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snRNA-seq analysis in multinucleated myogenic FSHD cells identifies heterogeneous FSHD transcriptome signatures associated with embryonic-like program activation and oxidative stress-induced apoptosis.

  • Zheng, Dongxu1
  • Wondergem, Annelot1
  • Kloet, Susan1
  • Willemsen, Iris1
  • Balog, Judit1
  • Tapscott, Stephen J2
  • Mahfouz, Ahmed1, 3
  • van den Heuvel, Anita1
  • van der Maarel, Silvère M1
  • 1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. , (Netherlands)
  • 2 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, USA.
  • 3 Delft Bioinformatics Lab, Delft University of Technology, Delft, Netherlands. , (Netherlands)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Nov 02, 2023
DOI: 10.1093/hmg/ddad186
PMID: 37934801


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. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

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