RNA-seq profiling of rexinoid responsive gene expression during early myogenic differentiation

While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor, promotes the specification and differentiation of skeletal muscle lineage. Here, we examine a genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between retinoid X receptor signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation. Overall design: We have profiled the global effect of bexarotene, a selective agonist of retinoid X receptor on myoblast gene expression by RNA-seq analysis using RNA isolated from C2C12 myoblasts following 12 or 24 hours of differentiation in the presence and absence of 50 nM bexarotene, with 2 biological replicates. Proliferating myoblasts were used as controls.