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

Dongxu Zheng, Annelot Wondergem, Susan Kloet, Iris Willemsen, Judit Balog, Stephen J. Tapscott, Ahmed Mahfouz, Anita Van Den Heuvel, Silvère M. Van Der Maarel*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)284-298
Number of pages15
JournalHuman Molecular Genetics
Volume33
Issue number3
DOIs
Publication statusPublished - 2024

Keywords

  • cellular heterogeneity
  • DUX4
  • FSHD
  • muscular dystrophy
  • single-nucleus RNA-sequencing

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