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Manjusha Dixit - One of the best experts on this subject based on the ideXlab platform.
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Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion.
BMC cancer, 2019Co-Authors: Ankit Tiwari, Archita Mohanty Jaiswal, Bratati Mukherjee, Khurshidul Hassan, Niharika Pattanaik, Manjusha DixitAbstract:Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression. Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot. In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines. FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.
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reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion
BMC Cancer, 2019Co-Authors: Ankit Tiwari, Archita Mohanty Jaiswal, Bratati Mukherjee, Niharika Pattanaik, Md Khurshidul Hassan, Manjusha DixitAbstract:Background Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.
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Additional file 3: of Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion
2019Co-Authors: Ankit Tiwari, Bratati Mukherjee, Niharika Pattanaik, Md. Hassan, Archita Jaiswal, Manjusha DixitAbstract:Correlation analysis of tumor IRS for FRG1, with Gleason score and MVD count. (PDF 96 kb
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Increased FSHD region gene1 expression reduces in vitro cell migration, invasion, and angiogenesis, ex vivo supported by reduced expression in tumors
Bioscience reports, 2017Co-Authors: Ankit Tiwari, Niharika Pattnaik, Archita Mohanty Jaiswal, Manjusha DixitAbstract:Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for FSHD. FRG1 regulates various muscle-related functions, but studies have proposed its role in development and angiogenesis also, where it is involved with tumor-associated molecules. Therefore, we decided to look into its role in tumor progression, tumor angiogenesis, and its impact on cellular properties. Cell proliferation, migration, invasion and in vitro angiogenesis assays were performed to decipher the effect of FRG1 on endothelial and epithelial cell functions. Q-RT PCR was done for human embyonic kidney (HEK293T) cells with altered FRG1 levels to identify associated molecules. Further, immunohistochemistry was done to identify FRG1 expression levels in various cancers and its association with tumor angiogenesis. Subsequently, inference was drawn from Oncomine and Kaplan-Meier plotter analysis, for FRG1 expression in different cancers. Ectopic expression of FRG1 affected cell migration and invasion in both HEK293T and human umbilical vein endothelial cells (HUVECs). In HUVECs, FRG1 overexpression led to reduced angiogenesis in vitro No effect was observed in cell proliferation in both the cell types. Q-RT PCR data revealed reduction in granulocyte-colony stimulating factor (G-CSF) expression with FRG1 overexpression and increased expression of matrix metalloproteinase 10 (MMP10) with FRG1 knockdown. Immunohistochemistry analysis showed reduced FRG1 levels in tumors which were supported by in silico analysis data. These findings suggest that reduction in FRG1 expression in gastric, colon and oral cavity tumor might have a role in tumor progression, by regulating cell migration and invasiveness. To elucidate a better understanding of molecular signaling involving FRG1 in angiogenesis regulation, further study is required.
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Current status and future prospect of FSHD region gene 1
Journal of Biosciences, 2017Co-Authors: Arman Kunwar Hansda, Ankit Tiwari, Manjusha DixitAbstract:FSHD region gene 1 ( FRG1 ), as the name suggests, is the primary candidate gene for fascioscapulohumeral muscular dystrophy disease. It seemingly affects muscle physiology in normal individuals but in FSHD, where it is found to be highly upregulated, might be involved in disruption of face, scapula and humeral skeletal muscle. Literature on FRG1 , reviewed from 1996 to 2016, reveals that it is primarily associated with muscle development and maintenance. Approximately 75% of FSHD patients also show vascular abnormalities indicating that FRG1 might have some part to play in these abnormalities. Research involving vasculature in X. laevis larvae shows that FRG1 positively affects normal vasculature. Few of the well-established angiogenic regulators seem to get affected by abnormal expression level of FRG1. Its primary localization in sub nuclear structures like Cajal bodies and nuclear speckles indicates regulation of the above-mentioned factors by transcriptional and post-transcriptional machineries, but in-depth studies need to be done to conclude a clear statement. In this review, we have attempted to present all the work done on FRG1, all the lacunas which need to be unraveled, and hypothesized a model for our readers to get an insight into its molecular mechanism.
Ankit Tiwari - One of the best experts on this subject based on the ideXlab platform.
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Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion.
