calcitriol and Leukemia--Monocytic--Acute

The signaling cascade of the transcription factor vitamin D receptor (VDR) is triggered by its specific ligand 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). In this study we demonstrate that in THP-1 human monocytic leukemia cells 87.4% of the 1034 most prominent genome-wide VDR binding sites co-localize with loci of open chromatin. At 165 of them 1α,25(OH)2D3 strongly increases chromatin accessibility and has at further 217 sites weaker effects. Interestingly, VDR binding sites in 1α,25(OH)2D3-responsive chromatin regions are far more often composed of direct repeats with 3 intervening nucleotides (DR3s) than those in ligand insensitive regions. DR3-containing VDR sites are enriched in the neighborhood of genes that are involved in controling cellular growth, while non-DR3 VDR binding is often found close to genes related to immunity. At the example of six early VDR target genes we show that the slope of their 1α,25(OH)2D3-induced transcription correlates with the basal chromatin accessibility of their major VDR binding regions. However, the chromatin loci controlling these genes are indistinguishable in their VDR association kinetics. Taken together, ligand responsive chromatin loci represent dynamically regulated contact points of VDR with the genome, from where it controls early 1α,25(OH)2D3 target genes.

Topics: Acetylation; Blotting, Western; Chromatin; Chromatin Immunoprecipitation; Fanconi Anemia Complementation Group E Protein; Heparin-binding EGF-like Growth Factor; Histone Deacetylase Inhibitors; Humans; Intercellular Signaling Peptides and Proteins; Leukemia, Monocytic, Acute; Lipopolysaccharide Receptors; NF-kappa B p50 Subunit; Programmed Cell Death 1 Ligand 2 Protein; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol; Repetitive Sequences, Nucleic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Vitamin D