The Experts below are selected from a list of 1245 Experts worldwide ranked by ideXlab platform
John W. Day - One of the best experts on this subject based on the ideXlab platform.
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RBFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences
Nature communications, 2018Co-Authors: Chantal Sellier, Estefanía Cerro-herreros, Markus Blatter, Fernande Freyermuth, Angeline Gaucherot, Frank Ruffenach, Jack Puymirat, Bjarne Udd, Partha S. Sarkar, John W. DayAbstract:Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the RBFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, RBFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of RBFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of RBFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
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RBFOX1 mbnl1 competition for ccug rna repeats binding contributes to myotonic dystrophy type 1 type 2 differences
Nature Communications, 2018Co-Authors: Chantal Sellier, Markus Blatter, Fernande Freyermuth, Angeline Gaucherot, Frank Ruffenach, Jack Puymirat, Bjarne Udd, Partha S. Sarkar, Estefania Cerroherreros, John W. DayAbstract:Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the RBFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, RBFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of RBFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of RBFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
Jennifer Winter - One of the best experts on this subject based on the ideXlab platform.
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the rna binding protein rbfox2 an essential regulator of emt driven alternative splicing and a mediator of cellular invasion
Oncogene, 2014Co-Authors: C Braeutigam, Luciano Rago, A Rolke, Lorenz Waldmeier, Gerhard Christofori, Jennifer WinterAbstract:The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion
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The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion
Oncogene, 2014Co-Authors: C Braeutigam, Luciano Rago, A Rolke, Lorenz Waldmeier, Gerhard Christofori, Jennifer WinterAbstract:The epithelial–mesenchymal transition (EMT), a prerequisite for cancer progression and metastasis formation, is regulated not only at the transcriptional but also at the post-transcriptional level, including at the level of alternative pre-mRNA splicing. Several recent studies have highlighted the involvement of splicing factors, including epithelial splicing regulatory proteins (Esrps) and RNA-binding Fox protein 2 (Rbfox2), in this process. Esrps regulate epithelial-specific splicing, and their expression is downregulated during EMT. By contrast, the role of Rbfox2 is controversial because Rbfox2 regulates epithelial as well as mesenchymal splicing events. Here, we have used several established cell culture models to investigate the functions of Rbfox2 during EMT. We demonstrate that induction of an EMT upregulates the expression of Rbfox2, which correlates with an increase in Rbfox2-regulated splicing events in the cortactin ( Cttn ), Pard3 and dynamin 2 ( Dnm2 ) transcripts. At the same time, however, the epithelial-specific ability to splice the Enah , Slk and Tsc2 transcripts is either reduced or lost completely by Rbfox2, which might be due, in part, to downregulation of the expression of the Esrps cooperative factors. Depletion of Rbfox2 during EMT did not prevent the activation of transforming growth factor-β signaling, the upregulation of mesenchymal markers or changes in cell morphology toward a mesenchymal phenotype. In addition, this depletion did not influence cell migration. However, depletion of Rbfox2 in cells that have completed an EMT significantly reduced their invasive potential. Taken together, our results suggest that during an EMT, Rbfox2-regulated splicing shifts from epithelial-to mesenchymal-specific events, leading to a higher degree of tissue invasiveness.
Chantal Sellier - One of the best experts on this subject based on the ideXlab platform.
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RBFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences
Nature communications, 2018Co-Authors: Chantal Sellier, Estefanía Cerro-herreros, Markus Blatter, Fernande Freyermuth, Angeline Gaucherot, Frank Ruffenach, Jack Puymirat, Bjarne Udd, Partha S. Sarkar, John W. DayAbstract:Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the RBFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, RBFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of RBFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of RBFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
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RBFOX1 mbnl1 competition for ccug rna repeats binding contributes to myotonic dystrophy type 1 type 2 differences
Nature Communications, 2018Co-Authors: Chantal Sellier, Markus Blatter, Fernande Freyermuth, Angeline Gaucherot, Frank Ruffenach, Jack Puymirat, Bjarne Udd, Partha S. Sarkar, Estefania Cerroherreros, John W. DayAbstract:Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the RBFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, RBFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of RBFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of RBFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
Davide Gabellini - One of the best experts on this subject based on the ideXlab platform.
