Interplay of bromodomain and histone acetylation in the regulation of p300-dependent genes

Abstract

The bromodomain is an evolutionarily conserved motif found in many transcriptional activators including p300 which contains an intrinsic histone acetyltransferase activity and is a general coactivator for many transcription factors. One mode of bromodomain action is to serve as a binding module to recognize specific acetyl-lysine residue of histones during chromatin remodeling and transcriptional activation. The function of p300 is required for diverse sets of gene expression. However, it is not known whether the p300 bromodomain is involved in the expression of all or only subset of p300-dependent genes. In this study, we examined the impact of either a wild-type or a bromo-deficient p300 on the expression of several p300-dependant genes. The effects of histone acetylation on the expression of these genes were also assessed by targeting histone deacetylase activities with an inhibitor approach. We show that the impact of these inhibitors on the transcriptional activation of p300-dependent genes is impaired in cells containing the bromo-deficient p300, indicating that the interplay of p300 and histone acetylation in p300-dependent gene transcription requires the bromodomain. We also observed an increase in the expression of bromo-deficient p300 at the level of transcription possibly to compensate for the loss of p300 function. However, the high level of bromo-deficient p300 is not able to maintain the basal level of histone acetylation. Thus, the bromodomain is important for p300 to maintain the basal level of histone acetylation and to induce the transcriptional activation of p300-dependent genes. Nevertheless, the requirement of bromodomain and histone acetylation in p300-dependent gene transcription is determined by a gene specific manner.