Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5

doi:10.1073/pnas.0607378104

Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5

^‡Graduate Program in Biochemistry and
Departments of *Biochemistry, Microbiology, and Immunology and
^†Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5; and
^§Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, ON, Canada K1Y 4E9

Edited by Keith R. Yamamoto, University of California, San Francisco, CA, and approved December 23, 2006 (received for review August 24, 2006)

Abstract

Preadipocyte differentiation in culture is driven by an insulin and cAMP dependant transcriptional cascade which induces the bzip transcription factors C/EBPβ and C/EBPδ. We have previously shown that glucocorticoid treatment, which strongly potentiates this differentiation pathway, stimulates the titration of the corepressor histone deacetylase 1 (HDAC1) from C/EBPβ. This results in a dramatic enhancement of C/EBPβ-dependent transcription from the C/EBPα promoter, concomitant with potentiation of preadipocyte differentiation. Here, we show that C/EBPβ is acetylated by GCN5 and PCAF within a cluster of lysine residues between amino acids 98–102 and that this acetylation is strongly induced by glucocorticoid treatment. Arginine substitution of the lysine residues within the acetylation motif of C/EBPβ prevented acetylation and blocked the ability of glucocorticoids to enhance C/EBPβ-directed transcription and to potentiate C/EBPβ-dependent preadipocyte differentiation. Moreover, acetylation of C/EBPβ appeared to directly interfere with the interaction of HDAC1 with C/EBPβ, suggesting that PCAF/GCN5-dependent acetylation of C/EBPβ serves as an important molecular switch in determining the transcriptional regulatory potential of this transcription factor.

Footnotes

^¶To whom correspondence should be addressed. E-mail: rhache{at}ohri.ca
Author contributions: N.W.-B. and R.J.G.H. designed research; N.W.-B., H.A.S., J.J.T., and D.W. performed research; N.W.-B. and R.J.G.H. analyzed data; and N.W.-B. and R.J.G.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

C/EBP,

CCAAT/enhancer-binding protein;

PCAF,

p300/CBP-associated factor;

DEX,

dexamethasone.