An in silico FSHD muscle fibre for modelling DUX4 dynamics and predicting the impact of therapy
- University of Bath, United Kingdom
- King's College London, United Kingdom
- The Alan Turing Institute, United Kingdom
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is an incurable myopathy linked to over-expression of the myotoxic transcription factor DUX4. Targeting DUX4 is the leading therapeutic approach, however it is only detectable in 0.1-3.8% of FSHD myonuclei. How rare DUX4 drives FSHD and the optimal anti-DUX4 strategy is unclear. We combine stochastic gene expression with compartment models of cell states, building a simulation of DUX4 expression and consequences in FSHD muscle fibres. Investigating iDUX4 myoblasts, scRNAseq and snRNAseq of FSHD muscle we estimate parameters including DUX4 mRNA degradation, transcription and translation rates and DUX4 target gene activation rates. Our model accurately recreates the distribution of DUX4 and target gene positive cells seen in scRNAseq of FSHD myocytes. Importantly we show DUX4 drives significant cell death despite expression in only 0.8% of live cells. Comparing scRNAseq of unfused FSHD myocytes to snRNAseq of fused FSHD myonuclei, we find evidence of DUX4 protein syncytial diffusion and estimate its rate via genetic algorithms. We package our model into freely available tools, to rapidly investigate consequences of anti-DUX4 therapy.
Data availability
All data generated or analysed during this study are publicly available or included in the manuscript, all code employed is published as part of our shiny app at 3 public domain URLs listed in the manuscript.
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facioscapulohumeral muscular dystrophyNCBI Gene Expression Omnibus GSE122873.
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Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nucleNCBI Gene Expression Omnibus GSE143492.
Article and author information
Author details
Christopher RS Banerji
Funding
EPSRC Centre for Doctoral Training in Sustainable Chemical Technologies (EP/L016354/1)
- Matthew V Cowley
Friends of FSH Research
- Matthew V Cowley
Muscular Dystrophy UK (19GRO-PG12-0493)
- Johanna Pruller
FSHD Society (FSHD-Winter2021-4491649104)
- Johanna Pruller
Medical Research Council (MR/S002472/1)
- Massimo Ganassi
Association Francaise contre les Myopathies
- Peter S Zammit
SOLVE FSHD
- Massimo Ganassi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Cowley et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An in silico FSHD muscle fibre for modelling DUX4 dynamics and predicting the impact of therapy
eLife 12:e88345.
https://doi.org/10.7554/eLife.88345
