Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Ubiquitination in Rett Syndrome.

Autor:	Rodrigues DC; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Mufteev M; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Weatheritt RJ; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada., Djuric U; Laboratory Medicine and Pathology Program, University Health Network, Toronto, ON M5G 2C4, Canada., Ha KCH; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, 661 University Avenue, Toronto, ON M5G 1M1, Canada., Ross PJ; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Wei W; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Piekna A; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Sartori MA; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Byres L; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Mok RSF; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Zaslavsky K; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Pasceri P; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Diamandis P; Laboratory Medicine and Pathology Program, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada., Morris Q; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, 661 University Avenue, Toronto, ON M5G 1M1, Canada., Blencowe BJ; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada., Ellis J; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jellis@sickkids.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Mar 24; Vol. 30 (12), pp. 4179-4196.e11.
DOI:	10.1016/j.celrep.2020.02.107
Abstrakt:	Regulation of translation during human development is poorly understood, and its dysregulation is associated with Rett syndrome (RTT). To discover shifts in mRNA ribosomal engagement (RE) during human neurodevelopment, we use parallel translating ribosome affinity purification sequencing (TRAP-seq) and RNA sequencing (RNA-seq) on control and RTT human induced pluripotent stem cells, neural progenitor cells, and cortical neurons. We find that 30% of transcribed genes are translationally regulated, including key gene sets (neurodevelopment, transcription and translation factors, and glycolysis). Approximately 35% of abundant intergenic long noncoding RNAs (lncRNAs) are ribosome engaged. Neurons translate mRNAs more efficiently and have longer 3' UTRs, and RE correlates with elements for RNA-binding proteins. RTT neurons have reduced global translation and compromised mTOR signaling, and >2,100 genes are translationally dysregulated. NEDD4L E3-ubiquitin ligase is translationally impaired, ubiquitinated protein levels are reduced, and protein targets accumulate in RTT neurons. Overall, the dynamic translatome in neurodevelopment is disturbed in RTT and provides insight into altered ubiquitination that may have therapeutic implications. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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