{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T14:26:25Z","timestamp":1779373585068,"version":"3.53.1"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the <jats:italic>DUX4<\/jats:italic> gene in skeletal muscles. Effective therapies will likely involve <jats:italic>DUX4<\/jats:italic> inhibition. RNA interference (RNAi) is one powerful approach to inhibit <jats:italic>DUX4<\/jats:italic>, and we previously described a RNAi gene therapy to achieve <jats:italic>DUX4<\/jats:italic> silencing in FSHD cells and mice using engineered microRNAs. Here we report a strategy to direct RNAi against <jats:italic>DUX4<\/jats:italic> using the natural microRNA <jats:italic>miR-675<\/jats:italic>, which is derived from the lncRNA <jats:italic>H19<\/jats:italic>. Human <jats:italic>miR-675<\/jats:italic> inhibits <jats:italic>DUX4<\/jats:italic> expression and associated outcomes in FSHD cell models. In addition, <jats:italic>miR-675<\/jats:italic> delivery using gene therapy protects muscles from DUX4-associated death in mice. Finally, we show that three known <jats:italic>miR-675<\/jats:italic>-upregulating small molecules inhibit <jats:italic>DUX4<\/jats:italic> and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes. To our knowledge, this is the first study demonstrating the use of small molecules to suppress a dominant disease gene using an RNAi mechanism.<\/jats:p>","DOI":"10.1038\/s41467-021-27430-1","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T11:03:07Z","timestamp":1638961387000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5453-1152","authenticated-orcid":false,"given":"Nizar Y.","family":"Saad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Al-Kharsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Garwick-Coppens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gholamhossein Amini","family":"Chermahini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison A.","family":"Harper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Palo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9800-5349","authenticated-orcid":false,"given":"Ryan L.","family":"Boudreau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5135-4317","authenticated-orcid":false,"given":"Scott Q.","family":"Harper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"27430_CR1","doi-asserted-by":"crossref","unstructured":"Flanigan, K. M. & Harper, S., Q. in Muscle Disease: Pathology and Genetics (Goebel, H.H., Sewry, C.A. & Weller, R.O, eds) 288\u2013297 (John Wiley & Sons, Ltd., 2013).","DOI":"10.1002\/9781118635469.ch32"},{"key":"27430_CR2","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1212\/WNL.0000000000007446","volume":"92","author":"NE Johnson","year":"2019","unstructured":"Johnson, N. E. & Statland, J. M. FSHD1 or FSHD2: that is the question: the answer: It\u2019s all just FSHD. Neurology 92, 881\u2013882 (2019).","journal-title":"Neurology"},{"key":"27430_CR3","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.nurt.2008.07.005","volume":"5","author":"R Tawil","year":"2008","unstructured":"Tawil, R. Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5, 601\u2013606 (2008).","journal-title":"Neurotherapeutics"},{"key":"27430_CR4","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1007\/s00415-016-8123-2","volume":"263","author":"G Ricci","year":"2016","unstructured":"Ricci, G. et al. A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes. J. Neurol. 263, 1204\u20131214 (2016).","journal-title":"J. Neurol."},{"key":"27430_CR5","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-35150-8","volume":"8","author":"D Bosnakovski","year":"2018","unstructured":"Bosnakovski, D. et al. Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression. Sci. Rep. 8, 16957 (2018).","journal-title":"Sci. Rep."},{"key":"27430_CR6","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1038\/emboj.2008.201","volume":"27","author":"D Bosnakovski","year":"2008","unstructured":"Bosnakovski, D. et al. An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. EMBO J. 27, 2766\u20132779 (2008).","journal-title":"EMBO J."