Program in Molecular Medicine
Amino Acids, Peptides, and Proteins | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Mental Disorders | Nervous System Diseases | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides
Silencing of FMR1 and loss of its gene product FMRP results in Fragile X Syndrome. FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wildtype tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes; and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. ChIP-Seq demonstrates that loss of FMRP alters the deployment of this epigenetic mark on chromatin. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders.
Neuroscience, autism spectrum disorders, FMRP, ribosomes, chromatin, Fragile X Syndrome, mRNAs
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 801076; doi: https://doi.org/10.1101/801076. Link to preprint on bioRxiv service.
Shah S, Molinaro G, Liu B, Wang R, Huber KM, Richter JD. (2019). FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/801076. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1642
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Amino Acids, Peptides, and Proteins Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Genetic Phenomena Commons, Mental Disorders Commons, Nervous System Diseases Commons, Neuroscience and Neurobiology Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons