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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation
  • Eukaryotic Initiation Factors / metabolism
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Intramolecular Transferases / antagonists & inhibitors
  • Intramolecular Transferases / genetics
  • Intramolecular Transferases / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Myelodysplastic Syndromes / pathology
  • Nucleic Acid Conformation
  • Phosphoproteins / metabolism
  • Poly(A)-Binding Protein I / antagonists & inhibitors
  • Poly(A)-Binding Protein I / genetics
  • Poly(A)-Binding Protein I / metabolism
  • Protein Biosynthesis*
  • Pseudouridine / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • RNA, Transfer / metabolism*
  • Stem Cell Niche

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Eukaryotic Initiation Factors
  • Phosphoproteins
  • Poly(A)-Binding Protein I
  • RNA, Small Interfering
  • Pseudouridine
  • RNA, Transfer
  • Intramolecular Transferases
  • pseudouridine synthases