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dc.contributor.authorShu, Huan
dc.contributor.authorDonnard, Elisa
dc.contributor.authorLiu, Botao
dc.contributor.authorRichter, Joel D.
dc.date2022-08-11T08:08:24.000
dc.date.accessioned2022-08-23T15:53:44Z
dc.date.available2022-08-23T15:53:44Z
dc.date.issued2019-10-10
dc.date.submitted2019-10-23
dc.identifier.citation<p>bioRxiv 801449; doi: https://doi.org/10.1101/801449. <a href="https://doi.org/10.1101/801449" target="_blank">Link to preprint on bioRxiv service.</a></p>
dc.identifier.doi10.1101/801449
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29413
dc.description<p>This is version 1 of this preprint. Version 2 is available: Shu H, Donnard E, Liu B, Wang R, Richter JD. (2020). FMRP Links Optimal Codons to mRNA stability in Neurons. <a href="https://escholarship.umassmed.edu/faculty_pubs/1690/" target="_blank" title="View Version 2 of this preprint ">https://escholarship.umassmed.edu/faculty_pubs/1690/</a></p>
dc.description.abstractFragile 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.
dc.language.isoen_US
dc.relationNow published in Proceedings of the National Academy of Sciences doi: 10.1073/pnas.2009161117
dc.rightsThe 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.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMolecular Biology
dc.subjectFragile X syndrome
dc.subjectFMR1 gene
dc.subjectRNA
dc.subjecttranscriptome analysis
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetic Phenomena
dc.subjectMolecular Biology
dc.subjectNervous System Diseases
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleGenetic Rescue of Fragile X Syndrome Links FMRP Deficiency to Codon Optimality-Dependent RNA Destabilization [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2653&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1641
dc.identifier.contextkey15606970
refterms.dateFOA2022-08-23T15:53:44Z
html.description.abstract<p>Fragile X syndrome (FXS) is caused by inactivation of <em>FMR1</em> 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., <em>Fmr1</em> knockout animals; <em>Fmr1</em> KO), deletion of <em>Cpeb1</em>, 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 <em>Fmr1</em> KO brain cortex and its rescue to normal levels in <em>Fmr1/Cpeb1</em> 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.</p>
dc.identifier.submissionpathfaculty_pubs/1641
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.contributor.departmentProgram in Molecular Medicine


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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.
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.