BMC cancer, 2019Co-Authors: Ankit Tiwari, Archita Mohanty Jaiswal, Bratati Mukherjee, Khurshidul Hassan, Niharika Pattanaik, Manjusha DixitAbstract:Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression. Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot. In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines. FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.
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reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion
BMC Cancer, 2019Co-Authors: Ankit Tiwari, Archita Mohanty Jaiswal, Bratati Mukherjee, Niharika Pattanaik, Md Khurshidul Hassan, Manjusha DixitAbstract:Background Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.
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Additional file 3: of Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion
2019Co-Authors: Ankit Tiwari, Bratati Mukherjee, Niharika Pattanaik, Md. Hassan, Archita Jaiswal, Manjusha DixitAbstract:Correlation analysis of tumor IRS for FRG1, with Gleason score and MVD count. (PDF 96 kb
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Increased FSHD region gene1 expression reduces in vitro cell migration, invasion, and angiogenesis, ex vivo supported by reduced expression in tumors
Bioscience reports, 2017Co-Authors: Ankit Tiwari, Niharika Pattnaik, Archita Mohanty Jaiswal, Manjusha DixitAbstract:Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for FSHD. FRG1 regulates various muscle-related functions, but studies have proposed its role in development and angiogenesis also, where it is involved with tumor-associated molecules. Therefore, we decided to look into its role in tumor progression, tumor angiogenesis, and its impact on cellular properties. Cell proliferation, migration, invasion and in vitro angiogenesis assays were performed to decipher the effect of FRG1 on endothelial and epithelial cell functions. Q-RT PCR was done for human embyonic kidney (HEK293T) cells with altered FRG1 levels to identify associated molecules. Further, immunohistochemistry was done to identify FRG1 expression levels in various cancers and its association with tumor angiogenesis. Subsequently, inference was drawn from Oncomine and Kaplan-Meier plotter analysis, for FRG1 expression in different cancers. Ectopic expression of FRG1 affected cell migration and invasion in both HEK293T and human umbilical vein endothelial cells (HUVECs). In HUVECs, FRG1 overexpression led to reduced angiogenesis in vitro No effect was observed in cell proliferation in both the cell types. Q-RT PCR data revealed reduction in granulocyte-colony stimulating factor (G-CSF) expression with FRG1 overexpression and increased expression of matrix metalloproteinase 10 (MMP10) with FRG1 knockdown. Immunohistochemistry analysis showed reduced FRG1 levels in tumors which were supported by in silico analysis data. These findings suggest that reduction in FRG1 expression in gastric, colon and oral cavity tumor might have a role in tumor progression, by regulating cell migration and invasiveness. To elucidate a better understanding of molecular signaling involving FRG1 in angiogenesis regulation, further study is required.
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Current status and future prospect of FSHD region gene 1
Journal of Biosciences, 2017Co-Authors: Arman Kunwar Hansda, Ankit Tiwari, Manjusha DixitAbstract:FSHD region gene 1 ( FRG1 ), as the name suggests, is the primary candidate gene for fascioscapulohumeral muscular dystrophy disease. It seemingly affects muscle physiology in normal individuals but in FSHD, where it is found to be highly upregulated, might be involved in disruption of face, scapula and humeral skeletal muscle. Literature on FRG1 , reviewed from 1996 to 2016, reveals that it is primarily associated with muscle development and maintenance. Approximately 75% of FSHD patients also show vascular abnormalities indicating that FRG1 might have some part to play in these abnormalities. Research involving vasculature in X. laevis larvae shows that FRG1 positively affects normal vasculature. Few of the well-established angiogenic regulators seem to get affected by abnormal expression level of FRG1. Its primary localization in sub nuclear structures like Cajal bodies and nuclear speckles indicates regulation of the above-mentioned factors by transcriptional and post-transcriptional machineries, but in-depth studies need to be done to conclude a clear statement. In this review, we have attempted to present all the work done on FRG1, all the lacunas which need to be unraveled, and hypothesized a model for our readers to get an insight into its molecular mechanism.
Davide Gabellini - One of the best experts on this subject based on the ideXlab platform.
