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Cell. 2018 May 17;173(5):1204-1216.e26. doi: 10.1016/j.cell.2018.03.008. Epub 2018 Apr 5.

Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells.

Author information

1
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden.
2
Division of Human Biology, Fred Hutchinson Cancer Research Center, Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA.
3
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
4
Biotech Research & Innovation Center, University of Copenhagen, Copenhagen, Denmark.
5
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
6
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
7
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
8
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden. Electronic address: cristian.bellodi@med.lu.se.

Abstract

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.

KEYWORDS:

PUS7; RNA modifications; embryogenesis; hematopoiesis; myelodysplastic syndromes; protein synthesis; pseudouridine; stem cell; tRNA fragments; translation control

PMID:
29628141
DOI:
10.1016/j.cell.2018.03.008
[Indexed for MEDLINE]
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