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

Guzzi, Nicola LU ; Cieśla, Maciej LU ; Ngoc, Phuong Cao Thi LU ; Lang, Stefan LU ; Arora, Sonali; Dimitriou, Marios; Pimková, Kristyna LU ; Sommarin, Mikael N.E. LU ; Munita, Roberto LU and Lubas, Michal, et al. (2018) In Cell
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... (More)

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. Translational control in stem cells is orchestrated by pseudouridylation of specific tRNA-derived fragments, impacting stem cell commitment during key developmental processes.

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@article{cd1298c9-11b6-483c-9240-50cf952c0262,
  abstract     = {<p>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. Translational control in stem cells is orchestrated by pseudouridylation of specific tRNA-derived fragments, impacting stem cell commitment during key developmental processes.</p>},
  author       = {Guzzi, Nicola and Cieśla, Maciej and Ngoc, Phuong Cao Thi and Lang, Stefan and Arora, Sonali and Dimitriou, Marios and Pimková, Kristyna and Sommarin, Mikael N.E. and Munita, Roberto and Lubas, Michal and Lim, Yiting and Okuyama, Kazuki and Soneji, Shamit and Karlsson, Göran and Hansson, Jenny and Jönsson, Göran and Lund, Anders H. and Sigvardsson, Mikael and Hellström-Lindberg, Eva and Hsieh, Andrew C. and Bellodi, Cristian},
  issn         = {0092-8674},
  keyword      = {embryogenesis,hematopoiesis,myelodysplastic syndromes,protein synthesis,pseudouridine,PUS7,RNA modifications,stem cell,translation control,tRNA fragments},
  language     = {eng},
  month        = {04},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells},
  url          = {http://dx.doi.org/10.1016/j.cell.2018.03.008},
  year         = {2018},
}