{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:43:31Z","timestamp":1789037011388,"version":"build-2803163510"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000069","name":"NIAMS","doi-asserted-by":"publisher","award":["R01AR045203"],"award-info":[{"award-number":["R01AR045203"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). Human DUX4 and mouse Dux are retrogenes derived from retrotransposition of the mRNA from the parental DUXC gene. Primates and rodents have lost the parental DUXC gene, and it is unknown whether DUXC had a similar role in driving an early pluripotent transcriptional program. Dogs and other Laurasiatherians have retained DUXC, providing an opportunity to determine the functional similarity to the retrotransposed DUX4 and Dux. Here, we identify the expression of two isoforms of DUXC mRNA in canine testis tissues: one encoding the canonical double homeodomain protein (DUXC), similar to DUX4\/Dux, and a second that includes an in-frame alternative exon that disrupts the conserved amino acid sequence of the first homeodomain (DUXC-ALT). The expression of DUXC in canine cells induces a pluripotent program similar to DUX4 and Dux and induces the expression of a similar set of retrotransposons of the ERV\/MaLR and LINE-1 families, as well as pericentromeric satellite repeats; whereas DUXC-ALT did not robustly activate gene expression in these assays. Important for preclinical models of FSHD, human DUX4 and canine DUXC show higher conservation of their homeodomains and corresponding binding motifs compared with the conservation between human DUX4 and mouse Dux, and human DUX4 activates a highly similar transcriptional program in canine cells. Together, these findings show that retrotransposition resulted in the loss of an alternatively spliced isoform and that DUXC containing mammals might be good candidates for certain preclinical models ofFSHD.<\/jats:p>","DOI":"10.1093\/hmg\/ddab352","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T13:43:57Z","timestamp":1638884637000},"page":"1694-1704","source":"Crossref","is-referenced-by-count":9,"title":["Canine DUXC: implications for DUX4 retrotransposition and preclinical models of FSHD"],"prefix":"10.1093","volume":"31","author":[{"given":"Chao-Jen","family":"Wong","sequence":"first","affiliation":[{"name":"Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L","family":"Whiddon","sequence":"additional","affiliation":[{"name":"Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlee T","family":"Langford","sequence":"additional","affiliation":[{"name":"Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea E","family":"Belleville","sequence":"additional","affiliation":[{"name":"Divisions of Public Health Sciences and Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-0968","authenticated-orcid":false,"given":"Stephen J","family":"Tapscott","sequence":"additional","affiliation":[{"name":"Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"},{"name":"Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"2022052023341523700_ref1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00412-012-0380-y","article-title":"Evolution of DUX gene macrosatellites in placental mammals","volume":"121","author":"Leidenroth","year":"2012","journal-title":"Chromosoma"},{"key":"2022052023341523700_ref2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1186\/1471-2148-10-364","article-title":"A family history of DUX4: phylogenetic analysis of DUXA, B, C and Duxbl reveals the ancestral DUX gene","volume":"10","author":"Leidenroth","year":"2010","journal-title":"BMC Evol. Biol."},{"key":"2022052023341523700_ref3","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1126\/science.1173275","article-title":"An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs","volume":"325","author":"Parker","year":"2009","journal-title":"Science"},{"key":"2022052023341523700_ref4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s42003-021-01698-x","article-title":"A novel canine reference genome resolves genomic architecture and uncovers transcript complexity","volume":"4","author":"Wang","year":"2021","journal-title":"Commun Biol"},{"key":"2022052023341523700_ref5","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/ana.22275","article-title":"DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo","volume":"69","author":"Wallace","year":"2011","journal-title":"Ann. Neurol."},{"key":"2022052023341523700_ref6","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1093\/nar\/gkw141","article-title":"DUX4 recruits p300\/CBP through its C-terminus and induces global H3K27 acetylation changes","volume":"44","author":"Choi","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2022052023341523700_ref7","doi-asserted-by":"crossref","first-page":"e1001181","DOI":"10.1371\/journal.pgen.1001181","article-title":"Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene","volume":"6","author":"Snider","year":"2010","journal-title":"PLoS Genet."},{"key":"2022052023341523700_ref8","doi-asserted-by":"crossref","first-page":"e0160022","DOI":"10.1371\/journal.pone.0160022","article-title":"Influence of repressive histone and DNA methylation upon D4Z4 transcription in non-myogenic cells","volume":"11","author":"Das","year":"2016","journal-title":"PLoS One"},{"key":"2022052023341523700_ref9","first-page":"4419","article-title":"Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells","volume":"25","author":"Jagannathan","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2022052023341523700_ref10","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.nmd.2007.04.002","article-title":"The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein","volume":"17","author":"Kowaljow","year":"2007","journal-title":"Neuromuscul. Disord."