The SRCAP chromatin-remodelling complex component p18 hamlet mediates p38α- induced myogenic gene expression
Author
Corrado, NadiaAdvisor
Rodríguez Nebreda, Manuel AngelEntity
UAM. Departamento de Biología MolecularDate
2008-07-17Subjects
Apoptosis-Tesis doctorales; Oncología-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17-07-2008Abstract
The stress-activated kinase p38α regulates several cellular processes, including cell
proliferation, differentiation and apoptosis. We have recently identified a new protein,
named Zn-HIT1 or p18Hamlet, which plays an important role in transcriptional
activation downstream of p38α 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 this protein in skeletal myogenesis, a process in which p38α plays a key role in the
regulation of muscle-specific gene transcription. 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 levels increase early in the process of muscle differentiation. We also found
by ChIP analysis that p18Hamlet is recruited to myogenic promoters in a p38α-
dependent manner. These results suggest that p18Hamlet might be directly involved in
the triggering events of muscle-specific gene expression. Interestingly, downregulation
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 downregulation.
Therefore, both the H2A.Z histone variant and the SRCAP histone
exchange complex are essential for myogenesis. Over-expression of the SRCAP
subunit p18Hamlet is sufficient to induce muscle-specific gene expression in C2C12
cells. Moreover, p18Hamlet concentrates at the TATA-box region of the myogenin
promoter in a p38 MAPK-dependent manner. Histone H2A.Z also accumulates in the
TATA-box region of myogenin during muscle differentiation and this accumulation
requires p18Hamlet, strongly suggesting a role of this protein on H2A.Z exchange in
8
vivo. Altogether, these data demonstrate an important role for histone H2A.Z
exchange in muscle differentiation and establish a new mechanism by which p38
MAPK, through the regulation of p18Hamlet levels, ensures the changes in chromatin
structure necessary for the transcriptional events that characterize the muscle-specificgene expression program.
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