show Abstracthide AbstractDeciphering the molecular mechanisms underpinning myoblast differentiation is a critical step in developing the best strategy to promote muscle regeneration in patients suffering from muscle-related diseases. We have previously established that a rexinoid x receptor (RXR)-selective agonist enhances the differentiation and fusion of myoblasts through a direct regulation of MyoD expression, coupled with an augmentation of myogenin protein. Here, we found that RXR signaling modifies the chromatin state distribution of myogenin, promoting the binding preference of myogenin for poised enhancers and a distinct motif. We also found an association of myogenin with rexinoid-responsive gene expression and identified an epigenetic signature related to histone acetyltransferase p300. Moreover, RXR signaling instigates residue-specific histone acetylation at enhancers co-occupied by p300 and myogenin. Thus, genomic distribution of transcriptional regulators is an important designate for identifying novel targets as well as developing therapeutics that modulate epigenetic landscape in a selective manner to promote muscle regeneration. Overall design: ChIP-seq of myogenin, histone acetyltransferase p300, and H3K27me3 in C2C12 myoblasts differentiated for 24 hours in the absence or presence of bexarotene. Untreated differentiating myoblasts and input chromatin DNA were used as controls.