Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.
Elife. 2021 Oct 1;10:e72289. doi: 10.7554/eLife.72289.
microRNAs associate with Argonaute proteins, forming the microRNA-induced silencing complex (miRISC), to repress target gene expression post-transcriptionally. Although microRNAs are critical regulators in mammalian cell differentiation, our understanding of how microRNA machinery, such as the miRISC, are regulated during development is still limited. We previously showed that repressing the production of one Argonaute protein, Ago2, by Trim71 is important for mouse embryonic stem cells (mESCs) self-renewal (Liu et al., 2021). Here, we show that among the four Argonaute proteins in mammals, Ago2 is the major developmentally regulated Argonaute protein in mESCs. Moreover, in pluripotency, besides the Trim71-mediated regulation of (Liu et al., 2021), also repress . Specific inhibition of this microRNA-mediated repression results in stemness defects and accelerated differentiation through the let-7 microRNA pathway. These results reveal a microRNA-mediated regulatory circuit on microRNA machinery that is critical to maintaining pluripotency.
microRNAs 与 Argonaute 蛋白结合，形成 microRNA 诱导的沉默复合物（miRISC），在后转录水平抑制靶基因表达。尽管 microRNAs 是哺乳动物细胞分化的关键调节因子，但我们对 miRISC 等 microRNA 机制如何在发育过程中受到调节的理解仍然有限。我们之前曾表明，Trim71 抑制 Argonaute 蛋白之一 Ago2 的产生对于小鼠胚胎干细胞（mESCs）的自我更新很重要（Liu 等人，2021 年）。在这里，我们表明在哺乳动物的四种 Argonaute 蛋白中，Ago2 是 mESCs 中主要受发育调控的 Argonaute 蛋白。此外，在多能性中，除了 Trim71 介导的调控（Liu 等人，2021 年）外，还抑制。特异性抑制这种 microRNA 介导的抑制会导致干性缺陷，并通过 let-7 microRNA 途径加速分化。这些结果揭示了 microRNA 介导的 microRNA 机制调节回路，对于维持多能性至关重要。
