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Identification of Epigenetic Regulators of DUX4-fl for Targeted Therapy of Facioscapulohumeral Muscular Dystrophy.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2018 Jul 05; Vol. 26 (7), pp. 1797-1807. Date of Electronic Publication: 2018 Apr 26. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenosine Triphosphatases genetics
Cell Line
Chromatin genetics
Clustered Regularly Interspaced Short Palindromic Repeats genetics
HEK293 Cells
Humans
Muscle Cells pathology
Muscle Fibers, Skeletal physiology
Muscle, Skeletal physiology
Promoter Regions, Genetic genetics
Transcription, Genetic genetics
Epigenesis, Genetic genetics
Homeodomain Proteins genetics
Muscular Dystrophy, Facioscapulohumeral genetics
Muscular Dystrophy, Facioscapulohumeral therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 26
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 29759937
- Full Text :
- https://doi.org/10.1016/j.ymthe.2018.04.019