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 journalArticle

2 Scopus citations

Abstract

Silencing of FMR1 and loss of its gene product, FMRP, results in fragile X syndrome (FXS). 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 wild-type 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. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrates that loss of FMRP alters the deployment of this histone mark. 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.

Original languageEnglish (US)
Pages (from-to)4459-4472.e6
JournalCell Reports
Volume30
Issue number13
DOIs
StatePublished - Mar 31 2020

Keywords

  • Fragile X Syndrome
  • alternative splicing
  • autism
  • chromatin modifications
  • ribosome stalling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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