},{"key":"27430_CR7","doi-asserted-by":"crossref","first-page":"18157","DOI":"10.1073\/pnas.0708659104","volume":"104","author":"M Dixit","year":"2007","unstructured":"Dixit, M. et al. DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc. Natl Acad. Sci. USA 104, 18157\u201318162 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"27430_CR8","doi-asserted-by":"crossref","unstructured":"Giesige, C. R. et al. AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight 3, e123538 (2018).","DOI":"10.1172\/jci.insight.123538"},{"key":"27430_CR9","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.nmd.2007.04.002","volume":"17","author":"V Kowaljow","year":"2007","unstructured":"Kowaljow, V. et al. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul. Disord. 17, 611\u2013623 (2007).","journal-title":"Neuromuscul. Disord."},{"key":"27430_CR10","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/ng.2454","volume":"44","author":"RJ Lemmers","year":"2012","unstructured":"Lemmers, R. J. et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat. Genet. 44, 1370\u20131374 (2012).","journal-title":"Nat. Genet"},{"key":"27430_CR11","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1126\/science.1189044","volume":"329","author":"RJ Lemmers","year":"2010","unstructured":"Lemmers, R. J. et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329, 1650\u20131653 (2010).","journal-title":"Science"},{"key":"27430_CR12","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.molmed.2011.01.001","volume":"17","author":"SM van der Maarel","year":"2011","unstructured":"van der Maarel, S. M., Tawil, R. & Tapscott, S. J. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol. Med. 17, 252\u2013258 (2011).","journal-title":"Trends Mol. Med"},{"key":"27430_CR13","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/ana.22275","volume":"69","author":"LM Wallace","year":"2011","unstructured":"Wallace, L. M. et al. DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann. Neurol. 69, 540\u2013552 (2011).","journal-title":"Ann. Neurol."},{"key":"27430_CR14","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/ng.3844","volume":"49","author":"PG Hendrickson","year":"2017","unstructured":"Hendrickson, P. G. et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL\/HERVL retrotransposons. Nat. Genet. 49, 925\u2013934 (2017).","journal-title":"Nat. Genet"},{"key":"27430_CR15","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1093\/hmg\/ddp180","volume":"18","author":"L Snider","year":"2009","unstructured":"Snider, L. et al. RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum. Mol. Genet. 18, 2414\u20132430 (2009).","journal-title":"Hum. Mol. Genet."},{"key":"27430_CR16","doi-asserted-by":"crossref","first-page":"e1001181","DOI":"10.1371\/journal.pgen.1001181","volume":"6","author":"L Snider","year":"2010","unstructured":"Snider, L. et al. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet. 6, e1001181 (2010).","journal-title":"PLoS Genet."},{"key":"27430_CR17","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/ng.3846","volume":"49","author":"JL Whiddon","year":"2017","unstructured":"Whiddon, J. L., Langford, A. T., Wong, C. J., Zhong, J. W. & Tapscott, S. J. Conservation and innovation in the DUX4-family gene network. Nat. Genet. 49, 935\u2013940 (2017).","journal-title":"Nat. Genet"},{"key":"27430_CR18","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/j.1582-4934.2012.01647.x","volume":"17","author":"D Tassin","year":"2013","unstructured":"Tassin, D. et al. DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy? J. Cell Mol. Med 17, 76\u201389 (2013).","journal-title":"J. Cell Mol. Med"},{"key":"27430_CR19","doi-asserted-by":"crossref","first-page":"e26820","DOI":"10.1371\/journal.pone.0026820","volume":"6","author":"E Vanderplanck","year":"2011","unstructured":"Vanderplanck, E. et al. The FSHD atrophic myotube phenotype is caused by DUX4 expression. PLoS ONE 6, e26820 (2011).","journal-title":"PLoS ONE"},{"key":"27430_CR20","doi-asserted-by":"crossref","DOI":"10.1186\/s13395-017-0148-4","volume":"8","author":"A Vanderplanck","year":"2018","unstructured":"Vanderplanck, A. et al. Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei. Skelet. Muscle 8, 2 (2018).","journal-title":"Skelet. Muscle"},{"key":"27430_CR21","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1038\/mt.2012.68","volume":"20","author":"LM Wallace","year":"2012","unstructured":"Wallace, L. M. et al. RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy. Mol. Ther. 20, 1417\u20131423 (2012).","journal-title":"Mol. Ther."},{"key":"27430_CR22","doi-asserted-by":"crossref","first-page":"D140","DOI":"10.1093\/nar\/gkj112","volume":"34","author":"S Griffiths-Jones","year":"2006","unstructured":"Griffiths-Jones, S., Grocock, R. J., van Dongen, S., Bateman, A. & Enright, A. J. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 34, D140\u2013D144 (2006).","journal-title":"Nucleic Acids Res."},{"key":"27430_CR23","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1038\/ng2135","volume":"39","author":"M Kertesz","year":"2007","unstructured":"Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U. & Segal, E. The role of site accessibility in microRNA target recognition. Nat. Genet 39, 1278\u20131284 (2007).","journal-title":"Nat. Genet"},{"key":"27430_CR24","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1093\/bioinformatics\/bts043","volume":"28","author":"M Reczko","year":"2012","unstructured":"Reczko, M., Maragkakis, M., Alexiou, P., Grosse, I. & Hatzigeorgiou, A. G. Functional microRNA targets in protein coding sequences. Bioinformatics 28, 771\u2013776 (2012).","journal-title":"Bioinformatics"},{"key":"27430_CR25","doi-asserted-by":"crossref","first-page":"R21","DOI":"10.1093\/hmg\/ddr137","volume":"20","author":"RL Boudreau","year":"2011","unstructured":"Boudreau, R. L., Rodriguez-Lebron, E. & Davidson, B. L. RNAi medicine for the brain: progresses and challenges. Hum. Mol. Genet 20, R21\u2013R27 (2011).","journal-title":"Hum. Mol. Genet"},{"key":"27430_CR26","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1038\/mt.2011.185","volume":"19","author":"RL Boudreau","year":"2011","unstructured":"Boudreau, R. L., Spengler, R. M. & Davidson, B. L. Rational design of therapeutic siRNAs: minimizing off-targeting potential to improve the safety of RNAi therapy for Huntington\u2019s disease. Mol. Ther. 19, 2169\u20132177 (2011).","journal-title":"Mol. Ther."},{"key":"27430_CR27","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1101\/gad.234419.113","volume":"28","author":"BK Dey","year":"2014","unstructured":"Dey, B. K., Pfeifer, K. & Dutta, A. The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration. Genes Dev. 28, 491\u2013501 (2014).","journal-title":"Genes Dev."},{"key":"27430_CR28","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1261\/rna.5248604","volume":"10","author":"M Rehmsmeier","year":"2004","unstructured":"Rehmsmeier, M., Steffen, P., Hochsmann, M. & Giegerich, R. Fast and effective prediction of microRNA\/target duplexes. RNA 10, 1507\u20131517 (2004).","journal-title":"RNA"},{"key":"27430_CR29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.omtm.2017.12.005","volume":"8","author":"LM Wallace","year":"2018","unstructured":"Wallace, L. M. et al. Pre-clinical safety and off-target studies to support translation of AAV-mediated RNAi therapy for FSHD. Mol. Ther. Methods Clin. Dev. 8, 121\u2013130 (2018).","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"27430_CR30","doi-asserted-by":"crossref","first-page":"R153","DOI":"10.1093\/hmg\/ddy162","volume":"27","author":"E Campbell","year":"2018","unstructured":"Campbell, E., Belleville, A. E., Resnick, R., Shadle, S. C. & Tapscott, S. J. Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle. Hum. Mol. Genet. 27, R153\u2013R162 (2018).","journal-title":"Hum. Mol. Genet."},{"key":"27430_CR31","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1002\/cphy.c160039","volume":"7","author":"M DeSimone","year":"2017","unstructured":"DeSimone, M., Pakula, A., Lek, A. & Emerson, C. P. Jr Facioscapulohumeral muscular dystrophy. Compr. Physiol. 