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dc.contributor.authorLek, Angela
dc.contributor.authorDeSimone, Alec
dc.contributor.authorKing, Oliver D.
dc.contributor.authorKunkel, Louis M.
dc.date2022-08-11T08:09:28.000
dc.date.accessioned2022-08-23T16:31:58Z
dc.date.available2022-08-23T16:31:58Z
dc.date.issued2020-03-25
dc.date.submitted2020-06-09
dc.identifier.citation<p>Lek A, Zhang Y, Woodman KG, Huang S, DeSimone AM, Cohen J, Ho V, Conner J, Mead L, Kodani A, Pakula A, Sanjana N, King OD, Jones PL, Wagner KR, Lek M, Kunkel LM. Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy. Sci Transl Med. 2020 Mar 25;12(536):eaay0271. doi: 10.1126/scitranslmed.aay0271. PMID: 32213627. <a href="https://doi.org/10.1126/scitranslmed.aay0271">Link to article on publisher's site</a></p>
dc.identifier.issn1946-6234 (Linking)
dc.identifier.doi10.1126/scitranslmed.aay0271
dc.identifier.pmid32213627
dc.identifier.urihttp://hdl.handle.net/20.500.14038/37778
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractThe emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32213627&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1126/scitranslmed.aay0271
dc.subjectBioinformatics
dc.subjectComputational Biology
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenomics
dc.subjectMusculoskeletal Diseases
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.subjectNeuroscience and Neurobiology
dc.subjectTherapeutics
dc.titleApplying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy
dc.typeArticle
dc.source.journaltitleScience translational medicine
dc.source.volume12
dc.source.issue536
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/neuro_pp/459
dc.identifier.contextkey18032511
html.description.abstract<p>The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.</p>
dc.identifier.submissionpathneuro_pp/459
dc.contributor.departmentKing Lab
dc.contributor.departmentWellstone Muscular Dystrophy Program, Department of Neurology
dc.source.pageseaay0271


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