ArticleGenome research2024
Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy.
Article in Genome research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Deciphering skeletal muscle development: cellular heterogeneity and molecular regulatory networks from single-cell and spatial transcriptomic perspectives.Frontiers in cell and developmental biology · 2026Review
- Genome-wide analysis of FSHD cell lines using Nanopore sequencing reveals allele-specific differences at DUX4 target genes and complex repeats.bioRxiv : the preprint server for biology · 2025Article
- Adaptive response to electrical pulse stimulation is impaired in FSHD myotubes by DUX4 gene network activation.Scientific reports · 2025Article
- Diversity challenges and reconciles genetics in facioscapulohumeral muscular dystrophy.Journal of human genetics · 2025Review
- Spatial Omics in Clinical Research: A Comprehensive Review of Technologies and Guidelines for Applications.International journal of molecular sciences · 2025Review
- In situ spatial transcriptomic analysis of human skeletal muscle using the Xenium platform.Cell and tissue research · 2025Article
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Authors and funding
8 authors.
Funding
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal derepression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use multiplexed error-robust fluorescent in situ hybridization (MERFISH) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated myotubes and unfused mononuclear cells (MNCs) of control, isogenic D4Z4 contraction mutant and FSHD patient samples, as well as the individual nuclei within them. We find myocyte nuclei segregate into two clusters defined by the expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, whereas MNCs cluster based on developmental states. Patient/mutant myotubes are found in "FSHD-hi" and "FSHD-lo" states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target-expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared with the control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.
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