7, 1229\u20131279 (2017).","journal-title":"Compr. Physiol."},{"key":"27430_CR32","doi-asserted-by":"crossref","first-page":"e1006658","DOI":"10.1371\/journal.pgen.1006658","volume":"13","author":"SC Shadle","year":"2017","unstructured":"Shadle, S. C. et al. DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS Genet. 13, e1006658 (2017).","journal-title":"PLoS Genet."},{"key":"27430_CR33","doi-asserted-by":"crossref","unstructured":"Wallace, L. M., Garwick, S. E. & Harper, S. Q. RNAi therapy for dominant muscular dystrophies and other myopathies. (Duan, D. ed) 99\u2013116 (Springer Press, 2010).","DOI":"10.1007\/978-1-4419-1207-7_7"},{"key":"27430_CR34","doi-asserted-by":"crossref","first-page":"e0150938","DOI":"10.1371\/journal.pone.0150938","volume":"11","author":"TI Jones","year":"2016","unstructured":"Jones, T. I., Parilla, M. & Jones, P. L. Transgenic Drosophila for investigating DUX4 and FRG1, Two genes associated with facioscapulohumeral muscular dystrophy (FSHD). PLoS ONE 11, e0150938 (2016).","journal-title":"PLoS ONE"},{"key":"27430_CR35","first-page":"386","volume":"3","author":"RD Wuebbles","year":"2010","unstructured":"Wuebbles, R. D., Long, S. W., Hanel, M. L. & Jones, P. L. Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J. Clin. Exp. Pathol. 3, 386\u2013400 (2010).","journal-title":"Int J. Clin. Exp. Pathol."},{"key":"27430_CR36","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.celrep.2014.08.049","volume":"9","author":"DJ Wang","year":"2014","unstructured":"Wang, D. J., Ratnam, N. M., Byrd, J. C. & Guttridge, D. C. NF-kappaB functions in tumor initiation by suppressing the surveillance of both innate and adaptive immune cells. Cell Rep. 9, 90\u2013103 (2014).","journal-title":"Cell Rep."},{"key":"27430_CR37","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.freeradbiomed.2016.08.007","volume":"99","author":"P Dmitriev","year":"2016","unstructured":"Dmitriev, P. et al. G. Carnac, M. Lipinski and Y. S. Vassetzky, DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients. Free Radic. Biol. Med. 99, 244\u2013258 (2016).","journal-title":"Free Radic. Biol. Med"},{"key":"27430_CR38","doi-asserted-by":"crossref","first-page":"5901","DOI":"10.1093\/hmg\/ddv315","volume":"24","author":"M Rickard","year":"2015","unstructured":"Rickard, M., Petek, L. M. & Miller, D. G. Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways. Hum. Mol. Genet. 24, 5901\u20135914 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"27430_CR39","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1093\/hmg\/dds284","volume":"21","author":"TI Jones","year":"2012","unstructured":"Jones, T. I. et al. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum. Mol. Genet. 21, 4419\u20134430 (2012).","journal-title":"Hum. Mol. Genet"},{"key":"27430_CR40","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1261\/rna.070177.118","volume":"25","author":"G Amini Chermahini","year":"2019","unstructured":"Amini Chermahini, G., Rashnonejad, A. & Harper, S. Q. RNAscope in situ hybridization-based method for detecting DUX4 RNA expression in vitro. RNA 25, 1211\u20131217 (2019).","journal-title":"RNA"},{"key":"27430_CR41","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nmeth.3485","volume":"12","author":"H Dweep","year":"2015","unstructured":"Dweep, H. & Gretz, N. miRWalk2.0: a comprehensive atlas of microRNA-target interactions. Nat. Methods 12, 697 (2015).","journal-title":"Nat. Methods"},{"key":"27430_CR42","doi-asserted-by":"crossref","first-page":"e0118813","DOI":"10.1371\/journal.pone.0118813","volume":"10","author":"E Ansseau","year":"2015","unstructured":"Ansseau, E. et al. Aberrant splicing in transgenes containing introns, exons, and V5 epitopes: lessons from developing an FSHD mouse model expressing a D4Z4 repeat with flanking genomic sequences. PLoS ONE 10, e0118813 (2015).","journal-title":"PLoS ONE"},{"key":"27430_CR43","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/jpi.12331","volume":"61","author":"W Cai","year":"2016","unstructured":"Cai, W. et al. Long noncoding RNA H19 mediates melatonin inhibition of premature senescence of c-kit(+) cardiac progenitor cells by promoting miR-675. J. Pineal Res. 61, 82\u201395 (2016).","journal-title":"J. Pineal Res."