Widespread Alterations in Translation Elongation in the Brain of Fmr1 Knock-Out Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA464051 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7124020.fastq.gz | Fastqsanger.gz | |||
| SRR7124021.fastq.gz | Fastqsanger.gz | |||
| SRR7124022.fastq.gz | Fastqsanger.gz | |||
| SRR7124023.fastq.gz | Fastqsanger.gz | |||
| SRR7124024.fastq.gz | Fastqsanger.gz |
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Project description:FMRP is a polysome-associated RNA-binding protein encoded by Fmr1 and lost in Fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene-specificity of these effects is unclear. To elucidate the effects of FMRP loss on translation, we used ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of Fmr1 knock-out mice. We found a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP, and an increase for terminal oligo-pyrimidine (TOP) motif-containing genes canonically controlled by mTOR-4EBP-eIF4E signaling. Amino acid motif- and gene-level analyses both showed a widespread reduction of translational pausing in Fmr1 knock-out mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in Fragile X syndrome.
2019-03-10 | GSE114064 | GEO
Project description:Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity.
2023-08-01 | GSE236056 | GEO
Project description:Lysine methylation is widespread on human proteins, however the enzymes that catalyse its addition remain largely unknown. This limits our capacity to study the function and regulation of this modification. Here we report that human METTL21B is a protein methyltransferase, which methylates lysine 165 of eukaryotic translation elongation factor 1A (eEF1A). The CRISPR/Cas9 system was used to knock out putative protein methyltransferases METTL21B and METTL23 in K562 cells. The known eEF1A methyltransferase EEF1AKMT1 was also knocked out as a control. Targeted mass spectrometry revealed the loss of lysine 165 methylation upon knock out of METTL21B, and the expected loss of lysine 79 methylation on knock out of EEF1AKMT1. No loss of eEF1A methylation was seen in the METTL23 knock out. Recombinant METTL21B was then shown to catalyse methylation on lysine 165 in eEF1A1 and eEF1A2 in vitro, confirming it as the methyltransferase responsible for this methylation site. Stable isotope labelling by amino acids in cell culture (SILAC) proteomic analysis revealed dysregulation of processes related to eEF1A function in knock outs of METTL21B and EEF1AKMT1, but specific dysregulation of ribosomal proteins in the knock out of METTL21B. This indicates a specific function for lysine 165 methylation of eEF1A in human. METTL21B is specific to vertebrates, with its target lysine showing similar evolutionary conservation. We suggest METTL21B be renamed eEF1A-KMT3. This is the first study to specifically generate CRISPR/Cas9 knock outs of the genes encoding putative protein methyltransferases, for the purpose of substrate discovery and site mapping. Our approach should prove useful for the discovery of further novel methyltransferases, and more generally for the discovery of sites for other protein-modifying enzymes.
2017-07-03 | PXD005497 | Pride
Project description:Widespread regulation of translation by elongation pausing in heat shock
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Project description:FMRP (fragile X mental retardation protein) is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we utilize ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24-day-old Fmr1 knockout mice. We find a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP and an increase for terminal oligopyrimidine (TOP) motif-containing genes canonically controlled by mammalian target of rapamycin-eIF4E-binding protein-eIF4E binding protein-eukaryotic initiation factor 4E (mTOR-4E-BP-eIF4E) signaling. Amino acid motif- and gene-level analyses both show a widespread reduction of translational pausing in Fmr1 knockout mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in fragile X syndrome.
| S-EPMC6457272 | biostudies-literature
Project description:Widespread transcriptional pausing and elongation control at enhancers
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Project description:Silencing of the Fmr1 gene causes fragile X syndrome. Although defects in synaptic plasticity in the cerebral cortex have been linked to cognitive impairments in Fmr1 knock-out (ko) mice, the specific cortical circuits affected in the syndrome are unknown. Here, we investigated the development of excitatory projections in the barrel cortex of Fmr1 ko mice. In 2-week-old Fmr1 ko mice, a major ascending projection connecting layer 4 (L4) to L3 (L4-->L3), was defective in multiple and independent ways: its strength was reduced, caused by a lower connection probability; the axonal arbors of L4 cells were spatially diffuse in L2/3; the L4-->L3 projection did not show experience-dependent plasticity. By 3 weeks, the strength of the L4-->L3 projection was similar to that of wild type. Our data indicate that Fmr1 shapes sensory cortical circuits during a developmental critical period.
