STEROID-RECEPTOR INDUCTION OF GENE-TRANSCRIPTION - A 2-STEP MODEL

Coactivators, such as steroid receptor coactivator 1 (SRC-1A) and CREB (cAMP response element binding protein)-binding protein (CBP), are re quired for efficient steroid receptor transactivation. Using an in vit ro transcription assay, we found that progesterone receptor (PR)-drive n transcription is inhibited by a dominant negative PR ligand-binding domain-interacting region of SRC-1A, indicating that SRC-1A is require d for actual transcriptional processes, In addition, these coactivator s also possess intrinsic histone acetyltransferase (HAT) activity and bind to each other and another HAT, p300/CBP-associated factor. Here w e show that the human PR also interacts with p300/CBP-associated facto r in vitro. Recruitment of multiple HATs to target promoters suggests an important role for chromatin remodeling in transcriptional activati on of genes by steroid receptors. In transient transfection assays, we found that addition of a histone deacetylase inhibitor, trichostatin A, strongly potentiated PR-driven transcription, In contrast, directin g histone deacetylase-1 (HD1) to a promoter using the GAL4 DNA binding domain inhibited transcription, Furthermore, PR transactivation was r epressed by recruiting HD1 into the PR-DNA complex by fusing HD1 to a PR ligand-binding domain-interacting portion of SRC-1, Collectively, t hese results suggest that targeted histone acetylation by recruited HA T cofactors and histone deacetylation are important factors affecting PR transactivation. Recruitment of coactivators and HATs by the ligand ed PR in vivo may result in (i) remodeling of transcriptionally repres sed chromatin to facilitate assembly and (ii) enhanced stabilization o f the preinitiation complex by the activation functions of coactivator s and the liganded PR itself.