},{"key":"27430_CR44","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2210-7-11","volume":"7","author":"F Gaube","year":"2007","unstructured":"Gaube, F., Wolfl, S., Pusch, L., Kroll, T. C. & Hamburger, M. Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7. BMC Pharmacol. 7, 11 (2007).","journal-title":"BMC Pharmacol."},{"key":"27430_CR45","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s00109-006-0146-1","volume":"85","author":"P Hanifi-Moghaddam","year":"2007","unstructured":"Hanifi-Moghaddam, P. et al. Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling. J. Mol. Med. (Berl., Ger.) 85, 471\u2013480 (2007).","journal-title":"J. Mol. Med. (Berl., Ger.)"},{"key":"27430_CR46","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/B978-0-12-386509-0.00014-4","volume":"507","author":"RL Boudreau","year":"2012","unstructured":"Boudreau, R. L. & Davidson, B. L. Generation of hairpin-based RNAi vectors for biological and therapeutic application. Methods Enzymol. 507, 275\u2013296 (2012).","journal-title":"Methods Enzymol."},{"key":"27430_CR47","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.cell.2009.04.021","volume":"137","author":"J Kota","year":"2009","unstructured":"Kota, J. et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137, 1005\u20131017 (2009).","journal-title":"Cell"},{"key":"27430_CR48","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1093\/hmg\/ddy173","volume":"27","author":"JW Lim","year":"2018","unstructured":"Lim, J. W. et al. Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures. Hum. Mol. Genet. 27, 2644\u20132657 (2018).","journal-title":"Hum. Mol. Genet"},{"key":"27430_CR49","doi-asserted-by":"crossref","first-page":"e20966","DOI":"10.1371\/journal.pone.0020966","volume":"6","author":"S Cheli","year":"2011","unstructured":"Cheli, S. et al. Expression profiling of FSHD-1 and FSHD-2 cells during myogenic differentiation evidences common and distinctive gene dysregulation patterns. PLoS ONE 6, e20966 (2011).","journal-title":"PLoS ONE"},{"key":"27430_CR50","doi-asserted-by":"crossref","first-page":"e108411","DOI":"10.1371\/journal.pone.0108411","volume":"9","author":"V Colangelo","year":"2014","unstructured":"Colangelo, V. et al. Next-generation sequencing analysis of miRNA expression in control and FSHD myogenesis. PLoS ONE 9, e108411 (2014).","journal-title":"PLoS ONE"},{"key":"27430_CR51","doi-asserted-by":"crossref","first-page":"34989","DOI":"10.1074\/jbc.M113.504522","volume":"288","author":"P Dmitriev","year":"2013","unstructured":"Dmitriev, P. et al.Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients. J. Biol. Chem. 288, 34989\u201335002 (2013).","journal-title":"J. Biol. Chem."},{"key":"27430_CR52","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-8-55","volume":"8","author":"N Harafuji","year":"2013","unstructured":"Harafuji, N., Schneiderat, P., Walter, M. C. & Chen, Y. W. miR-411 is up-regulated in FSHD myoblasts and suppresses myogenic factors. Orphanet J. Rare Dis. 8, 55 (2013).","journal-title":"Orphanet J. Rare Dis."},{"key":"27430_CR53","doi-asserted-by":"crossref","first-page":"e0116853","DOI":"10.1371\/journal.pone.0116853","volume":"10","author":"M Portilho","year":"2015","unstructured":"Portilho, M. et al. miRNA expression in control and FSHD fetal human muscle biopsies. PLoS ONE 10, e0116853 (2015).","journal-title":"PLoS ONE"},{"key":"27430_CR54","doi-asserted-by":"crossref","unstructured":"Feng, Q. et al. A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. Elife 4, e04996 (2015).","DOI":"10.7554\/eLife.04996"},{"key":"27430_CR55","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1038\/mt.2011.118","volume":"19","author":"LM Wallace","year":"2011","unstructured":"Wallace, L. M., Garwick-Coppens, S. E., Tupler, R. & Harper, S. Q. RNA interference improves myopathic phenotypes in mice over-expressing FSHD region gene 1 (FRG1). Mol. Ther. 19, 2048\u20132054 (2011).","journal-title":"Mol. Ther."