| S-EPMC2696604 | biostudies-literature
Project description:ene pleiotropy defines the capacity of a gene to impact multiple phenotypic characters. The Fragile X Mental Retardation 1 (FMR1) gene is a candidate for pleiotropy, as it controls protein synthesis through its product, the translational regulator FMRP. As FMR1 loss-of-function leads to neurodevelopmental defects and Fragile X Syndrome (FXS), intellectual disability and autism, FMR1 functions have been mostly studied in the brain. FMR1-deficiency could also have yet unexplored consequences in periphery and impact metabolism through translational repression in peripheral organs. We combined 1H NMR-based metabolic phenotyping and proteomics to reveal the pleiotropic metabolic effects associated with FMR1-deficiency in mouse and human. We demonstrate that Fmr1-deficiency in the mouse increases hepatic translation, improves glucose tolerance and insulin sensitivity and reduces adiposity, while enhancing -adrenergic driven lipolysis and utilization of lipid energetic substrates. Last, we provide converging evidences in FXS patients that the levels of glucose, insulin and free fatty acids are modified, suggesting that FMR1-deficiency also drives metabolic readjustments in human. As part of a larger study investigating the involvement of fmr in metabolic alteration in fmr1-KO mice, fmr1-KO mouse livers were analysed by MS.
2022-02-28 | PXD007241 | Pride
Project description:Autism spectrum disorder (ASD) is a hereditary intellectual disability. Fragile X syndrome (FXS) is the leading cause of ASD and mainly results from the abnormal CGG amplification (>200 repeats) of the fragile X mental retardation 1 (Fmr1) gene. All-trans retinoic acid (RA) is involved in synaptic plasticity, neuronal differentiation and brain maturation. RA-mediated synaptic strength regulation was abolished in FXS patient-derived induced pluripotent stem (iPS) cells. Previous work on the ASD model with excessive UBE3A expression, of which the ASD-like behaviors caused by repression in RA signaling were successfully ameliorated by oral supplementation of RA. In this study, we used male Fmr1 knock-out (KO) mice to explore the effect of RA exerting on the behaviors. Our results indicated that RA supplementation can alleviate the defects in social novelty. We performed RNA sequencing to find out the differentially expressed genes (DEGs) in the Fmr1 KO group, of which the expression levels were restored to the similar level as those in the wild-type (WT) group after RA supplementation, such as Per1, Per2 and Foxp2. Besides, several DEGs associated with neuronal functions were also identified, like Arc, Ccn2, Foxp2, Xdh, Lepr, Serpina3n andTnfsf10. our findings that RA supplementation improved social novelty behavior in Fmr1 KO mice provided a potential therapeutic intervention method for FXS, which may further be used in other disease models with defective RA signaling.
2022-04-30 | GSE201672 | GEO
Project description:Global repression of protein synthesis is a hallmark of the cellular stress response and has been attributed primarily to inhibition of translation initiation, although this mechanism may not always explain the full extent of repression. Here, using ribosome footprinting, we show that 2 hr of severe heat stress triggers global pausing of translation elongation at around codon 65 on most mRNAs in both mouse and human cells. The genome-wide nature of the phenomenon, its location, and features of protein N termini suggested the involvement of ribosome-associated chaperones. After severe heat shock, Hsp70's interactions with the translational machinery were markedly altered and its association with ribosomes was reduced. Pretreatment with mild heat stress or overexpression of Hsp70 protected cells from heat shock-induced elongation pausing, while inhibition of Hsp70 activity triggered elongation pausing without heat stress. Our findings suggest that regulation of translation elongation in general, and by chaperones in particular, represents a major component of cellular stress responses.
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