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Direct interplay between two candidate genes in FSHD muscular dystrophy
Human molecular genetics, 2014Co-Authors: Giulia Ferri, Roberta Caccia, Claudia Huichalaf, Davide GabelliniAbstract:Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are double homeobox 4 (DUX4), encoded by the most telomeric D4Z4 unit, and FSHD region gene 1 (FRG1). DUX4 is a sequence-specific transcription factor. Here, we located putative DUX4 binding sites in the human FRG1 genomic area and we show specific DUX4 association to these regions. We found also that ectopically expressed DUX4 up-regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse FRG1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse FRG1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD.
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FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis
Journal of molecular cell biology, 2013Co-Authors: Maria Victoria Neguembor, Alexandros Xynos, Roberta Caccia, Mariaelena Pistoni, Sergia Bortolanza, Maria Cristina Onorati, Cristina Godio, Davide Corona, Gunnar Schotta, Davide GabelliniAbstract:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leading to over-expression of the nearby genes. Among them, we focused on FSHD region gene 1 (FRG1) since its over-expression in mice, Xenopus laevis and Caenorhabditis elegans, leads to muscular dystrophy-like defects, suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. Moreover, Suv4-20h KO mice develop muscular dystrophy signs. Finally, we identify the FRG1/Suv4-20h1 target Eid3 as a novel myogenic inhibitor that contributes to the muscle differentiation defects. Our study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis.
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Overexpression of facioscapulohumeral muscular dystrophy region gene 1 causes primary defects in myogenic stem cells.
Journal of Cell Science, 2013Co-Authors: Alexandros Xynos, Maria Victoria Neguembor, Roberta Caccia, Danilo Licastro, Alessandro Nonis, Clelia Di Serio, Elia Stupka, Davide GabelliniAbstract:Summary Overexpression of facioscapulohumeral muscular dystrophy region gene 1 (FRG1) in mice, frogs and worms leads to muscular and vascular abnormalities. Nevertheless, the mechanism that follows FRG1 overexpression and finally leads to muscular defects is currently unknown. Here, we show that the earliest phenotype displayed by mice overexpressing FRG1 is a postnatal muscle-growth defect. Long before the development of muscular dystrophy, FRG1 mice also exhibit a muscle regeneration impairment. Ex vivo and in vivo experiments revealed that FRG1 overexpression causes myogenic stem cell activation and proliferative, clonogenic and differentiation defects. A comparative gene expression profiling of muscles from young pre-dystrophic wild-type and FRG1 mice identified differentially expressed genes in several gene categories and networks that could explain the emerging tissue and myogenic stem cell defects. Overall, our study provides new insights into the pathways regulated by FRG1 and suggests that muscle stem cell defects could contribute to the pathology of FRG1 mice.
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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, Alexandros Xynos, Maria Victoria Neguembor, Lily Shiue, Melissa S. Cline, 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.
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AAV6-mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy.
Molecular therapy : the journal of the American Society of Gene Therapy, 2011Co-Authors: Sergia Bortolanza, Alessandro Nonis, Clelia Di Serio, Francesca Sanvito, S. Maciotta, Giovanni Sitia, Jessica Wei, Yvan Torrente, Joel R. Chamberlain, Davide GabelliniAbstract:Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans.
Archita Mohanty Jaiswal - One of the best experts on this subject based on the ideXlab platform.
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reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion
BMC Cancer, 2019Co-Authors: Ankit Tiwari, Archita Mohanty Jaiswal, Bratati Mukherjee, Niharika Pattanaik, Md Khurshidul Hassan, Manjusha DixitAbstract:Background Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.
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Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion.
BMC cancer, 2019Co-Authors: Ankit Tiwari, Archita Mohanty Jaiswal, Bratati Mukherjee, Khurshidul Hassan, Niharika Pattanaik, Manjusha DixitAbstract:Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression. Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot. In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines. FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.
