Quiescent muscle progenitors called satellite cells persist in adult
skeletal muscle and, upon injury to muscle, re-enter the cell cycle and either
undergo self-renewal or differentiate to regenerate lost myofibers. Using
synchronized cultures of C2C12 myoblasts to model these divergent programs, we
show that p8 (also known as Nupr1), a G1-induced gene,
negatively regulates the cell cycle and promotes myogenic differentiation. p8
is a small chromatin protein related to the high mobility group (HMG) family
of architectural factors and binds to histone acetyltransferase p300 (p300,
also known as CBP). We confirm this interaction and show that p300-dependent
events (Myc expression, global histone acetylation and post-translational
acetylation of the myogenic regulator MyoD) are all affected in p8-knockdown
myoblasts, correlating with repression of MyoD target-gene expression and
severely defective differentiation. We report two new partners for p8 that
support a role in muscle-specific gene regulation: p68 (Ddx5), an RNA helicase
reported to bind both p300 and MyoD, and MyoD itself. We show that, similar to
MyoD and p300, p8 and p68 are located at the myogenin promoter, and that
knockdown of p8 compromises chromatin association of all four proteins. Thus,
p8 represents a new node in a chromatin regulatory network that coordinates
myogenic differentiation with cell-cycle exit