Skeletal muscle has an extraordinary ability to regenerate, but this process declines sharply with age and disease, leading to weakness and frailty. A major challenge is that the genetic programs driving muscle growth and repair become locked in inactive states over time. With support from an ISCRM fellowship, Caleb Kono is developing new ways to reawaken these programs by directly rewriting the epigenetic instructions that control them. Specifically, he is engineering CRISPR-based “Epibinders” that recruit the cell’s own chromatin machinery—such as the DNA methyltransferase DNMT3A—to precisely turn genes off or on without introducing foreign enzymes. By pairing these systems to repress anti-myogenic genes and activate pro-myogenic ones, his work aims to enhance the efficiency of stem cell and fibroblast differentiation into mature muscle. Ultimately, this research seeks to establish a new framework for stable, programmable gene regulation that can drive more effective regenerative therapies.