Swiss Federal Institute of Technology Zurich, Institute of Molecular Health Sciences, Chair of RNAi and Genome Integrity, Zurich, Switzerland; Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland.
Swiss Federal Institute of Technology Zurich, Institute of Molecular Health Sciences, Chair of RNAi and Genome Integrity, Zurich, Switzerland.
Stem Cell Reports. 2022 May 10;17(5):1070-1080. doi: 10.1016/j.stemcr.2022.03.014. Epub 2022 Apr 21.
The Argonaute proteins (AGOs) are well known for their role in post-transcriptional gene silencing in the microRNA (miRNA) pathway. Here we show that in mouse embryonic stem cells, AGO1&2 serve additional functions that go beyond the miRNA pathway. Through the combined deletion of both Agos, we identified a specific set of genes that are uniquely regulated by AGOs but not by the other miRNA biogenesis factors. Deletion of Ago2&1 caused a global reduction of the repressive histone mark H3K27me3 due to downregulation at protein levels of Polycomb repressive complex 2 components. By integrating chromatin accessibility, prediction of transcription factor binding sites, and chromatin immunoprecipitation sequencing data, we identified the pluripotency factor KLF4 as a key modulator of AGO1&2-regulated genes. Our findings revealed a novel axis of gene regulation that is mediated by noncanonical functions of AGO proteins that affect chromatin states and gene expression using mechanisms outside the miRNA pathway.
Argonaute 蛋白 (AGOs) 以其在 microRNA (miRNA) 途径中的转录后基因沉默作用而闻名。在这里，我们表明在小鼠胚胎干细胞中，AGO1&2 具有超越 miRNA 途径的额外功能。通过同时删除两个 Agos，我们鉴定出一组特定的基因，这些基因仅受 AGOs 调控，而不受其他 miRNA 生物发生因子调控。AGO2&1 的缺失导致组蛋白标记 H3K27me3 的全局抑制，因为多梳抑制复合物 2 成分的蛋白水平下调。通过整合染色质可及性、转录因子结合位点预测和染色质免疫沉淀测序数据，我们鉴定出多能性因子 KLF4 是 AGO1&2 调节基因的关键调节剂。我们的发现揭示了一种新的基因调控轴，该轴由 AGO 蛋白的非典型功能介导，这些功能通过 miRNA 途径以外的机制影响染色质状态和基因表达。
