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

Nicola Guzzi; Maciej Cieśla; Phuong Cao Thi Ngoc; Stefan Lang; Sonali Arora; Marios Dimitriou; Kristyna Pimková; Mikael N E Sommarin; Roberto Munita; Michal Lubas; Yiting Lim; Kazuki Okuyama; Shamit Soneji; Göran Karlsson; Jenny Hansson; Göran Jönsson; Anders H Lund; Mikael Sigvardsson; Eva Hellström-Lindberg; Andrew C Hsieh; Cristian Bellodi

doi:10.1016/j.cell.2018.03.008

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

Nicola Guzzi, Maciej Cieśla, Phuong Cao Thi Ngoc, Stefan Lang, Sonali Arora, Marios Dimitriou, Kristyna Pimková, Mikael N E Sommarin, Roberto Munita, Michal Lubas, Yiting Lim, Kazuki Okuyama, Shamit Soneji, Göran Karlsson, Jenny Hansson, Göran Jönsson, Anders H Lund, Mikael Sigvardsson, Eva Hellström-Lindberg, Andrew C HsiehCristian Bellodi

105 Citations (Scopus)

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

Original language	English
Journal	Cell
Volume	173
Issue number	5
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2018.03.008
Publication status	Published - 17 May 2018

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Guzzi, N., Cieśla, M., Ngoc, P. C. T., Lang, S., Arora, S., Dimitriou, M., Pimková, K., Sommarin, M. N. E., Munita, R., Lubas, M., Lim, Y., Okuyama, K., Soneji, S., Karlsson, G., Hansson, J., Jönsson, G., Lund, A. H., Sigvardsson, M., Hellström-Lindberg, E., ... Bellodi, C. (2018). Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells. Cell, 173(5). https://doi.org/10.1016/j.cell.2018.03.008

Guzzi, N, Cieśla, M, Ngoc, PCT, Lang, S, Arora, S, Dimitriou, M, Pimková, K, Sommarin, MNE, Munita, R, Lubas, M, Lim, Y, Okuyama, K, Soneji, S, Karlsson, G, Hansson, J, Jönsson, G, Lund, AH, Sigvardsson, M, Hellström-Lindberg, E, Hsieh, AC & Bellodi, C 2018, 'Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells', Cell, vol. 173, no. 5. https://doi.org/10.1016/j.cell.2018.03.008

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title = "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells",

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

author = "Nicola Guzzi and Maciej Cie{\'s}la and Ngoc, {Phuong Cao Thi} and Stefan Lang and Sonali Arora and Marios Dimitriou and Kristyna Pimkov{\'a} and Sommarin, {Mikael N E} and Roberto Munita and Michal Lubas and Yiting Lim and Kazuki Okuyama and Shamit Soneji and G{\"o}ran Karlsson and Jenny Hansson and G{\"o}ran J{\"o}nsson and Lund, {Anders H} and Mikael Sigvardsson and Eva Hellstr{\"o}m-Lindberg and Hsieh, {Andrew C} and Cristian Bellodi",

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T1 - Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells

AU - Guzzi, Nicola

AU - Cieśla, Maciej

AU - Ngoc, Phuong Cao Thi

AU - Lang, Stefan

AU - Arora, Sonali

AU - Dimitriou, Marios

AU - Pimková, Kristyna

AU - Sommarin, Mikael N E

AU - Munita, Roberto

AU - Lubas, Michal

AU - Lim, Yiting

AU - Okuyama, Kazuki

AU - Soneji, Shamit

AU - Karlsson, Göran

AU - Hansson, Jenny

AU - Jönsson, Göran

AU - Lund, Anders H

AU - Sigvardsson, Mikael

AU - Hellström-Lindberg, Eva

AU - Hsieh, Andrew C

AU - Bellodi, Cristian

PY - 2018/5/17

Y1 - 2018/5/17

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2018.03.008

DO - 10.1016/j.cell.2018.03.008

M3 - Journal article

C2 - 29628141

SN - 0092-8674

VL - 173

JO - Cell

JF - Cell

IS - 5

ER -

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

Abstract

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