RT Journal Article
SR Electronic
T1 FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 801076
DO 10.1101/801076
A1 Sneha Shah
A1 Gemma Molinaro
A1 Botao Liu
A1 Ruijia Wang
A1 Kimberly M. Huber
A1 Joel D. Richter
YR 2020
UL http://biorxiv.org/content/early/2020/01/27/801076.abstract
AB 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