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dc.contributor.authorShah, Sneha
dc.contributor.authorMolinaro, Gemma
dc.contributor.authorLiu, Botao
dc.contributor.authorWang, Ruijia
dc.contributor.authorHuber, Kimberly M.
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 801076; doi: https://doi.org/10.1101/801076. <a href="https://doi.org/10.1101/801076" target="_blank">Link to preprint on bioRxiv service.</a></p>
dc.identifier.doi10.1101/801076
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29414
dc.description.abstractSilencing 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.
dc.language.isoen_US
dc.relationNow published in Cell Reports doi: 10.1016/j.celrep.2020.02.076
dc.rightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.subjectNeuroscience
dc.subjectautism spectrum disorders
dc.subjectFMRP
dc.subjectribosomes
dc.subjectchromatin
dc.subjectFragile X Syndrome
dc.subjectmRNAs
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetic Phenomena
dc.subjectMental Disorders
dc.subjectNervous System Diseases
dc.subjectNeuroscience and Neurobiology
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleFMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2652&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1642
dc.identifier.contextkey15606678
refterms.dateFOA2022-08-23T15:53:45Z
html.description.abstract<p>Silencing of <em>FMR1</em> 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 <em>Fmr1</em>-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.</p>
dc.identifier.submissionpathfaculty_pubs/1642
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.