FMRP control of ribosome translocation promotes chromatin modifications and alternative splicing of neuronal genes linked to autism

Sneha Shah, Gemma Molinaro, Botao Liu, Ruijia Wang, Kimberly M. Huber, Joel D. Richter

Research output: Contribution to journalArticlepeer-review

Abstract

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. Highlights - Loss of FMRP results in decline of ribosome stalling on specific mRNAs (eg., SETD2)- Increased SETD2 protein levels alter H3K36me3 marks in FMRP deficient hippocampus- Genome-wide changes in mRNA alternative splicing occur in FMRP deficient hippocampus- H3K36me3 marks and alternative splicing changes occur on transcripts linked to autism.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Oct 10 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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