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dc.contributor.authorJones, Takako I.
dc.contributor.authorParilla, Megan
dc.contributor.authorJones, Peter L.
dc.date2022-08-11T08:10:14.000
dc.date.accessioned2022-08-23T17:00:52Z
dc.date.available2022-08-23T17:00:52Z
dc.date.issued2016-03-04
dc.date.submitted2016-03-21
dc.identifier.citationJones TI, Parilla M, Jones PL. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD). PLoS One. 2016 Mar 4;11(3):e0150938. doi: 10.1371/journal.pone.0150938. eCollection 2016. PubMed PMID: 26942723. <a href="http://dx.doi.org/10.1371/journal.pone.0150938">Link to article on publisher's site</a>
dc.identifier.issn1932-6203 (Linking)
dc.identifier.doi10.1371/journal.pone.0150938
dc.identifier.pmid26942723
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43884
dc.description.abstractFacioscapulohumeral 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26942723&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<p>Copyright 2016 Jones et al. This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCell Biology
dc.subjectDevelopmental Biology
dc.subjectMolecular Biology
dc.subjectMolecular Genetics
dc.subjectMusculoskeletal Diseases
dc.subjectNervous System Diseases
dc.titleTransgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD)
dc.typeJournal Article
dc.source.journaltitlePloS one
dc.source.volume11
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1027&amp;context=peterjones&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peterjones/28
dc.identifier.contextkey8353275
refterms.dateFOA2022-08-23T17:00:52Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathpeterjones/28
dc.contributor.departmentDepartment of Cell and Developmental Biology
dc.source.pagese0150938


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<p>Copyright 2016 Jones et al. This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>
Except where otherwise noted, this item's license is described as <p>Copyright 2016 Jones et al. This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>