Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden.
Division of Human Biology, Fred Hutchinson Cancer Research Center, Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA.
Cell. 2018 May 17;173(5):1204-1216.e26. doi: 10.1016/j.cell.2018.03.008. Epub 2018 Apr 5.
Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification. Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes. Our findings unveil a critical function of Ψ in directing translation control in stem cells with important implications for development and disease.
假尿嘧啶核苷（Ψ）是生物体内最丰富和广泛存在的 RNA 表观遗传修饰类型；然而，Ψ 的生物学功能仍知之甚少。在这里，我们表明，Ψ 驱动的转录后程序指导翻译控制，从而影响早期胚胎发生中的干细胞分化。在机制上，Ψ“写入器”PUS7 修饰和激活了一个针对翻译起始复合物的新型 tRNA 衍生小片段（tRF）网络。胚胎干细胞中 PUS7 的失活会损害 tRF 介导的翻译调控，导致蛋白质生物合成增加和胚层特化缺陷。值得注意的是，这种转录后调节回路的失调会损害造血干细胞的分化，并常见于人类骨髓增生异常综合征的侵袭性亚型中。我们的发现揭示了 Ψ 在指导干细胞中翻译控制方面的关键功能，这对发育和疾病具有重要意义。
