Resumen de The srcap chromatin-remodelling complex component p 18hamlet mediates p38alpha-induced myogenic gene expression
p18Hamlet is a new identified p38alpha MAPK substrate which plays an important role in transcriptional activation dowstream p38alpha during p53-induced apoptosis. This protein is an essential component of the chromatin-remodelling complex SRCAP (SNF2-related CBP Activator Protein), which regulates the exchange of histone H2A for the H2A.Z variant, suggesting that p18Hamlet might have a general role in transcriptional regulation via chromatin remodelling. We have investigated the possible implication of p18Hamlet in skeletal myogenesis, a process where p38alpha is known to play an important role regulating the transcription of muscle-specific genes. Using as a model C2C12 murine myoblasts, we found that p18Hamlet down-regulation inhibits both muscle specific gene expression and the formation of multinucleated muscle fibers. Moreover, p18Hamlet protein increase early in the process of muscle differentiation. We also found by ChIP analysis that p18Hamlet is recruited to myogenic promoters in a p38alpha-dependent manner. Interestingly, down-regulation of either YL-1, or histone H2A.Z, other subunits of the SRCAP complex, both result in impaired muscle gene transcription, as in the case of p18Hamlet down-regulation.
We propose that the p38alpha-induced recruitment of p18Hamlet to myogenic promoters plays a key role in the transcription of muscle-specific genes, probably involving the SRCAP chromatin-remodelling complex.