},{"key":"2022052023341523700_ref11","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/ng.3846","article-title":"Conservation and innovation in the DUX4-family gene network","volume":"49","author":"Whiddon","year":"2017","journal-title":"Nat. Genet."},{"key":"2022052023341523700_ref12","doi-asserted-by":"crossref","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Zhang","year":"2008","journal-title":"Genome Biol."},{"key":"2022052023341523700_ref13","doi-asserted-by":"crossref","first-page":"e744","DOI":"10.1371\/journal.pcbi.0030074","article-title":"Dog as an outgroup to human and mouse","volume":"3","author":"Lunter","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"2022052023341523700_ref14","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13395-020-00227-4","article-title":"Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity","volume":"10","author":"Jones","year":"2020","journal-title":"Skelet. 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Commun."},{"key":"2022052023341523700_ref18","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.123538","article-title":"AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD","volume":"3","author":"Giesige","year":"2018","journal-title":"JCI Insight"},{"key":"2022052023341523700_ref19","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/ng.3844","article-title":"Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL\/HERVL retrotransposons","volume":"49","author":"Hendrickson","year":"2017","journal-title":"Nat. Genet."},{"key":"2022052023341523700_ref20","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/dnares\/dsv013","article-title":"Transient bursts of Zscan4 expression are accompanied by the rapid derepression of heterochromatin in mouse embryonic stem cells","volume":"22","author":"Akiyama","year":"2015","journal-title":"DNA Res."},{"key":"2022052023341523700_ref21","doi-asserted-by":"crossref","first-page":"e1003947","DOI":"10.1371\/journal.pgen.1003947","article-title":"DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis","volume":"9","author":"Young","year":"2013","journal-title":"PLoS Genet."},{"key":"2022052023341523700_ref22","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.devcel.2011.11.013","article-title":"DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy","volume":"22","author":"Geng","year":"2012","journal-title":"Dev. Cell"},{"key":"2022052023341523700_ref23","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/ng.3858","article-title":"DUX-family transcription factors regulate zygotic genome activation in placental mammals","volume":"49","author":"De Iaco","year":"2017","journal-title":"Nat. Genet."},{"key":"2022052023341523700_ref24","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/s41422-019-0238-4","article-title":"Precise temporal regulation of dux is important for embryo development","volume":"29","author":"Guo","year":"2019","journal-title":"Cell Res."},{"key":"2022052023341523700_ref25","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/s41588-019-0418-7","article-title":"Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development","volume":"51","author":"Chen","year":"2019","journal-title":"Nat. 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Reprod."},{"key":"2022052023341523700_ref27","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1089\/scd.2012.0643","article-title":"Expression of the human FSHD-linked DUX4 gene induces neurogenesis during differentiation of murine embryonic stem cells","volume":"22","author":"Dandapat","year":"2013","journal-title":"Stem Cells Dev."},{"key":"2022052023341523700_ref28","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1016\/j.celrep.2018.11.060","article-title":"Crystal structure of the double homeodomain of DUX4 in complex with DNA","volume":"25","author":"Lee","year":"2018","journal-title":"Cell Rep."},{"key":"2022052023341523700_ref29","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"2022052023341523700_ref30","article-title":"A novel canine reference genome resolves genomic architecture and uncovers transcript complexity","volume":"4","year":"2021","journal-title":"Commun Biol."},{"key":"2022052023341523700_ref31","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0076-6879(06)11008-3","article-title":"Bioconductor: an open source framework for bioinformatics and computational biology","volume":"411","author":"Reimers","year":"2006","journal-title":"Methods Enzymol."},{"key":"2022052023341523700_ref32","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene expression omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab352\/42210399\/ddab352.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/10\/1694\/43755186\/ddab352.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/10\/1694\/43755186\/ddab352.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T23:36:15Z","timestamp":1653089775000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/10\/1694\/6457948"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,9]]},"references-count":32,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,12,9]]},"published-print":{"date-parts":[[2022,5,19]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab352","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5,15]]},"published":{"date-parts":[[2021,12,9]]}}}