The chromatin-remodelling complex SNF2-related CBP activator protein (SRCAP) regulates chromatin structure in yeast by modulating the exchange of histone H2A for the H2A.Z variant. Here, we have investigated the contribution of H2A.Z-mediated chromatin remodelling to mammalian cell differentiation reprogramming. We show that the SRCAP subunit named ZNHIT1 or p18(Hamlet), which is a substrate of p38 MAPK, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 MAPK-dependent manner. We also show that p18(Hamlet) is required for H2A.Z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. Accordingly, downregulation of several subunits or the SRCAP complex impairs muscle gene expression. These results identify SRCAP/H2A.Z-mediated chromatin remodelling as a key early event in muscle differentiation-specific gene expression. We also propose a mechanism by which p38 MAPK-mediated signals are converted into chromatin structural changes, thereby facilitating transcriptional activation during mammalian cell differentiation.