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

被引：56

作者：

Shah, Sneha ^{[1
]}

Molinaro, Gemma ^{[2
]}

Liu, Botao ^{[1
]}

Wang, Ruijia ^{[1
]}

Huber, Kimberly M. ^{[2
]}

Richter, Joel D. ^{[1
]}

机构：

[1] Univ Massachusetts, Program Mol Med, Sch Med, Worcester, MA 01605 USA

[2] Univ Texas Southwestern Med Sch, Dept Neurosci, Dallas, TX 75390 USA

来源：

CELL REPORTS | 2020年 / 30卷 / 13期

基金：

美国国家卫生研究院;

关键词：

MENTAL-RETARDATION PROTEIN; FRAGILE-X-SYNDROME; TRANSLATION ELONGATION; SYNAPTIC PLASTICITY; PROFILING REVEALS; DNA METHYLATION; MOUSE MODEL; RNA; POLYRIBOSOMES; EXPRESSION;

D O I：

10.1016/j.celrep.2020.02.076

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：4459 / +

页数：20