FXR1 dominates mRNA export fate via riboregulation during hESC differentiation
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ABSTRACT:
PROVIDER: PRJNA1029970 | ENA |
REPOSITORIES: ENA
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Project description:mRNA export is required for its translation into functional protein, facilitated by the interaction between mRNA transporters and nuclear pore complex (NPC). However, only a few mRNA transporters associated with NPC were identified. Here, we comprehensively depicted NPC interactome in human embryonic stem cells (hESCs), from which we identified a series of novel mRNA transporters. Among them, FXR1 functioned as a cytoplasmic mRNA acceptor, promoted the release of G-quadruplex containing mRNA from its export receptor, simultaneously mediated the localization of nucleoporins mRNA on nuclear pore. FXR1 bound G-quadruplex or nucleoporin AGAA RNA via its RGG and KH domain respectively, which in turn weakened or enhanced its binding to nuclear pore, thus resulted in mRNA release or localization. More importantly, the decline of FXR1 and nuclear pore activity helped hESCs to achieve fate transition by impeding the nuclear export of transcribed RNAs, which was required for hESC differentiation.
2025-08-22 | GSE245777 | GEO
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: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
Project description:iCLIP of FXR1-WT and FXR1-V361P in HeLa cells
| PRJEB70255 | ENA
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
Project description:FXR1 is an RNA binding protein and it is post traslationally modified by a methyltrasferase to facilitate its RNA binding activity FXR1 is methylated by PRMT5, an arginine methyltransferase, to promote its stability and facilitate its association with mRNAs. Both genetic and small molecule PRMT5 inhibition failed to methylate recombinant as well as the endogenous FXR1, resulting in protein instability and downregulation of FXR1 target mRNA levels in HNSCC cells. To study the differentially regulated gene under the loss of PRMT5, we knocked- down the PRMT5 using shRNA and confirmed the transcript and protein levels using qRT PCR and immunoblot respectively.
2024-04-08 | GSE256352 | GEO
Project description:Dysregulated oestrogen signaling plays a critical role in the development of endocrine resistance and bone metastasis of ER+ breast cancer. Screening of estrogen-regulated RNA-binding proteins by using iTRAQ technology identified that elevated expression of FXR1 is associated with anti-oestrogen resistance. FXR1 belongs to the fragile X mental retardation protein family and participates in RNA splicing, modification, localization, stability, and protein translation. To study the role of FXR1 in breast cancer, we performed RNA-seq assays in FXR1 knockdown and control cells.
2025-08-25 | GSE276081 | GEO
Project description:Ovarian cancer is one of the leading causes of cancer-related mortality among women and remains exceptionally difficult to manage and treat effectively in the clinic. Fragile X-related protein 1 (FXR1) is significantly amplified and overexpressed in ovarian and various other cancers. We have shown that FXR1 acts as a key regulator of the stability and translation of multiple oncogenic mRNAs, establishing it as an excellent therapeutic target for ovarian cancer. Our Single-cell RNA sequencing (scRNA-seq) analysis demonstrates a complex involvement of FXR1 in cancer progression mainly due to its dual role attributed through its autonomous actions in tumor cells and the modulation of tumor microenvironment (TME). Recent advances in RNA interference (RNAi) therapies have enabled targeting previously undruggable genes. In this study, we developed a locked nucleic acid (LNA)-based small interfering RNA (siRNA) to target FXR1 for ovarian cancer therapy. Compared to native siRNA, siFXR1-LNA demonstrates resistance to RNase degradation, improved tumor tissue uptake, and robust inhibition of its target FXR1. siFXR1-LNA inhibited proteins essential for tumor growth and survival while increasing the levels of pro-apoptotic proteins. Importantly, the polyethylenimine-mediated delivery of siFXR1-LNA effectively reduced tumor growth and peritoneal metastasis in ovarian cancer models, without causing toxicity in both immunocompromised and immunocompetent mice. scRNA-seq further revealed that siFXR1-LNA treatment not only suppressed FXR1 in cancer cells but also disrupted translation mechanisms linked to oncogenesis. In TME, siFXR1-LNA diminished tumor cell proliferation, reduced tumor-promoting M2-like macrophages, increased tumor inhibitory T and NK cells and increased dendritic cells with anti-tumor characteristics. Given the autonomous role of FXR1 in tumor cells and TME for oncogenesis, targeting FXR1 with siFXR1-LNA presents a unique opportunity for treating ovarian cancer and other cancers express high levels of FXR1.
2026-01-18 | GSE292799 | GEO
Project description:Fxr1 regulates sleep and synaptic homeostasis
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Project description:FXR1 depletion in THP1 cells causes changes in polysome associated mRNAs. This leads to a distinct translatome in the cell.
2022-08-25 | GSE211933 | GEO