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Increased FSHD region gene1 expression reduces in vitro cell migration, invasion, and angiogenesis, ex vivo supported by reduced expression in tumors
Bioscience reports, 2017Co-Authors: Ankit Tiwari, Niharika Pattnaik, Archita Mohanty Jaiswal, Manjusha DixitAbstract:Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for FSHD. FRG1 regulates various muscle-related functions, but studies have proposed its role in development and angiogenesis also, where it is involved with tumor-associated molecules. Therefore, we decided to look into its role in tumor progression, tumor angiogenesis, and its impact on cellular properties. Cell proliferation, migration, invasion and in vitro angiogenesis assays were performed to decipher the effect of FRG1 on endothelial and epithelial cell functions. Q-RT PCR was done for human embyonic kidney (HEK293T) cells with altered FRG1 levels to identify associated molecules. Further, immunohistochemistry was done to identify FRG1 expression levels in various cancers and its association with tumor angiogenesis. Subsequently, inference was drawn from Oncomine and Kaplan-Meier plotter analysis, for FRG1 expression in different cancers. Ectopic expression of FRG1 affected cell migration and invasion in both HEK293T and human umbilical vein endothelial cells (HUVECs). In HUVECs, FRG1 overexpression led to reduced angiogenesis in vitro No effect was observed in cell proliferation in both the cell types. Q-RT PCR data revealed reduction in granulocyte-colony stimulating factor (G-CSF) expression with FRG1 overexpression and increased expression of matrix metalloproteinase 10 (MMP10) with FRG1 knockdown. Immunohistochemistry analysis showed reduced FRG1 levels in tumors which were supported by in silico analysis data. These findings suggest that reduction in FRG1 expression in gastric, colon and oral cavity tumor might have a role in tumor progression, by regulating cell migration and invasiveness. To elucidate a better understanding of molecular signaling involving FRG1 in angiogenesis regulation, further study is required.
Peter L. Jones - One of the best experts on this subject based on the ideXlab platform.
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Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD).
PloS one, 2016Co-Authors: Takako I. Jones, Megan Parilla, Peter L. JonesAbstract:Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development and pathogenic mechanisms in FSHD.
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Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and sarcomeric protein.
Differentiation; research in biological diversity, 2011Co-Authors: Meredith L. Hanel, Chia Yun Jessica Sun, Steven W. Long, Takako I. Jones, Simona Zanotti, Derek J. Milner, Peter L. JonesAbstract:Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for mediating FSHD pathophysiology, however, very little is known about the endogenous FRG1 protein. This study uses immunocytochemistry (ICC) and histology to provide insight into FRG1's role in vertebrate muscle development and address its potential involvement in FSHD pathophysiology. In cell culture, primary myoblast/myotube cultures, and mouse and human muscle sections, FRG1 showed distinct nuclear and cytoplasmic localizations and nuclear shuttling assays indicated the subcellular pools of FRG1 are linked. During myoblast differentiation, FRG1's subcellular distribution changed dramatically with FRG1 eventually associating with the matured Z-discs. This Z-disc localization was confirmed using isolated mouse myofibers and found to be maintained in adult human skeletal muscle biopsies. Thus, FRG1 is not likely involved in the initial assembly and alignment of the Z-disc but may be involved in sarcomere maintenance or signaling. Further analysis of human tissue showed FRG1 is strongly expressed in arteries, veins, and capillaries, the other prominently affected tissue in FSHD. Overall, we show that in mammalian cells, FRG1 is a dynamic nuclear and cytoplasmic protein, however in muscle, FRG1 is also a developmentally regulated sarcomeric protein suggesting FRG1 may perform a muscle-specific function. Thus, FRG1 is the only FSHD candidate protein linked to the muscle contractile machinery and may address why the musculature and vasculature are specifically susceptible in FSHD.
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Testing the effects of FSHD candidate gene expression in vertebrate muscle development
International journal of clinical and experimental pathology, 2010Co-Authors: Ryan D. Wuebbles, Steven W. Long, Meredith L. Hanel, Peter L. JonesAbstract:The genetic lesion leading to facioscapulohumeral muscular dystrophy (FSHD) is a dominant deletion at the 4q35 locus. The generally accepted disease model involves an epigenetic dysregulation in the region resulting in the upregulation of one or more proximal genes whose overexpression specifically affects skeletal muscle. However, multiple FSHD candidate genes have been proposed without clear consensus. Using Xenopus laevis as a model for vertebrate development our lab has studied the effects of overexpression of the FSHD candidate gene ortholog, FRG1 (FSHD region gene 1), showing that increased levels of FRG1 systemically led specifically to an abnormal musculature and increased angiogenesis, the two most prominent clinical features of FSHD. Here we studied the overexpression effects of three other promising FSHD candidate genes, DUX4, DUX4c, and PITX1 using the same model system and methods for direct comparison. Expression of even very low levels of either DUX4 or pitx1 early in development led to massive cellular loss and severely abnormal development. These abnormalities were not muscle specific. In contrast, elevated levels of DUX4c resulted in no detectable adverse affects on muscle and DUX4c levels did not alter the expression of myogenic regulators. This data supports a model for DUX4 and PITX1 in FSHD only as pro-apoptotic factors if their expression in FSHD is confined to cells within the myogenic pathway; neither could account for the vascular pathology prevalent in FSHD. Taken together, increased FRG1 expression alone leads to a phenotype that most closely resembles the pathophysiology observed in FSHD patients.
