisht Ajay, Merrett Stephanie, Flamand Mathieu N, Wohlschlegel James, Sarov Mihail, Miska Eric A, Duchaine Thomas F
Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Mol Cell. 2020 Jun 4;78(5):862-875.e8. doi: 10.1016/j.molcel.2020.04.007. Epub 2020 Apr 28.
Nuclear RNA interference (RNAi) pathways work together with histone modifications to regulate gene expression and enact an adaptive response to transposable RNA elements. In the germline, nuclear RNAi can lead to trans-generational epigenetic inheritance (TEI) of gene silencing. We identified and characterized a family of nuclear Argonaute-interacting proteins (ENRIs) that control the strength and target specificity of nuclear RNAi in C. elegans, ensuring faithful inheritance of epigenetic memories. ENRI-1/2 prevent misloading of the nuclear Argonaute NRDE-3 with small RNAs that normally effect maternal piRNAs, which prevents precocious nuclear translocation of NRDE-3 in the early embryo. Additionally, they are negative regulators of nuclear RNAi triggered from exogenous sources. Loss of ENRI-3, an unstable protein expressed mostly in the male germline, misdirects the RNAi response to transposable elements and impairs TEI. The ENRIs determine the potency and specificity of nuclear RNAi responses by gating small RNAs into specific nuclear Argonautes.
核RNA干扰（RNAi）途径与组蛋白修饰协同作用，以调节基因表达并对转座RNA元件做出适应性反应。在生殖细胞系中，核RNAi可导致基因沉默的跨代表观遗传继承（TEI）。我们鉴定并表征了一个核AGO相互作用蛋白（ENRIs）家族，该家族控制秀丽隐杆线虫中核RNAi的强度和靶标特异性，确保表观遗传记忆的忠实遗传。ENRI-1/2可防止核AGO蛋白NRDE-3被通常影响母体piRNA的小RNA错误装载，从而防止NRDE-3在早期胚胎中过早发生核转位。此外，它们是外源触发的核RNAi的负调节因子。ENRI-3是一种主要在雄性生殖细胞系中表达的不稳定蛋白，其缺失会将RNAi反应错误导向转座元件并损害TEI。ENRIs通过将小RNA选通到特定的核AGO蛋白中，来决定核RNAi反应的效力和特异性。
