The small chromatin-binding protein p8 coordinates the association of anti-proliferative and pro-myogenic proteins at the myogenin promoter.
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.
Sambasivan
Ramkumar
R
Centre for Cellular and Molecular Biology, Hyderabad, 500 007 India.
Cheedipudi
Sirisha
S
Pasupuleti
NagaRekha
N
Saleh
Amena
A
Pavlath
Grace K
GK
Dhawan
Jyotsna
J
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D018008:Myogenin / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; D006133:Growth Substances; D017570:MyoD Protein; D018008:Myogenin; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D019892:eIF-2 Kinase