Research ArticleMuscular Dystrophy

Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy

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Science Translational Medicine  25 Mar 2020:
Vol. 12, Issue 536, eaay0271
DOI: 10.1126/scitranslmed.aay0271

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Screening for survival

Facioscapulohumeral muscular dystrophy (FSHD) is caused by altered expression of DUX4, a gene important during development that is not usually present in adult cells. In FSHD skeletal muscle, activation of DUX4 leads to apoptosis. To identify potential targets that mediate DUX4-induced cell death, Lek et al. performed an unbiased screen using CRISPR-Cas9. Hypoxia signaling emerged as a target, and treating patient cells and zebrafish models of FSHD with inhibitors of hypoxia signaling reduced cell death and expression of DUX4 target genes and improved structural defects and muscle function. Results demonstrate the utility of this CRISPR-Cas9 screen for identifying putative therapeutic targets for FSHD.

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