An in silico FSHD muscle fiber for modeling DUX4 dynamics and predicting the impact of therapy

• Published in: eLife Vol. 12
• Main Authors: Cowley, Matthew V, Pruller, Johanna, Ganassi, Massimo, Zammit, Peter S, Banerji, Christopher R S
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 15.05.2023; eLife Sciences Publications, Ltd
• Subjects: Apoptosis; Biopsy; Cell Biology; Cell culture; Cell death; cellular automaton; Clinical trials; Computational and Systems Biology; DUX4; Epigenetics; facioscapulohumeral muscular dystrophy; FSHD; Gene expression; Gene Expression Regulation; Genes, Homeobox; Haplotypes; Homeodomain Proteins - metabolism; Humans; muscle; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - metabolism; Muscular dystrophy; Muscular Dystrophy, Facioscapulohumeral - genetics; Muscular Dystrophy, Facioscapulohumeral - metabolism; Myoblasts; Myocytes; Myopathy; Overexpression; Pathology; Proteins; Simulation; stochastic gene expression; Stochasticity; Transcription factors; computational biology; systems biology; stochastic gene expression; cell biology; facioscapulohumeral muscular dystrophy; muscle; FSHD; DUX4; human; cellular automaton
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88345

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable myopathy linked to the 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 are unclear. We combine stochastic gene expression with compartment models of cell states, building a simulation of DUX4 expression and consequences in FSHD muscle fibers. 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 targets 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 the consequences of anti-DUX4 therapy.