Transcriptional profiling of EDMD-causing emerin mutant myogenic progenitors identified pathways implicated in impaired myogenic differentiation


Muscle Regeneration in Disease (includes satellite cells)

Poster Number: 107


James Holaska, PhD, Ashvin Iyer


1. Cooper Medical School of Rowan University, 2. Cooper Medical School of Rowan University

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. Emerin is a ubiquitously expressed integral inner nuclear membrane protein. 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. We previously found 1,945 genes were differentially expressed during myogenic commitment of emerin-null (EMD-/y) myogenic progenitors. We created stable myogenic progenitors expressing WT emerin and each EDMD-causing missense emerin mutant in the EMD-/y background to refine the genes and pathways involved in the EDMD mechanism. We hypothesized similar mechanisms would be utilized by each EDMD-causing emerin mutant to impair myogenic differentiation. Thus, comparing the gene expression profiles amongst the EDMD mutants was predicted to identify molecular pathways responsible for impaired myogenic differentiation in EDMD. We first tested if the mutant progenitors exhibited impaired myogenic differentiation. Wildtype emerin expression rescued EMD-/y differentiation. All EDMD mutant myogenic progenitors failed to rescue EMD-/y differentiation. RNA sequencing was done on differentiating EMD-/y progenitors expressing WT emerin and each EDMD-causing emerin mutant (S54F, Q133H and 95-99). Approximately 100 transcripts were differentially expressed amongst all EDMD mutants and EMD-/y cells during the transition from cell cycle withdrawal to myoblast commitment. Pathway analysis narrowed the putative pathways important for differentiation defects in EDMD1 to HIPPO signaling, RAP1 signaling, ECM-receptor interactions, and proteoglycans in cancer. Small molecule inhibitors and activators will be used to further interrogate these pathways.