Emerin loss of function inhibits MyoD-driven differentiation of human iPSCs into skeletal myotubes

Loss of function of the nuclear lamina-associated protein emerin causes Emery-Dreifuss muscular dystrophy (EDMD). Efforts to define emerin's essential functions in skeletal muscle have been limited by poor concordance between mouse models and human disease phenotypes. Here, we adapt transgene-driven differentiation of human induced pluripotent stem cells (hiPSCs) into skeletal muscle (iSMs) as a tractable human model for emerin loss of function. We find that EMD knockout (KO) hiPSCs are poorly responsive to combined overexpression of MyoD and Baf60c and produce fewer mature iSMs, indicating that emerin influences muscle differentiation downstream of these differentiation factors. While MyoD acetylation and heterodimerization with E-box proteins are unaffected by emerin loss, MyoD targets including p21 and myogenin are downregulated, and EMD KO cells exhibit impaired cell cycle exit in response to differentiation signals. Transcriptomic analysis of EMD KO iSMs revealed persistent expression of cell cycle genes and decreased expression of terminal muscle differentiation genes. Dysregulated genes do not overlap with lamina-associated domains (LADs) but are instead enriched for targets of polycomb repressive complex 2 (PRC2), which deposits H3K27 trimethylation. Altogether, our data indicate a functional overlap between emerin and PRC2-mediated regulation of terminal muscle differentiation.