UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; Department of Cell and Developmental Biology

Publication Date


Document Type



Cell Biology | Genetic Phenomena | Genetics and Genomics | Molecular Biology | Musculoskeletal Diseases | Nervous System Diseases | Therapeutics


Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic de-repression of the disease locus, leading to pathogenic misexpression of the DUX4 gene in skeletal muscle. While the factors and pathways involved in normal repression of the FSHD locus in healthy cells have been well characterized, very little is known about those responsible for the aberrant activation of DUX4-fl in FSHD myocytes. Reasoning that DUX4-fl activators might represent useful targets for small molecule inhibition, we performed a highly targeted, candidate-based screen of epigenetic regulators in primary FSHD myocytes. We confirmed several of the strongest and most specific candidates (ASH1L, BRD2, KDM4C, and SMARCA5) in skeletal myocytes from two other unrelated FSHD1 patients, and we showed that knockdown led to reduced levels of DUX4-fl and DUX4-FL target genes, as well as altered chromatin at the D4Z4 locus. As a second mode of validation, targeting the CRISPR/dCas9-KRAB transcriptional repressor to the promoters of several candidates also led to reduced levels of DUX4-fl. Furthermore, these candidates can be repressed by different methods in skeletal myocytes without major effects on certain critical muscle genes. Our results demonstrate that expression of DUX4-fl is regulated by multiple epigenetic pathways, and they indicate viable, druggable candidates for therapeutic target development.


FSHD, chromatin, epigenetics, facioscapulohumeral muscular dystrophy, gene regulation, muscular dystrophy, therapeutic targets

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Copyright 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (

DOI of Published Version



Mol Ther. 2018 Apr 26. pii: S1525-0016(18)30192-8. doi: 10.1016/j.ymthe.2018.04.019. [Epub ahead of print]. Link to article on publisher's site

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy

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Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.