Dystroglycan, a component of the dystrophin-associated glycoprotein complex, connects the extracellular matrix and cytoskeleton to maintain muscle membrane integrity. As such, abnormalities of dystroglycan are linked to different types of muscular dystrophies. In an effort to develop therapeutic approaches to re-establish signal integration for muscle repair and homeostasis, we have previously determined that a clinically approved agonist of retinoid X receptor enhances myoblast differentiation through direct regulation of gene expression of the muscle master regulator MyoD. Using comprehensive omics and molecular analyses, we found that dystroglycan gene expression is responsive to retinoid X receptor-selective signaling in early myoblast differentiation. In addition, the dystroglycan gene is a MyoD target, and residue-specific histone acetylation coincides with the occupancy of histone acetyltransferase p300 at the MyoD binding sites. Consequently, the p300 function is important for rexinoid-augmented dystroglycan gene expression. Finally, dystroglycan plays a role in myoblast differentiation. Our study sheds new light on dystroglycan regulation and function in myoblast differentiation and presents a potential avenue for re-establishing signal integration of a specific chromatin state pharmacologically to overcome muscle pathology and identify additional myogenic interactions for therapeutic applications.