Journal
CELL REPORTS
Volume 30, Issue 12, Pages 4179-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.02.107
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Funding
- Canadian Institutes of Health Research (CIHR) [PJT-148746, EPS-129129]
- Canadian Institutes of Health Research (ERARE Team grant) [ERT-161303, FDN-14834]
- Canada First Research Excellence Fund (Medicine by Design Cycle I)
- Col. Harland Sanders Rett Syndrome Research Fund, University of Toronto
- Ontario Brain Institute (POND Network)
- Ontario Institute for Regenerative Medicine (New Ideas Grant)
- Ontario Molecular Pathology Research Network at the Ontario Institute for Cancer Research
- University Health Network Pathology Department
- International Rett Syndrome Foundation Fellowship
- Brain Tumour Foundation of Canada Research Fellowship
- CIHR Banting and Best Doctoral Research Award
- Ontario Graduate Scholarship
- Marie Curie IOF fellowship
- EMBL Australia
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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.
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