Investigating the role and regulation of histone deacetylase 1 (HDAC1) in glucocorticoid-potentiated preadipocyte differentiation

Abstract

Corticosteroids promote central obesity in humans and enhance the efficiency of preadipocyte differentiation in culture. The glucocorticoid receptor(GR) stimulates preadipocyte differentiation, in part, by enhancing transcription of the adipogenic commitment factor C/EBPalpha. GR is hypothesized to enhance C/ebpalpha transcription through a mechanism that involves promoting the titration, and subsequent degradation, of the co-repressor histone deacetylase 1(HDAC1) from the C/EBPalpha promoter. The first section of this investigation demonstrates that HDAC1, and not HDAC2 is involved in suppressing GR-potentiated preadipocyte differentiation and that the ability of HDAC1 to inhibit the adipogenic program is dependent on its deacetylase activity. Furthermore, the results imply that additional inhibitors assist HDAC1 in actively suppressing C/ebpalpha transcription in the absence of corticosteroids, as well as indicating that HDAC1 likely has supplementary deacetylation targets at the C/EBPalpha promoter, in addition to K98,101 and 102 of C/EBPbeta. Finally, we demonstrate that D181A HDAC1 is a catalytically compromised, dominant negative mutant of HDAC1. In the second section of this investigation we provide evidence that, contrary to published results, acetylation of HDAC1 at lysine residues 218, 220, 432, 438, 439 and 441 does not inactivate the deacetylase activity of the enzyme. However, we propose a new hypothesis which reconciles our results with the published findings: Alterations in the acetylation status of the six identified lysine residues of HDAC1 regulate the substrate specificity of the enzyme, rather than its catalytic activity.