Inhibition of histone deacetylase activity causes cell type-specific induction of the PDGF-B promoter only in the absence of activation by its enhancer

There is a strong correlation between the acetylation status of nucleosomal histones and transcriptional activity. Here we show that the histone deace tylase inhibitor trichostatin A (TSA) activates reporter gene constructs dr iven by the human platelet-derived growth factor B (PDGF-B) gene promoter. This activation showed an inverse correlation with the cell type-specific t ranscriptional activities of the promoter. The TSA response was minimal in three tumor cell lines that exhibit high-level promoter activity. In JEG-3 choriocarcinoma cells, however, where the basal promoter activity is consid erably lower, there was a strong response to TSA. This was in contrast to c onstructs that included a PDGF-B enhancer, which were refractory to TSA eff ects, indicating a possible function of the enhancer in modulating acetylat ion status. Analysis of PDGF-B promoter mutants with respect to TSA inducti on revealed no specific TSA-responsive element, but suggested that associat ion of nonacetylated histones to the PDGF-B promoter may be a default proce ss in the absence of enhancer activation. TSA treatment of JEG-3 cells, eit her alone or in combination with the demethylating agent 5-azacytidine, fai led to activate the silenced endogenous PDGF-B transcript, however, which a ppears to be repressed by additional mechanisms. (C) 2001 Academic Press.