{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T08:01:42Z","timestamp":1778832102456,"version":"3.51.4"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004243","name":"Prinses Beatrix Spierfonds","doi-asserted-by":"publisher","award":["W.OR19-06"],"award-info":[{"award-number":["W.OR19-06"]}],"id":[{"id":"10.13039\/501100004243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,20]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The sporadic nature of DUX4 expression in FSHD muscle challenges comparative transcriptome analyses between FSHD and control samples. A variety of DUX4 and FSHD-associated transcriptional changes have been identified, but bulk RNA-seq strategies prohibit comprehensive analysis of their spatiotemporal relation, interdependence and role in the disease process. In this study, we used single-nucleus RNA-sequencing of nuclei isolated from patient- and control-derived multinucleated primary myotubes to investigate the cellular heterogeneity in FSHD. Taking advantage of the increased resolution in snRNA-sequencing of fully differentiated myotubes, two distinct populations of DUX4-affected nuclei could be defined by their transcriptional profiles. Our data provides insights into the differences between these two populations and suggests heterogeneity in two well-known FSHD-associated transcriptional aberrations: increased oxidative stress and inhibition of myogenic differentiation. Additionally, we provide evidence that DUX4-affected nuclei share transcriptome features with early embryonic cells beyond the well-described cleavage stage, progressing into the 8-cell and blastocyst stages. Altogether, our data suggests that the FSHD transcriptional profile is defined by a mixture of individual and sometimes mutually exclusive DUX4-induced responses and cellular state-dependent downstream effects.<\/jats:p>","DOI":"10.1093\/hmg\/ddad186","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T19:10:27Z","timestamp":1699384227000},"page":"284-298","source":"Crossref","is-referenced-by-count":15,"title":["snRNA-seq analysis in multinucleated myogenic FSHD cells identifies heterogeneous FSHD transcriptome signatures associated with embryonic-like program activation and oxidative stress-induced apoptosis"],"prefix":"10.1093","volume":"33","author":[{"given":"Dongxu","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annelot","family":"Wondergem","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Kloet","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Willemsen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Balog","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J","family":"Tapscott","sequence":"additional","affiliation":[{"name":"Division of Human Biology, Fred Hutchinson Cancer Research Center , 1100 Fairview Ave N, Seattle, WA 98109 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Mahfouz","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"},{"name":"Delft Bioinformatics Lab, Delft University of Technology , Van Mourik Broekmanweg 2628 XE, Delft , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silv\u00e8re M","family":"van der Maarel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Einthovenweg 20, 2333 ZC, Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,11,2]]},"reference":[{"key":"2024012109545957000_ref1","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1126\/science.1189044","article-title":"A unifying genetic model for facioscapulohumeral muscular dystrophy","volume":"329","author":"Lemmers","year":"2010","journal-title":"Science"},{"key":"2024012109545957000_ref2","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 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