Chromatin acetylation at transcription start sites and vitamin D receptor binding regions relates to effects of 1 alpha,25-dihydroxyvitamin D-3 and histone deacetylase inhibitors on gene expression

The nuclear hormone 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3 or 1,25D) regulates its target genes via activation of the transcription factor vitamin D receptor (VDR) far more specifically than the chromatin modifier trichostatin A (TsA) via its inhibitory action on histone deacetylases. We selected the thrombomodulin gene locus with its complex pattern of five VDR binding sites and multiple histone acetylation and open chromatin regions as an example to investigate together with a number of reference genes, the primary transcriptional responses to 1 alpha,25(OH)(2)D-3 and TsA. Transcriptome-wide, 18.4% of all expressed genes are either up-or down-regulated already after a 90 min TsA treatment; their response pattern to 1 alpha,25(OH)(2)D-3 and TsA sorts them into at least six classes. TsA stimulates a far higher number of genes than 1 alpha,25(OH)(2)D-3 and dominates the outcome of combined treatments. However, 200 TsA target genes can be modulated by 1 alpha,25(OH)(2)D-3 and more than 1000 genes respond only when treated with both compounds. The genomic view on the genes suggests that the degree of acetylation at transcription start sites and VDR binding regions may determine the effect of TsA on mRNA expression and its interference with 1 alpha,25(OH)(2)D-3. Our findings hold true also for other HDAC inhibitors and may have implications on dual therapies using chromatin modifiers and nuclear receptor ligands.