@article{b695d3d5beea4fe58e85df1178134e83,
title = "FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism",
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.",
keywords = "Fragile X Syndrome, alternative splicing, autism, chromatin modifications, ribosome stalling",
author = "Sneha Shah and Gemma Molinaro and Botao Liu and Ruijia Wang and Huber, {Kimberly M.} and Richter, {Joel D.}",
note = "Funding Information: We thank Lori Lorenz, Craig Peterson, Huan Shu, and Danesh Moazed for valuable discussions. J.D.R. K.M.H. B.L. and S.S. conceived various aspects of the project. We thank Maria Ivshina and Suna Jung for providing reagents. This work was supported by grants from the National Institutes of Health (NIH) (grants U54HD82013 to J.D.R. and U54HD082008 to K.M.H.), the Simons Foundation for Autism Research Initiative (grant 400998 to J.D.R. and K.M.H.), and the Charles H. Hood Foundation (to J.D.R.). S.S. was supported by a postdoctoral fellowship from the FRAXA Foundation. B.L. G.M. and S.S. performed the experiments. R.W. provided essential help with bioinformatics. J.D.R. wrote the manuscript with input from all authors. The authors declare no competing interests. Funding Information: We thank Lori Lorenz, Craig Peterson, Huan Shu, and Danesh Moazed for valuable discussions. J.D.R., K.M.H., B.L., and S.S. conceived various aspects of the project. We thank Maria Ivshina and Suna Jung for providing reagents. This work was supported by grants from the National Institutes of Health ( NIH ) (grants U54HD82013 to J.D.R. and U54HD082008 to K.M.H.), the Simons Foundation for Autism Research Initiative (grant 400998 to J.D.R. and K.M.H.), and the Charles H. Hood Foundation (to J.D.R.). S.S. was supported by a postdoctoral fellowship from the FRAXA Foundation . Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = mar,
day = "31",
doi = "10.1016/j.celrep.2020.02.076",
language = "English (US)",
volume = "30",
pages = "4459--4472.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}