Published on May 17, 2018 in Cell volume 173.
PubMed ID: 29628141
Pseudouridylation (Psi) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Psi remains poorly understood. Here, we show that a Psi-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Psi "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 Psi in directing translation control in stem cells with important implications for development and disease.