TY - JOUR T1 - FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism JF - bioRxiv DO - 10.1101/801076 SP - 801076 AU - Sneha Shah AU - Gemma Molinaro AU - Botao Liu AU - Ruijia Wang AU - Kimberly M. Huber AU - Joel D. Richter Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/01/27/801076.abstract N2 - 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 ER -