FMRP Links Optimal Codons to mRNA stability in Neurons [preprint]
UMass Chan Affiliations
Program in Bioinformatics and Integrative BiologyProgram in Molecular Medicine
Document Type
PreprintPublication Date
2020-05-08Keywords
molecular BiologyFragile X syndrome
FMRP
mRNAs
Amino Acids, Peptides, and Proteins
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Molecular Biology
Nervous System Diseases
Neuroscience and Neurobiology
Nucleic Acids, Nucleotides, and Nucleosides
Metadata
Show full item recordAbstract
Fragile X syndrome (FXS) is caused by inactivation of the FMR1 gene and loss of encoded FMRP, an RNA binding protein that represses translation of some of its target transcripts. Here we use ribosome profiling and RNA-seq to investigate the dysregulation of translation in the mouse brain cortex. We find that most changes in ribosome occupancy on hundreds of mRNAs are largely driven by dysregulation in transcript abundance. Many downregulated mRNAs, which are mostly responsible for neuronal and synaptic functions, are highly enriched for FMRP binding targets. RNA metabolic labeling demonstrates that in FMRP-deficient cortical neurons, mRNA downregulation is caused by elevated degradation, and is correlated with codon optimality. Moreover, FMRP preferentially binds mRNAs with optimal codons, suggesting that it stabilizes such transcripts through direct interactions via the translational machinery. Finally, we show that the paradigm of genetic rescue of FXS-like phenotypes in FMRP-deficient mice by deletion of the Cpeb1 gene is mediated by restoration of steady state RNA levels and consequent rebalancing of translational homeostasis. Our data establish an essential role of FMRP in codon optimality-dependent mRNA stability as an important factor in FXS.Source
bioRxiv 801449; doi: https://doi.org/10.1101/801449. Link to preprint on bioRxiv service.
DOI
10.1101/801449Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29466Rights
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/801449
Scopus Count
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.