UCSF

The nuclear periphery is critical to establishing eukaryotic cell fate. The inner nuclear membrane (INM) protein emerin has been shown to play a role in cardiac and skeletal muscle development and maintenance. Mutations in the protein lead to X-linked Emery-Dreifuss Muscular Dystrophy, a degenerative disease characterized by both muscle wasting and cardiomyopathy. However, emerin-null mice do not develop muscular dystrophy phenotypes, making in vivo murine models impractical. To gain insight into emerin’s functions in human cardiac and skeletal muscle, we need a tractable human model system. Here, we have adapted an induced skeletal muscle (iSM) model system to efficiently direct skeletal muscle differentiation from human induced pluripotent stem cells (hiPSCs).Chapter 1 provides an overview of the nuclear periphery, skeletal muscle development, and current understanding of emerin function. Chapter 2 describes the use of iSMs to define the role of emerin in myogenesis. Chapter 3 summarizes experiments investigating the mechanism by which emerin regulates the Wnt effector β-catenin. Lastly, Chapter 4 highlights the challenges of using combinatorial CRISPR screening to investigate redundancy among LEM family proteins. This work establishes emerin’s requirement during late myogenesis as well as the consequences of its loss in gene regulation and expression.