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Mol Ther. 2018 Jul 5;26(7):1797-1807. doi: 10.1016/j.ymthe.2018.04.019. Epub 2018 Apr 26.

Identification of Epigenetic Regulators of DUX4-fl for Targeted Therapy of Facioscapulohumeral Muscular Dystrophy.

Author information

1
Department of Pharmacology, University of Nevada, Reno, School of Medicine, Reno, NV 89557, USA; Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Programs in Molecular Medicine and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: michael.green@umassmed.edu.
5
Department of Pharmacology, University of Nevada, Reno, School of Medicine, Reno, NV 89557, USA; Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: peterjones@med.unr.edu.

Abstract

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.

KEYWORDS:

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

PMID:
29759937
PMCID:
PMC6035737
[Available on 2019-07-05]
DOI:
10.1016/j.ymthe.2018.04.019
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