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While DUX4 activates similar programs in early embryos and FSHD muscle, the isoform usage of known DUX4 targets is notably distinct between the two contexts. DUX4 also activates hundreds of previously unannotated intergenic loci dominated by repetitive elements. The transcriptional and epigenetic profiles of these loci in myogenic and embryonic contexts indicate that the usage of DUX4-binding sites at these intergenic loci is influenced by the cellular environment. These findings demonstrate that DUX4 induces context-specific transcriptomic programs, enriching our understanding of DUX4-induced muscle pathology.<\/jats:p>","DOI":"10.1126\/sciadv.adt5356","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T13:58:56Z","timestamp":1746626336000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["DUX4 activates common and context-specific intergenic transcripts and isoforms"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1068-8403","authenticated-orcid":true,"given":"Dongxu","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-6109","authenticated-orcid":true,"given":"Anita","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0552-7544","authenticated-orcid":true,"given":"Judit","family":"Balog","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5104-3777","authenticated-orcid":true,"given":"Iris M.","family":"Willemsen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9189-0640","authenticated-orcid":true,"given":"Susan","family":"Kloet","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-0968","authenticated-orcid":true,"given":"Stephen J.","family":"Tapscott","sequence":"additional","affiliation":[{"name":"Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."},{"name":"Department of Neurology, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-2149","authenticated-orcid":true,"given":"Ahmed","family":"Mahfouz","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."},{"name":"Delft Bioinformatics Lab, Delft University of Technology, Delft, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8103-711X","authenticated-orcid":true,"given":"Silv\u00e8re M.","family":"van der Maarel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3858"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3844"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3846"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.11.013"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1189044"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv315"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy364"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09242-y"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa031"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.08.007"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102251"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.201"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2012.06.041"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2012.01647.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001181"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35150-8"},{"key":"e_1_3_2_18_2","first-page":"4419","article-title":"Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells","volume":"25","author":"Jagannathan S.","year":"2016","unstructured":"S. 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