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Facioscapulohumeral muscular dystrophy region gene-1 (FRG-1) is an actin-bundling protein associated with muscle-attachment sites.
Journal of cell science, 2010Co-Authors: Qian Liu, Takako I. Jones, William M. Brieher, Vivian W Tang, Peter L. JonesAbstract:In vertebrates, overexpression of facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) recapitulates the pathophysiology exhibited by FSHD patients, although the role of FRG1 in FSHD remains controversial and no precise function for FRG1 has been described in any organism. To gain insight into the function and potential role of FRG1 in FSHD, we analyzed the highly conserved Caenorhabditis elegans ortholog, frg-1. C. elegans body-wall muscles contain two distinct subcellular pools of FRG-1: nuclear FRG-1, concentrated in the nucleoli; and cytoplasmic FRG-1, associated with the Z-disk and costamere-like structures known as dense bodies. Functionally, we demonstrate that FRG-1 is an F-actin-bundling protein, consistent with its localization to dense bodies; this activity is conserved in human FRG1. This is particularly intriguing because it places FRG-1 along side the list of dense-body components whose vertebrate orthologs are involved in the myriad myopathies associated with disrupted costameres and Z-disks. Interestingly, overexpressed FRG-1 preferentially accumulates in the nucleus and, when overexpressed specifically from the frg-1 promoter, disrupts the adult ventral muscle structure and organization. Together, these data further support a role for FRG1 overexpression in FSHD pathophysiology and reveal the previously unsuspected direct involvement of FRG-1 in muscle structure and integrity.
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FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy
Disease models & mechanisms, 2009Co-Authors: Ryan D. Wuebbles, Meredith L. Hanel, Peter L. JonesAbstract:The genetic lesion that is diagnostic for facioscapulohumeral muscular dystrophy (FSHD) results in an epigenetic misregulation of gene expression, which ultimately leads to the disease pathology. FRG1 (FSHD region gene 1) is a leading candidate for a gene whose misexpression might lead to FSHD. Because FSHD pathology is most prominent in the musculature, most research and therapy efforts focus on muscle cells. Previously, using Xenopus development as a model, we showed that altering FRG1 expression levels systemically leads to aberrant muscle development, illustrating the potential for aberrant FRG1 levels to disrupt the musculature. However, 50-75% of FSHD patients also exhibit retinal vasculopathy and FSHD muscles have increased levels of vascular- and endothelial-related FRG1 transcripts, illustrating an underlying vascular component to the disease. To date, no FSHD candidate gene has been proposed to affect the vasculature. Here, we focus on a role for FRG1 expression in the vasculature. We found that endogenous FRG1 is expressed in both the developing and adult vasculature in Xenopus. Furthermore, expression of FRG1 was found to be essential for the development of the vasculature, as a knockdown of FRG1 resulted in decreased angiogenesis and reduced expression of the angiogenic regulator DAB2. Conversely, tadpoles subjected to FRG1 overexpression displayed the pro-angiogenic phenotypes of increased blood vessel branching and dilation of blood vessels, and developed edemas, suggesting that their circulation was disrupted. Thus, the systemic upregulation of the FRG1 protein shows the potential for acquiring a disrupted vascular phenotype, providing the first link between a FSHD candidate gene and the vascular component of FSHD pathology. Overall, in conjunction with our previous analysis, we show that FRG1 overexpression is capable of disrupting both the musculature and vasculature, recapitulating the two most prominent features of FSHD.
