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  • 1
    Online Resource
    Online Resource
    Abstract 263: Cytosolic RBFox1 in Cardiac Pathological Remodeling
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Research Vol. 123, No. Suppl_1 ( 2018-08-03)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 123, No. Suppl_1 ( 2018-08-03)
    Abstract: Background: RBFox1 is known to be an RNA splicing regulator with enriched expression in cardiac muscle. Loss of RBFox1 expression is a molecular hallmark associated with heart failure in mouse and human. Genetic manipulation of RBFox1 reveals a major function of RBFox1 in the pathogenesis of cardiac hypertrophy, fibrosis and dysfunction under pathological stresses. However, much of our current knowledge about RBFox1 focuses on the nuclear RBFox1 with a major impact on global alternative splicing changes. Yet, RBFox1 gene also generates a cytosolic isoform-RBFox1c through alternative splicing, and the specific function of RBFox1c has not been characterized. Goal and Methods: This study investigated the functional impact and the underlying mechanism of the RBFox1c in cardiac pathological remodeling and targeted gene regulation. Results: RBFox1c expression is significantly repressed in stressed cardiomyocytes in vivo and in vitro. RNA-Seq combined with IPA analyses from cardiomyocytes revealed RBFox1c but not the nucleus RBFox1 specifically suppressed pro-inflammatory genes. In the cardiac specific RBFox1 knockout mice, enhanced cardiac fibrosis is observed following I/R injury associated with elevated expression of pro-inflammatory genes. In contrast, cardiac specific expression of RBFox1c reduced cardiac fibrosis and inflammatory gene expression following pressure-overload and myocardial infarct injury associated with improved ejection fraction. Motif enrichment analysis identified significant enrichment of the RBFox1 binding motif in the 3’UTR of the RBFox1c regulated genes. We performed CLIP analysis followed by RT-PCR and observed RBFox1c interacted with inflammatory gene 3’UTR. Lastly, we explored the interactome of RBFox1c and found RBFox1c specifically interacted with a component of RNA decay machinery-Upf1. Indeed, while expression of RBFox1c repressed inflammatory gene expression, inactivation of Upf1 abolished this effect in cardiomyocytes. Conclusion: RBFox1 regulates cardiac transcriptome reprogramming at two post-transcriptional steps. The RBFox1 nuclei isoform regulates RNA splicing reprogramming, and the RBFox1c represses proinflammatory genes via recruitment of Upf1 mediated RNA degradation.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.123.suppl_1.263
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467838-X
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  • 2
    Online Resource
    Online Resource
    Abstract 401: Functional Impact Of Rbfox1c In Cardiac Pathological Remodeling Through Targeted Mrna Stability Regulation
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Research Vol. 129, No. Suppl_1 ( 2021-09-03)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 129, No. Suppl_1 ( 2021-09-03)
    Abstract: Post-transcriptional regulation plays a key role in transcriptome reprogramming during cardiac pathogenesis. In previous studies, we have identified that cardiac enriched RNA-binding protein, RBFox1 plays key role in cardiac hypertrophy through mRNA alternative splicing regulation in nuclei. However, RBFox1 gene also generates a cytosolic isoform (RBFox1c), suggesting additional functions of post-transcriptional regulation in heart. In adult heart, RBFox1c mRNA constituted ~ 40% of total RBFox1 level but was significantly repressed in pressure-overloaded failing mouse heart. Using CRISPR-Cas9 technology, we have established an isoform specific RBFox1c-cKO mouse. At baseline inactivation of RBFox1c led to decreased cardiac function along with induction of cardiac fibrosis. RBFox1c-cKO mice also showed macrophages infiltration into myocardium post 7days MI. In contrast, restoration of RBFox1c expression in adult intact hearts significantly reduced cardiac fibrosis post stress. RNA-seq analyses in RBFox1c expressing cardiomyocytes showed that RBFox1c specifically suppressed the expression of pro-inflammatory genes. Secondly, CLIP-Seq analysis and targeted RNA-IP showed that RBFox1c could directly interact with inflammatory pathway mRNAs. These results suggested the inflammatory mRNAs are direct downstream targets regulated by RBFox1c. Using both in vitro cultured cardiomyocytes and intact mouse hearts, we demonstrated that expression of RBFox1c reduces pro-inflammatory mRNA expression at baseline and upon hypertrophy stimulation. Lastly, we characterized the interactome of RBFox1c through proteomic analysis and found RBFox1c specifically interacted with a component of the RNA NMD machinery-Upf1. RBFox1c interaction with Upf1 in cardiomyocytes was diminished upon hypertrophic stress. Furthermore, by inactivation of Upf1 via siRNA, we demonstrated that RBFox1c mediated repression of proinflammatory genes was Upf1 dependent.RBFox1 regulates cardiac transcriptome reprogramming in two post-transcriptional processes via distinct isoforms. While the RBFox1n regulates RNA splicing, the RBFox1c functions through targeted mRNA repression of proinflammatory genes by recruitment of Upf1 mediated RNA degradation.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.129.suppl_1.401
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Abstract 15949: Post-transcriptional Regulation of Cardiac Pathological Remodeling-- Role of Cytosolic Rbfox1c
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Post-transcriptional regulation plays a key role in transcriptome reprogramming during cardiac development and pathogenesis. In previous study, we have identified that loss of RBFox1 is a molecular hallmark associated with cardiac pathological hypertrophy and heart failure. We further demonstrate that RBFox1 regulates cardiac gene expression and function at post-transcriptional level through targeted RNA splicing in nuclei. However, RBFox1 gene also generates a cytosolic isoform RBFox1c, suggesting that it might also regulate other aspects of post-transcriptional regulation in heart. We detected that RBFox1c mRNA constituted 40% of total RBFox1 level in normal adult heart but repressed in diseased heart. In RBFox1-cKO mice, enhanced cardiac fibrosis was associated with loss of cardiac function following MI or TAC. Restoration of RBFox1c expression (RBFox1c-TG) significantly reduced cardiac fibrosis. RNA sequencing in RBFox1c expressing cardiomyocytes showed that RBFox1c specifically suppressed the expression of pro-inflammatory genes. The pro-inflammatory genes were induced in the RBFox1 deficient hearts but suppressed upon cardiomyocyte specific RBFox1c expression. In vitro, RBFox1c expression in NRVM suppressed PE induced proinflammatory genes and significantly blocked the effects of the conditioned media on fibroblast proliferation. De novo motif discovery identified a significant enrichment of the conserved RBFox1 binding motif in the 3’UTRs of the RBFox1c dependent genes. RNA-CLIP analysis further demonstrated a direct binding of RBFox1c to the pro-inflammatory gene 3’UTR. We characterized the interactome of RBFox1c and found RBFox1c specifically interacted with a component of the RNA non-sense mediated decay machinery-Upf1. RBFox1c interaction with Upf1 in cardiomyocytes was diminished upon hypertrophic stress. By inactivation of Upf1 via siRNA, we demonstrated that RBFox1c mediated repression of proinflammatory genes was Upf1 dependent. Finally, by temporally induced expression of RBFox1c in post-TAC heart, we provided proof-of-concept evidence that targeted expression of RBFox1c was sufficient to ameliorate pathological remodeling and progression of heart failure as a potential gene-based therapy.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.15949
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
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