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Comparison of the specificities of the RGG/RG-domains of FMR1, FXR1 and FXR2 for small RNA

ABSTRACT: In previous studies, we identified a sequence motif (GDCGG) in almost all microRNAs downregulated in the serum of patients with amyotrophic lateral sclerosis. We found that FMR1, FXR1 and FXR2 directly and specifically interact with microRNAs containing the GDCGG motif via their RGG/RG-domains. Here, we compare the specificities for microRNAs of the RGG/RG-domains of FMR1, FXR1 and FXR2 on a transcriptome-wide scale using the Affymetrix GeneChip™ miRNA 3.0 Arrays.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE101067 | GEO | 2021/04/21

REPOSITORIES: GEO

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Homo sapiens

Project description:Comparison of the specificities of the RGG/RG-domains of FMR1, FXR1 and FXR2 for small RNA

| PRJNA393667 | ENA

Effect of depletion of FXR1 on gene expression in head and neck squamous cell carcinoma (HNSCC) cells

Project description:FXR1 is an essential RNA-binding protein. This chromosome 3q26-28 gene is overexpressed in many epithelial tumors. FXR1 controls the turnover and translation of multiple mRNAs and is involved in cellular transformation. We identified critical residues in the protein that are post-translationally modified. These regulate the stability of FXR1 protein, its RNA-binding function, cell growth, and proliferation. Here we show that PRMT5-mediated arginine methylation of FXR1 increases the protein's binding to G-quadruplex RNAs in vivo and controls their expression in cancer cells. Independent point mutations of specific arginine residues in the nuclear export signal (R386, R388) and arginine-glycine rich (R453, R455, R459) domains of FXR1 abrogate the RNA-binding in vitro. Genetic and small molecule inhibition of PRMT5 minimizes methylation and levels of FXR1 and suppresses oral tumor growth and proliferation. RNA-seq analyses of FXR1 KD cells show an increase in the expression of PLK2, TCN2, and TRAF4 along with FXR1’s well-known target CDKN1A. Like CDKN1A, these targets possess strong G4 sequences. FXR1 and G4-RNA interactions provide new insights into the molecular mechanism of FXR1 and its interaction with target mRNAs. Furthermore, an increased expression of FXR1 and PRMT5 is colocalized in cancer tissues, leading to a poor patient prognosis. Thus, our data demonstrate that PRMT5-mediated arginine methylation of FXR1 arginine residues in the NES and RGG domains plays a critical role in binding and controlling G4-RNAs, which encode tumor suppressors and promote cancer cell growth and proliferation.

2023-09-30 | GSE212760 | GEO

Arginine methylation-mediated FXR1-G4 RNA binding in cancer cells

Project description:The RBP, FXR1, is overexpressed in many epithelial tumors containing a canonical RGG box domain. FXR1 controls post-transcriptional gene regulation through changes in mRNA turnover and translation of target genes. Here we show that arginine methyltransferase PRMT5- mediated specific arginine methylation of FXR1 increases its stability in cancer cells. FXR1-dependent gene signatures show decreased expression and instability of G4-rich sequences containing mRNAs such as CDKN1A, PLK2, TCN2, and TRAF4. Furthermore, structural features of FXR1 and G4-RNA interactions provide novel insights into the critical arginine amino acids of FXR1 essential for G4-RNA-binding and turnover activity. In addition, analysis of the eCLIP data provides various RNA targets and the G-rich sequence motifs of FXR1 in head and neck cancer cell line. Thus, our results indicate that PRMT5-mediated methylation of FXR1 binding with G4-RNAs favors mRNA stability and turnover, contributing to cancer cell growth and proliferation.

2024-04-08 | GSE252916 | GEO

FMR1 targets distinct mRNA sequence elements to regulate protein expression [PAR-CLIP]

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

The RNA-binding protein FXR1P regulates cell-cycle progression by modulating the expression of p21/cdkn1a/Cip1/Waf in myoblasts

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

Rgg-dependent transcriptional regulation in SF370 Streptococcus pyogenes strain

Project description:Rgg-dependent transcriptional regulation in SF370 Streptococcus pyogenes strain was analyzed during post-exponential phase of growth Keywords: rgg mutant Microarray analysis was performed using RNA samples isolated from both wild-type SF370 and SF370 rgg mutant strains during post-exponential phase of growth

2010-05-26 | E-GEOD-7335 | biostudies-arrayexpress

RG/RGG boxes are common binding motifs in RNA-G-quadruplex-interacting proteins

Project description:G-quadruplexes (rG4s) are recognized as key structures involved in RNA biology and are linked to neurodegenerative disease and cancer. However, detailed knowledge of rG4s and their binding partners is lacking. Here, a systematic, unbiased affinity proteomics approach identified 80 potential high-confidence interactors of the rG4 structure in the 5’UTR of the NRAS oncogene. Using epitope-tagged protein expression, we validated a subset of interactions including DDX3X, DDX5, DDX17, DHX9, DHX36, FXR1, FXR2, GRSF1 and NSUN5. More than half of the identified rG4 interactors were enriched in glycine-arginine (GAR) domains, and for DDX3X and DDX17, we show that the GAR domain is required for rG4 interaction. Transcriptome-wide binding analysis using DDX3X iCLIP revealed a striking association with rG4s in 5’UTRs that was lacking in the GAR-domain mutant. Overall, our work highlights a hitherto unrecognized complexity in rG4 structure-protein interactions that should be considered for the understanding of rG4 function.

2018-04-30 | GSE106476 | GEO

Exploring the occupancy and interaction with FXR2, STAT1/3 and H3K4me3 at genomic level of FXR1 in H358 and AGS cell line by ChIP-seq

Project description:The chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was conducted in the human cancer cell lines H358 and AGS using FXR1, FXR2, STAT1/3 and H3K4me3 specific antibodies on the platform Illumina HiSeq 2000. ChIP-seq data quality was analyzed using FastQC. Target protein binding genomic regions (called ChIP-seq peaks) were identified by Model-based Analysis of ChIP-Seq (MACS) algorithm using the default p-value cutoff of 1e-5.

2017-09-01 | GSE79707 | GEO

Rgg-dependent transcriptional regulation in Streptococcus pyogenes strains MGAS5005 and CS101

Project description:Rgg-dependent transcriptional regulation in Streptococcus pyogenes strains MGAS5005 and CS101 was analyzed during post-exponential phase of growth Keywords: strain comparion, post-exponential growth, rgg mutant Microarray analysis was performed using RNA samples isolated from wild-type MGAS5005 and CS101 strains as well as their rgg mutant strains during post-exponential phase of growth

2010-05-26 | E-GEOD-7341 | biostudies-arrayexpress

Rgg-dependent transcriptional regulation in SF370 Streptococcus pyogenes strain

Project description:Rgg-dependent transcriptional regulation in SF370 Streptococcus pyogenes strain was analyzed during post-exponential phase of growth Keywords: rgg mutant

2008-02-01 | GSE7335 | GEO

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