},{"key":"27430_CR56","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.msec.2019.01.122","volume":"99","author":"J Han","year":"2019","unstructured":"Han, J. et al. Delivery of miR-675 by stem cell-derived exosomes encapsulated in silk fibroin hydrogel prevents aging-induced vascular dysfunction in mouse hindlimb. Mater. Sci. Eng. 99, 322\u2013332 (2019).","journal-title":"Mater. Sci. Eng."},{"key":"27430_CR57","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/mus.20356","volume":"32","author":"PB Kang","year":"2005","unstructured":"Kang, P. B. et al. Variations in gene expression among different types of human skeletal muscle. Muscle Nerve 32, 483\u2013491 (2005).","journal-title":"Muscle Nerve"},{"key":"27430_CR58","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ejogrb.2012.02.020","volume":"162","author":"C Awater","year":"2012","unstructured":"Awater, C., Zerres, K. & Rudnik-Schoneborn, S. Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients. Eur. J. Obstet. Gynecol. Reprod. Biol. 162, 153\u2013159 (2012).","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"27430_CR59","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.bbadis.2014.05.021","volume":"1852","author":"S Sacconi","year":"2015","unstructured":"Sacconi, S., Salviati, L. & Desnuelle, C. Facioscapulohumeral muscular dystrophy. Biochim. Biophys. Acta 1852, 607\u2013614 (2015).","journal-title":"Biochim. Biophys. Acta"},{"key":"27430_CR60","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/(SICI)1096-8628(19980501)77:2<155::AID-AJMG9>3.0.CO;2-R","volume":"77","author":"M Zatz","year":"1998","unstructured":"Zatz, M. et al. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am. J. Med. Genet. 77, 155\u2013161 (1998).","journal-title":"Am. J. Med. Genet."},{"key":"27430_CR61","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1172\/JCI89401","volume":"127","author":"M Teveroni","year":"2017","unstructured":"Teveroni, M. et al. Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity. The. J. Clin. Investig. 127, 1531\u20131545 (2017).","journal-title":"J. Clin. Investig."},{"key":"27430_CR62","doi-asserted-by":"crossref","DOI":"10.1186\/s13395-020-00227-4","volume":"10","author":"TI Jones","year":"2020","unstructured":"Jones, T. I. et al. Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity. Skelet. Muscle 10, 8 (2020).","journal-title":"Skelet. Muscle"},{"key":"27430_CR63","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.nmd.2018.02.012","volume":"28","author":"K Mul","year":"2018","unstructured":"Mul, K., Horlings, C. G. C., Voermans, N. C., Schreuder, T. H. A. & van Engelen, B. G. M. Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy. Neuromuscul. Disord. 28, 508\u2013511 (2018).","journal-title":"Neuromuscul. Disord."},{"key":"27430_CR64","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1600-079X.2011.00871.x","volume":"51","author":"Y Hibaoui","year":"2011","unstructured":"Hibaoui, Y., Reutenauer-Patte, J., Patthey-Vuadens, O., Ruegg, U. T. & Dorchies, O. M. Melatonin improves muscle function of the dystrophic mdx5Cv mouse, a model for Duchenne muscular dystrophy. J. Pineal Res. 51, 163\u2013171 (2011).","journal-title":"J. Pineal Res."},{"key":"27430_CR65","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.1093\/hmg\/ddt314","volume":"22","author":"J Block","year":"2013","unstructured":"Block, J. et al. Wnt\/beta-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells. Hum. Mol. Genet. 22, 4661\u20134672 (2013).","journal-title":"Hum. Mol. Genet"},{"key":"27430_CR66","doi-asserted-by":"crossref","first-page":"e64691","DOI":"10.1371\/journal.pone.0064691","volume":"8","author":"V Sharma","year":"2013","unstructured":"Sharma, V., Harafuji, N., Belayew, A. & Chen, Y. W. DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells. PLoS ONE 8, e64691 (2013).","journal-title":"PLoS ONE"},{"key":"27430_CR67","doi-asserted-by":"crossref","first-page":"e1008754","DOI":"10.1371\/journal.pgen.1008754","volume":"16","author":"S Jiang","year":"2020","unstructured":"Jiang, S. et al. Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei. PLoS Genet. 16, e1008754 (2020).","journal-title":"PLoS Genet."},{"key":"27430_CR68","doi-asserted-by":"crossref","unstructured":"Shadle, S. C. et al. DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double stranded RNA foci in human cell models of FSHD. Hum. Mol. Genet. 8, 3997\u20134011 (2019).","DOI":"10.1093\/hmg\/ddz242"},{"key":"27430_CR69","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1101\/gad.198085.112","volume":"26","author":"BK Dey","year":"2012","unstructured":"Dey, B. K., Gagan, J., Yan, Z. & Dutta, A. miR-26a is required for skeletal muscle differentiation and regeneration in mice. Genes Dev. 26, 2180\u20132191 (2012).","journal-title":"Genes Dev."},{"key":"27430_CR70","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.celrep.2019.03.105","volume":"27","author":"JM Goldstein","year":"2019","unstructured":"Goldstein, J. M. et al. In situ modification of tissue stem and progenitor cell genomes. Cell Rep. 27, 1254\u20131264 e1257 (2019).","journal-title":"Cell Rep."},{"key":"27430_CR71","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1089\/hum.2019.173","volume":"31","author":"L Muraine","year":"2020","unstructured":"Muraine, L. et al. Transduction efficiency of adeno-associated virus serotypes after local injection in mouse and human skeletal muscle. Hum. Gene Ther. 31, 233\u2013240 (2020).","journal-title":"Hum. Gene Ther."},{"key":"27430_CR72","doi-asserted-by":"crossref","unstructured":"V. Sharma, et al. PARP1 Differentially interacts with promoter region of DUX4 gene in FSHD myoblasts. J. Genet. Syndr. Gene Ther. 7, 303 (2016).","DOI":"10.4172\/2157-7412.1000303"},{"key":"27430_CR73","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1093\/nar\/gkr1016","volume":"40","author":"MB Baker","year":"2012","unstructured":"Baker, M. B., Bao, G. & Searles, C. D. In vitro quantification of specific microRNA using molecular beacons. Nucleic Acids Res. 40, e13 (2012).","journal-title":"Nucleic Acids Res."},{"key":"27430_CR74","doi-asserted-by":"crossref","first-page":"5868","DOI":"10.1073\/pnas.0801775105","volume":"105","author":"JL McBride","year":"2008","unstructured":"McBride, J. L. et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl Acad. Sci. USA 105, 5868\u20135873 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"27430_CR75","doi-asserted-by":"crossref","first-page":"8304","DOI":"10.3390\/molecules20058304","volume":"20","author":"SN Pandey","year":"2015","unstructured":"Pandey, S. N., Khawaja, H. & Chen, Y. W. Culture conditions affect expression of DUX4 in FSHD myoblasts. Molecules 20, 8304\u20138315 (2015).","journal-title":"Molecules"},{"key":"27430_CR76","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nm0302-253","volume":"8","author":"SQ Harper","year":"2002","unstructured":"Harper, S. Q. et al. Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Nat. Med. 8, 253\u2013261 (2002).","journal-title":"Nat. Med."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27430-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27430-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27430-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T19:04:46Z","timestamp":1670007886000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27430-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":76,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["27430"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-27430-1","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]},"assertion":[{"value":"30 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"N.Y.S. and S.Q.H. declare the following competing interests: provisional patent application N\u00b0 63\/145,255, covering <i>miR-675<\/i> upregulation as a therapeutic strategy for FSHD. M.A., S.E.G., G.A.C., M.A.H., A.P., and R.L.B. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7128"}}