Program in Molecular Medicine; Program in Bioinformatics and Integrative Biology
Amino Acids, Peptides, and Proteins | Animal Experimentation and Research | Biochemical Phenomena, Metabolism, and Nutrition | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Molecular Biology | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides
Fragile X syndrome (FXS) is caused by inactivation of FMR1 gene and loss of its encoded product the RNA binding protein FMRP, which generally represses translation of its target transcripts in the brain. In mouse models of FXS (i.e., Fmr1 knockout animals; Fmr1 KO), deletion of Cpeb1, which encodes a translational activator, mitigates nearly all pathophysiologies associated with the disorder. Here we reveal unexpected wide-spread dys-regulation of RNA abundance in Fmr1 KO brain cortex and its rescue to normal levels in Fmr1/Cpeb1 double KO mice. Alteration and restoration of RNA levels are the dominant molecular events that drive the observed dys-regulation and rescue of translation as measured by whole transcriptome ribosome occupany in the brain. The RNAs down-regulated and rescued in these animal models are highly enriched for FMRP binding targets and have an optimal codon bias that would predict their stability in wild type and possible instability in FMRP knock-out brain. Indeed, whole transcriptome analysis of RNA metabolic rates demonstrates a codon optimality-dependent elevation of RNA destruction in FMRP knock-out cortical neurons. This elevated RNA destruction leads to a massive reshuffling of the identities of stabilizing versus destabilizing codons in neurons upon loss of FMRP. Our results show a widespread RNA instability in FXS, which results from the uncoupling of codon optimality, ribosome occupancy, and RNA degradation mechanisms. Re-establishment of the linkage among these events is likely required by the genetic rescue of the disorder.
Molecular Biology, Fragile X syndrome, FMR1 gene, RNA, transcriptome analysis
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.
DOI of Published Version
bioRxiv 801449; doi: https://doi.org/10.1101/801449. Link to preprint on bioRxiv service.
Shu H, Donnard E, Liu B, Richter JD. (2019). Genetic Rescue of Fragile X Syndrome Links FMRP Deficiency to Codon Optimality-Dependent RNA Destabilization. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/801449. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1641
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