Department of Urology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.
PLoS Genet. 2013;9(9):e1003821. doi: 10.1371/journal.pgen.1003821. Epub 2013 Sep 26.
Argonaute proteins are often credited for their cytoplasmic activities in which they function as central mediators of the RNAi platform and microRNA (miRNA)-mediated processes. They also facilitate heterochromatin formation and establishment of repressive epigenetic marks in the nucleus of fission yeast and plants. However, the nuclear functions of Ago proteins in mammalian cells remain elusive. In the present study, we combine ChIP-seq (chromatin immunoprecipitation coupled with massively parallel sequencing) with biochemical assays to show that nuclear Ago1 directly interacts with RNA Polymerase II and is widely associated with chromosomal loci throughout the genome with preferential enrichment in promoters of transcriptionally active genes. Additional analyses show that nuclear Ago1 regulates the expression of Ago1-bound genes that are implicated in oncogenic pathways including cell cycle progression, growth, and survival. Our findings reveal the first landscape of human Ago1-chromosomal interactions, which may play a role in the oncogenic transcriptional program of cancer cells.
Argonaute 蛋白常因其在细胞质中的活性而受到赞誉，在细胞质中，它们作为 RNAi 平台和 microRNA（miRNA）介导过程的中心介质发挥作用。它们还促进有丝分裂酵母和植物核内异染色质的形成和抑制性表观遗传标记的建立。然而，哺乳动物细胞中 Ago 蛋白的核功能仍不清楚。在本研究中，我们将 ChIP-seq（染色质免疫沉淀结合大规模平行测序）与生化分析相结合，表明核 Ago1 直接与 RNA 聚合酶 II 相互作用，并广泛与基因组中的染色体位置相关联，在转录活跃基因的启动子中优先富集。进一步的分析表明，核 Ago1 调节 Ago1 结合基因的表达，这些基因参与包括细胞周期进程、生长和存活在内的致癌途径。我们的研究结果揭示了人类 Ago1-染色体相互作用的第一个全景图，这可能在癌细胞的致癌转录程序中发挥作用。
