FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism

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. [Display omitted] •Loss of FMRP reduces ribosome stalling on specific mRNAs, including Setd2•Increased SETD2 protein alters H3K36me3 marks in FMRP-deficient hippocampus•Alternative splicing is dysregulated in FMRP-deficient hippocampus•Altered H3K36me3 and splicing occur on genes and transcripts linked to autism Shah et al. show that many neuronal mRNAs are associated with FMRP-stalled ribosomes. FMRP-regulated ribosome stalling influences the chromatin landscape. These events in turn mediate alternative processing of pre-mRNAs linked to autism.