RNA Seq of Fmr1 NPC nuclear fractions
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ABSTRACT:
PROVIDER: PRJNA498497 | ENA |
REPOSITORIES: ENA
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Project description:N6-methyladenosine (m6A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP), an RNA-binding protein, reads m6A to regulate nuclear export of methylated mRNA targets during neural stem cell differentiation. In Fmr1 KO mice neural progenitors show delayed cell cycle exit and differentiation, resulting in their progressive accumulation in the ventricular and subventricular zones. RNA-seq of neural precursor cells (NPCs) from Fmr1 KO mice and m6A-seq uncovered nuclear retention of m6A-modified FMRP target mRNAs involved in regulating neural differentiation, including components of Notch and Hedgehog signaling pathways. Analysis of NPCs from Mettl14 cKO mice, which are devoid of m6A, revealed that methylation of RNAs promotes their nuclear export through CRM1. Altogether, our findings suggest that FMRP reads and facilitates nuclear export of m6A-modified mRNAs to regulate neural stem cell differentiation, contributing to Fragile X syndrome.
2019-07-23 | GSE121809 | GEO
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Project description:The Fragile X Mental Retardation Protein, FMRP, is thought to regulate the translation of a specific set of neuronal mRNAs on polyribosomes. Therefore, we prepared polyribosomes on sucrose gradients and purified mRNA specifically from these fractions, as well as the total mRNA levels, to determine whether a set of mRNAs might be changed in its % association with polyribosomes in the absence of FMRP in the KO mouse model. No significant differences were found, other than the Fmr1 transcript itself, in total mRNA levels or % polyribosome association that withstood multiple test correction, in P7 Fmr1 KO mouse cerebral cortex compared with WT littermates.. We prepared polyribosomes on sucrose gradients from 6 littermate pairs of Fmr1 KO and WT littermates (FVB background, P7 males, cerebral cortex) and purified RNA from both polyribosomal fractions and input to the gradient, reflecting total mRNA levels for comparison.
2011-07-20 | E-GEOD-26745 | biostudies-arrayexpress
Project description:We use subcellular fractionation to probe the regulation of RNA localization by FMR1 in neuronal cells.
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Project description:To investigate the function of nuclear pore complex (NPC) in the regulation of zygotic genome activation (ZGA), we microinjected medium dosage of WGA in zebrafish embryos at 1-cell stage to block NPC function. We then performed gene expression profiling analysis using data obtained from RNA-seq of control or WGA treated embryo at comparable developmental time point (4.3 hours post fertilization (hpf) ) or develomental stage (dome).
2023-02-22 | GSE212929 | GEO
Project description:During mitotic exit, thousands of nuclear pore complexes (NPCs) assemble concomitant with the nuclear envelope to build a transport-competent nucleus. Here, we show that Nup50 plays a crucial role in NPC assembly independent of its well-established function in nuclear transport. RNAi-mediated downregulation in cells or immunodepletion of Nup50 protein in Xenopus egg extracts interferes with NPC assembly. We define a conserved central region of 46 residues in Nup50 that is crucial for Nup153 and MEL28/ELYS binding, and for NPC interaction. Surprisingly, neither NPC interaction nor binding of Nup50 to importin /, the GTPase Ran, or chromatin is crucial for its function in the assembly process. Instead, an N-terminal fragment of Nup50 can stimulate the Ran GTPase guanyl-nucleotide exchange factor RCC1 and NPC assembly, indicating that Nup50 acts via the Ran system in NPC reformation at the end of mitosis. In support of this conclusion, Nup50 mutants defective in RCC1 binding and stimulation cannot replace the wild-type protein in in vitro NPC assembly assays, while excess RCC1 can compensate the loss of Nup50.
2021-11-03 | PXD028701 | Pride
Project description:Fragile X syndrome (FXS), the most common genetic form of intellectual disability in male, is caused by silencing of the FMR1 gene by hypermethylation of the CGG expansion mutation in the 5’UTR region of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/sgRNA switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state restoring a persistent expression of FMR1 in FXS iPSCs. Neurons derived from methylation edited FXS iPSCs rescued the electrophysiological abnormalities and restored a wild-type phenotype upon the mutant neurons. FMR1 expression in edited neurons was maintained in vivo after engrafting into the mouse brain. Finally, demethylation of the CGG repeats in post-mitotic FXS neurons also reactivated FMR1. Our data establish demethylation of the CGG expansion is sufficient for FMR1 reactivation, suggesting potential therapeutic strategies for FXS.
2018-02-16 | GSE108498 | GEO
Project description:The Fragile X Mental Retardation Protein, FMRP, is thought to regulate the translation of a specific set of neuronal mRNAs on polyribosomes. Therefore, we prepared polyribosomes on sucrose gradients and purified mRNA specifically from these fractions, as well as the total mRNA levels, to determine whether a set of mRNAs might be changed in its % association with polyribosomes in the absence of FMRP in the KO mouse model. No significant differences were found, other than the Fmr1 transcript itself, in total mRNA levels or % polyribosome association that withstood multiple test correction, in P7 Fmr1 KO mouse cerebral cortex compared with WT littermates..
2011-07-21 | GSE26745 | GEO
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