EDMD-Causing Emerin Mutant Myogenic Progenitors Exhibit Impaired Differentiation Using Similar Mechanisms
Open Access
- 15 June 2020
- Vol. 9 (6), 1463
- https://doi.org/10.3390/cells9061463
Abstract
Mutations in the gene encoding emerin (EMD) cause Emery–Dreifuss muscular dystrophy (EDMD1), an inherited disorder characterized by progressive skeletal muscle wasting, irregular heart rhythms and contractures of major tendons. The skeletal muscle defects seen in EDMD are caused by failure of muscle stem cells to differentiate and regenerate the damaged muscle. However, the underlying mechanisms remain poorly understood. Most EDMD1 patients harbor nonsense mutations and have no detectable emerin protein. There are three EDMD-causing emerin mutants (S54F, Q133H, and Δ95–99) that localize correctly to the nuclear envelope and are expressed at wildtype levels. We hypothesized these emerin mutants would share in the disruption of key molecular pathways involved in myogenic differentiation. We generated myogenic progenitors expressing wildtype emerin and each EDMD1-causing emerin mutation (S54F, Q133H, Δ95–99) in an emerin-null (EMD−/y) background. S54F, Q133H, and Δ95–99 failed to rescue EMD−/y myogenic differentiation, while wildtype emerin efficiently rescued differentiation. RNA sequencing was done to identify pathways and networks important for emerin regulation of myogenic differentiation. This analysis significantly reduced the number of pathways implicated in EDMD1 muscle pathogenesis.Keywords
Funding Information
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R15AR069935)
This publication has 120 references indexed in Scilit:
- Single-Cell Dynamics of Genome-Nuclear Lamina InteractionsCell, 2013
- The Nuclear Envelope Protein Emerin Binds Directly to Histone Deacetylase 3 (HDAC3) and Activates HDAC3 ActivityPublished by Elsevier BV ,2012
- DNA Sequence-Dependent Compartmentalization and Silencing of Chromatin at the Nuclear LaminaCell, 2012
- Genome-wide MyoD Binding in Skeletal Muscle Cells: A Potential for Broad Cellular ReprogrammingDevelopmental Cell, 2010
- Emerging roles of E2Fs in cancer: an exit from cell cycle controlNature Reviews Cancer, 2009
- Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatinGenes & Development, 2008
- A novel role for the nuclear membrane protein emerin in association of the centrosome to the outer nuclear membraneThe Journal of cell biology, 2007
- An Emerin “Proteome”: Purification of Distinct Emerin-Containing Complexes from HeLa Cells Suggests Molecular Basis for Diverse Roles Including Gene Regulation, mRNA Splicing, Signaling, Mechanosensing, and Nuclear ArchitectureBiochemistry, 2007
- Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cellsNature Clinical Practice Cardiovascular Medicine, 2007
- The inner nuclear membrane protein Emerin regulates β-catenin activity by restricting its accumulation in the nucleusThe EMBO Journal, 2006