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

Molecular Therapy : the Journal of the American Society of Gene Therapy
Charis L HimedaPeter L Jones

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 th...Continue Reading

Citations

Feb 23, 2020·Clinical Genetics·Anna GrecoSilvère M van der Maarel
Aug 1, 2020·Journal of Personalized Medicine·Eva SidlauskaiteJulie Dumonceaux
Aug 17, 2020·Current Opinion in Neurology·Linde F BouwmanJessica C de Greef
Apr 25, 2019·Annual Review of Genomics and Human Genetics·Charis L Himeda, Peter L Jones
Aug 9, 2019·Journal of Muscle Research and Cell Motility·Amber L Mueller, Robert J Bloch
Sep 11, 2020·Journal of Clinical Medicine·Laura Le GallJulie Dumonceaux
Oct 7, 2020·Nature Reviews. Drug Discovery·Navneet Matharu, Nadav Ahituv
Jan 30, 2021·Molecular Therapy. Methods & Clinical Development·Charis L HimedaPeter L Jones
Nov 12, 2020·Disease Models & Mechanisms·Alec M DeSimoneAngela Lek
Nov 7, 2020·Epigenomics·Fabio Coppedè
Mar 30, 2021·Frontiers in Pharmacology·Kenji Rowel Q Lim, Toshifumi Yokota
Jun 9, 2019·Trends in Cancer·Carla DibYegor S Vassetzky

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Methods Mentioned

BETA
gene knockdown
immunoprecipitation
ChIP

Software Mentioned

R

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