Pseudouridylation of tRNA-derived fragments steers translation control in stem cells [small RNA-seq]

Pseudouridylation (?) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of ? remains poorly understood. Here, we show that a ?-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the ? 'writer' PUS7 modifies and activates a network of tRNA-derived fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translational regulation leading to high protein biosynthesis and abnormal germ layer specification. Dysregulation of PUS7 and tRFs in myeloid malignancies associates with altered translation rates, suggesting a role of ? in tumorigenesis. Our findings unveil a critical function of ? in directing translational control in stem cells with promisingly broad implications for human disease. Overall design: Small RNA (<200nt) sequencing of WT and PUS7KO human embryonic stem cell (hESC). 4 replicates per condition.