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RBFOX1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD). PLoS Genet. 2013; 9:e1003186. [PubMed: 23300487
2016Co-Authors: Mariaelena Pistoni, Melissa S. Cline, Maria Victoria Neguembor, Lily Shiue, Sergia Bortolanza, Manuel Ares, Ros Xynos, Davide GabelliniAbstract:Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle disease whose molecular pathogenesis remains largely unknown. Over-expression of FSHD region gene 1 (FRG1) in mice, frogs, and worms perturbs muscle development and causes FSHD–like phenotypes. FRG1 has been implicated in splicing, and we asked how splicing might be involved in FSHD by conducting a genome-wide analysis in FRG1 mice. We find that splicing perturbations parallel the responses of different muscles to FRG1 over-expression and disease progression. Interestingly, binding sites for the Rbfox family of splicing factors are over-represented in a subset of FRG1-affected splicing events. RBFOX1 knockdown, over-expression, and RNA-IP confirm that these are direct RBFOX1 targets. We find that FRG1 is associated to the RBFOX1 RNA and decreases its stability. Consistent with this, RBFOX1 expression is down-regulated in mice and cells over-expressing FRG1 as well as in FSHD patients. Among the genes affected is Calpain 3, which is mutated in limb girdle muscular dystrophy, a disease phenotypically similar to FSHD. In FRG1 mice and FSHD patients, the Calpain 3 isoform lacking exon 6 (Capn3 E6–) is increased. Finally, RBFOX1 knockdown and over-expression of Capn3 E6- inhibit muscle differentiation. Collectively, our results suggest that a component of FSHD pathogenesis may arise by over-expression of FRG1, reducing RBFOX1 levels an
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rbfox proteins regulate tissue specific alternative splicing of mef2d required for muscle differentiation
Journal of Cell Science, 2015Co-Authors: Valeria Runfola, Soji Sebastian, Jeffrey F Dilworth, Davide GabelliniAbstract:Among the Mef2 family of transcription factors, Mef2D is unique in that it undergoes tissue-specific splicing to generate an isoform that is essential for muscle differentiation. However, the mechanisms mediating this muscle-specific processing of Mef2D remain unknown. Using bioinformatics, we identified Rbfox proteins as putative modulators of Mef2D muscle-specific splicing. Accordingly, we found direct and specific RBFOX1 and Rbfox2 binding to Mef2D pre-mRNA in vivo. Gain- and loss-of-function experiments demonstrated that RBFOX1 and Rbfox2 cooperate in promoting Mef2D splicing and subsequent myogenesis. Thus, our findings reveal a new role for Rbfox proteins in regulating myogenesis through activation of essential muscle-specific splicing events.
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RBFOX1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).
PLoS genetics, 2013Co-Authors: Mariaelena Pistoni, Melissa S. Cline, Alexandros Xynos, Maria Victoria Neguembor, Lily Shiue, Sergia Bortolanza, Manuel Ares, Davide GabelliniAbstract:Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle disease whose molecular pathogenesis remains largely unknown. Over-expression of FSHD region gene 1 (FRG1) in mice, frogs, and worms perturbs muscle development and causes FSHD–like phenotypes. FRG1 has been implicated in splicing, and we asked how splicing might be involved in FSHD by conducting a genome-wide analysis in FRG1 mice. We find that splicing perturbations parallel the responses of different muscles to FRG1 over-expression and disease progression. Interestingly, binding sites for the Rbfox family of splicing factors are over-represented in a subset of FRG1-affected splicing events. RBFOX1 knockdown, over-expression, and RNA-IP confirm that these are direct RBFOX1 targets. We find that FRG1 is associated to the RBFOX1 RNA and decreases its stability. Consistent with this, RBFOX1 expression is down-regulated in mice and cells over-expressing FRG1 as well as in FSHD patients. Among the genes affected is Calpain 3, which is mutated in limb girdle muscular dystrophy, a disease phenotypically similar to FSHD. In FRG1 mice and FSHD patients, the Calpain 3 isoform lacking exon 6 (Capn3 E6–) is increased. Finally, RBFOX1 knockdown and over-expression of Capn3 E6- inhibit muscle differentiation. Collectively, our results suggest that a component of FSHD pathogenesis may arise by over-expression of FRG1, reducing RBFOX1 levels and leading to aberrant expression of an altered Calpain 3 protein through dysregulated splicing.
Halyna R Shcherbata - One of the best experts on this subject based on the ideXlab platform.
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stress dependent mir 980 regulation of RBFOX1 a2bp1 promotes ribonucleoprotein granule formation and cell survival
Nature Communications, 2018Co-Authors: Mariya M Kucherenko, Halyna R ShcherbataAbstract:Upon stress, profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs). Here, we show that RBFOX1 is an LCD-containing protein that aggregates into liquid droplets and amyloid-like fibers and promiscuously joins different nuclear and cytoplasmic RNP granules. Using Drosophila oogenesis as an in vivo system for stress response, we demonstrate a mechanism by which RBFOX1 promotes cell survival. The stress-dependent miRNA miR-980 acts to buffer RBFOX1 levels, since it targets only those RBFOX1 transcripts that contain extended 3′UTRs. Reduced miR-980 expression during stress leads to increased RBFOX1 levels, widespread formation of various RNP granules, and increased cell viability. We show that human RBFOX proteins also contain multiple LCDs and form membraneless compartments, suggesting that the RNP granule-linked control of cellular adaptive responses may contribute to a wide range of RBFOX-associated pathologies in humans.
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Stress-dependent miR-980 regulation of RBFOX1/A2bp1 promotes ribonucleoprotein granule formation and cell survival
Nature Publishing Group, 2018Co-Authors: Mariya M Kucherenko, Halyna R ShcherbataAbstract:RBFOX1, a pro-survival RNA-binding protein, is expressed in a complex manner and mediates diverse developmental processes. Here, the authors observe alternative splicing of RBFOX1 and stress-dependent regulation by miR-980 in Drosophila ovaries and RBFOX1 localisation in ribonucleoprotein granules in human cells
