Androgen and glucocorticoid receptor mediated changes in histone acetylation at the MMTV promoter

Abstract

Post-translational modifications of histones play an important role in regulation of gene transcription. The most well studied histone modification is acetylation that is regulated by the enzymatic activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs). Histone acetylation has generally been associated with transcriptional activation and deacetylation with repression. However, there are a number of genes for which activation is associated with deacetylation. Previous results from our laboratory show that increased histone acetylation induced by the HDAC inhibitor Trichostatin A (TSA) reduced androgen receptor (AR) mobility at the mouse mammary tumor virus (MMTV) promoter, concomitant with an increase in transcriptional activity. The effect of TSA was specific to AR as the dynamics and transcriptional activity of the glucocorticod receptor (GR), another ligand-regulated transcription factor of the steroid receptor family, was not affected by TSA. These data further demonstrated that histone acetylation does not always induce transcription, but is dependent on promoter and transcription factor context. In this study, the impact of TSA on the acetylation level of histones H3 and H4 at the MMTV promoter during AR- and GR-mediated transcriptional activation was investigated. Chromatin immunoprecipitation (ChIP) analysis revealed no significant change in histone acetylation at the MMTV promoter following TSA treatment, even though global levels of histone acetylation were greatly increased. Furthermore, global acetylation of histones occurred independently of the presence of androgen or glucocorticoid. These results demonstrate that although TSA treatment induces a global increase in histone acetylation, specific locations of the genome, such as the MMTV promoter may be relatively unaffected. Interestingly, androgen treatment resulted in a decrease in the basal histone H3 acetylation level at the MMTV promoter. Preliminary studies suggest a different acetylation profile of histone H3 in the presence of GR compared to AR. However, additional studies are necessarry to reveal the details of histone acetylation during AR- and GR-mediated transcriptional activation.