Profiling of Oestrogen Regulated RNA Binding Protein Landscape Identifies a Role for FXR1 in Endocrine Resistance
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE276081 | GEO | 2025/08/25
REPOSITORIES: GEO
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Project description:The Fragile X Mental Retardation-Related 1 gene (FXR1) belongs to the Fragile X Related gene family, together with FMR1 and FXR2. While inactivation of FMR1 causes Fragile X syndrome, the most common form of inherited mental retardation, inactivation of FXR1 in various animal models suggest a critical role for the RNA-binding protein FXR1P during myogenesis. Seven alternatively spliced FXR1 transcripts have been identified, three of them being muscle-specific. We previously reported a reduction of these isoforms in myoblasts from Fascio Scapulo Humeral Distrophy (FSHD) myopathic patients. However, so far, no mRNA target of FXR1P has been linked to the drastic muscular phenotypes caused by its absence and the exact molecular role of FXR1P in muscular development remains unknown. In the present study, gene expression profiling of C2C12 myoblasts reveals that transcripts involved in cell cycle and muscular development pathways are modulated by Fxr1-depletion. In addition, Fxr1-depletion translates physiologically into a premature cell cycle exit of myoblasts, accompanied by a robust up-regulation of the cyclin-dependant kinase inhibitor p21/Cdkn1a/Waf/Cip1 mRNA. Importantly, we also observe this P21 increase in FSHD human myoblasts depleted in FXR1P muscular isoforms. Our data further indicate that FXR1P muscle-specific isoforms are involved in the post-transcriptional control of p21 mRNA levels via direct interaction with a conserved G-quadruplex structure located in its 3’ untranslated region. This study has crucial implications for the understanding of FXR1P role during myogenesis and the pathophysiology of FSHD. 2 independent experiments performed in a one color design, corresponding to 2 conditions: si-control and si-fxr1, for a total of 4 samples.
2013-02-01 | E-GEOD-40577 | biostudies-arrayexpress
Project description:The Fragile X Mental Retardation-Related 1 gene (FXR1) belongs to the Fragile X Related gene family, together with FMR1 and FXR2. While inactivation of FMR1 causes Fragile X syndrome, the most common form of inherited mental retardation, inactivation of FXR1 in various animal models suggest a critical role for the RNA-binding protein FXR1P during myogenesis. Seven alternatively spliced FXR1 transcripts have been identified, three of them being muscle-specific. We previously reported a reduction of these isoforms in myoblasts from Fascio Scapulo Humeral Distrophy (FSHD) myopathic patients. However, so far, no mRNA target of FXR1P has been linked to the drastic muscular phenotypes caused by its absence and the exact molecular role of FXR1P in muscular development remains unknown. In the present study, gene expression profiling of C2C12 myoblasts reveals that transcripts involved in cell cycle and muscular development pathways are modulated by Fxr1-depletion. In addition, Fxr1-depletion translates physiologically into a premature cell cycle exit of myoblasts, accompanied by a robust up-regulation of the cyclin-dependant kinase inhibitor p21/Cdkn1a/Waf/Cip1 mRNA. Importantly, we also observe this P21 increase in FSHD human myoblasts depleted in FXR1P muscular isoforms. Our data further indicate that FXR1P muscle-specific isoforms are involved in the post-transcriptional control of p21 mRNA levels via direct interaction with a conserved G-quadruplex structure located in its 3’ untranslated region. This study has crucial implications for the understanding of FXR1P role during myogenesis and the pathophysiology of FSHD.
2013-02-01 | GSE40577 | 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. 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:Profiling of Oestrogen Regulated RNA Binding Protein Landscape Identifies a Role for FXR1 in Endocrine Resistance
| PRJNA1154652 | ENA
Project description:In the associated paper FXR1 is shown to package exceptionally long mRNAs in the cytoplasm and organizes them into an mRNP network. We performed iCLIP of FXR-WT and its mutant FXR1-V361P in HeLa cells where we knocked down endogenous FXR1 and replaced it with either GFP-tagged WT or V361P-mutant FXR1. The GFP-tagged proteins were immunoprecipitated using an anti-GFP antibody.
2024-11-01 | E-MTAB-13545 | biostudies-arrayexpress
Project description:Up to 80% of endometrial and breast cancers express the oestrogen receptor ERa. Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in the two cancer types. We investigated the role of oestrogen in endometrial and breast cancers using cell lines and found that oestrogen-responsive genes were predominantly unique between the two cancer types.
2018-08-29 | GSE107693 | 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. 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.
2012-12-13 | GSE39504 | 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:Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1 and FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have slightly attenuated replication in vitro and reduced levels of viral antigen in lungs during early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight to the possible underlying molecular defects in fragile X syndrome.
2023-12-28 | PXD047232 | Pride