Gene expression profile of FMR1-KO iPSCs-derived NPCs
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108560 | GEO | 2018/08/07
REPOSITORIES: GEO
Similar Datasets
Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders. The mRNA profile of RNA recovered from FLAG-antibody immunoprecipitated FMRP was compared to the mRNA profile of the starting lysate material.
2012-12-13 | E-GEOD-39504 | biostudies-arrayexpress
Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders. PAR-CLIP profiling for wild-type and I304N mutant FMRP isoforms as well as paralogs, FXR1 and FXR2.
2012-12-13 | E-GEOD-39682 | biostudies-arrayexpress
Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders.
2012-12-13 | GSE39504 | GEO
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
Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders.
2012-12-13 | GSE39682 | 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: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:Fragile X syndrome (FXS), the leading cause of inherited form of mental retardation and autism, is caused by the transcriptional silencing of fmr1 encoding the protein of FMRP. FMRP, acting as an RNA binding protein, FMRP is a wide expressed protein, but primarily in the brain and testis and can regulate approximately 4% of transcripts. Macroorchidism is one of the common symptoms observed both in the FXS people and mice. Thus, we analyzed the protein profiles of cerebral cortex, hippocampus and testis from both the fmr1-KO and WT mouse using a quantitative proteomics. Proteins (FMRP, RS8, RL23A and MPZ) identified by MS/MS were also verified by Western blot. Among the identified proteins, most of the significant changed proteins were downregulated in the FMRP absence. The Gene Ontology and pathway analysis revealed that the changed proteins were clustered in polyribosome and RNA binding proteins in both cerebral cortex and hippocampus, but not the same in testis. Our results provide detailed insights to the ribosome protein profiles of cerebral cortex, hippocampus and testis in the absence of FMRP. Our studies also give a better understanding of protein profile changes and underling dysregulated pathways arising from the fmr1 silencing in the FXS.
2022-02-28 | PXD005089 | Pride
Project description:Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissue of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1 expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissue. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2′-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that mis-regulated RNA processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a new therapeutic approach to mitigate the disorder.
2023-06-14 | GSE202178 | GEO
Project description:Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissue of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1 expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissue. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2′-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that mis-regulated RNA processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a new therapeutic approach to mitigate the disorder.
2023-06-14 | GSE202177 | GEO