Histone acetyltransferase inhibition rescues differentiation of emerin‐deficient myogenic progenitors

• Published in: Muscle & nerve Vol. 62; no. 1; pp. 128 - 136
• Main Authors: Bossone, Katherine A., Ellis, Joseph A., Holaska, James M.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2020; Wiley Subscription Services, Inc
• Subjects: Acetylation; Adenine; Animals; Cell Differentiation - drug effects; Cell Differentiation - physiology; cell signaling; Cells, Cultured; Conduction; Differentiation; Dystrophy; emerin; Emery‐Dreifuss muscular dystrophy; Histone acetyltransferase; Histone Acetyltransferases - antagonists & inhibitors; Histone Acetyltransferases - metabolism; Histone deacetylase; Histones; Lysine; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Muscular dystrophy; Muscular Dystrophy, Emery-Dreifuss - drug therapy; Muscular Dystrophy, Emery-Dreifuss - pathology; Musculoskeletal system; Mutation; myogenic differentiation; NAD; Nicotinamide; Nicotinamide adenine dinucleotide; SIRT1 protein; Skeletal muscle; Stem Cells - drug effects; Stem Cells - pathology; Thiazoles - pharmacology; Thiazoles - therapeutic use; emerin; Emery-Dreifuss muscular dystrophy; myogenic differentiation; cell signaling
• ISSN: 0148-639X; 1097-4598
• DOI: 10.1002/mus.26892

Introduction Emery‐Dreifuss muscular dystrophy (EDMD) is a disease characterized by skeletal muscle wasting, major tendon contractures, and cardiac conduction defects. Mutations in the gene encoding emerin cause EDMD1. Our previous studies suggested that emerin activation of histone deacetylase 3 (HDAC3) to reduce histone 4‐lysine 5 (H4K5) acetylation (ac) is important for myogenic differentiation. Methods Pharmacological inhibitors (Nu9056, L002) of histone acetyltransferases targeting acetylated H4K5 were used to test whether increased acetylated H4K5 was responsible for the impaired differentiation seen in emerin‐deficient myogenic progenitors. Results Nu9056 and L002 rescued impaired differentiation in emerin deficiency. SRT1720, which inhibits the nicotinamide adenine dinucleotide (NAD)+‐dependent deacetylase sirtuin 1 (SIRT1), failed to rescue myotube formation. Discussion We conclude that emerin regulation of HDAC3 activity to affect H4K5 acetylation dynamics is important for myogenic differentiation. Targeting H4K5ac dynamics represents a potential new strategy for ameliorating the skeletal muscle wasting seen in EDMD1.