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

Abstract

Preadipocyte differentiation in culture is driven by an insulin and cAMP dependant transcriptional cascade which induces the bzip transcription factors C/EBPbeta and C/EBPdelta. 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/EBPbeta. This results in a dramatic enhancement of C/EBPbeta-dependent transcription from the C/EBPalpha promoter, concomitant with potentiation of preadipocyte differentiation. Here, we show that C/EBPbeta 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/EBPbeta prevented acetylation and blocked the ability of glucocorticoids to enhance C/EBPbeta-directed transcription and to potentiate C/EBPbeta-dependent preadipocyte differentiation. Moreover, acetylation of C/EBPbeta appeared to directly interfere with the interaction of HDAC1 with C/EBPbeta, suggesting that PCAF/GCN5-dependent acetylation of C/EBPbeta serves as an important molecular switch in determining the transcriptional regulatory potential of this transcription factor.

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

“…C/EBP interacts with cofactors with HAT activities and increases the H3K27ac levels in the IGFBP-1 promoter region by cAMP stimulation in ESCs (20,26,27). Therefore, we hypothesized that C/EBP recruitment is responsible for the increase in H3K27ac levels in the IGFBP-1 enhancer region.…”

A chromatin perspective of adipogenesis

“…83 Glucocorticoids have the same effect by stimulating C/EBPb acetylation by GCN5. 84,113 High levels of PPARg and C/EBPa direct terminal differentiation. 75,76 Decrease of H3K27/H3K9 methylation is observed in adipogenic promoters, accompanied by increased histone acetylation and H3K4/ H3K20 methylation.…”

Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

“…[14][15][16] C/EBPe deficiency, demonstrated in knockout murine models, resembles the clinical phenotype of patients with neutrophil-specific granule deficiency, characterized by an increase in circulating immature neutrophils and recurrent pyogenic infections. 12,[17][18][19] As a result of differential RNA splicing and alternative translational start sites, human-C/EBPe is expressed as 4 protein isoforms (32,30,27, and 14 kDa) that represent functionally different roles during myeloid differentiation. These functional differences, transcriptional activation by C/EBPe 32/30 , transcriptional repression by C/EBPe 27 , and dominant negative regulation by C/EBPe 14 , can, at least partly, be explained by analysis of the functional domains of human-C/EBPe.…”