Abstract
The genome-wide analysis of the binding sites of the transcription factor vitamin D receptor (VDR) is essential for a global appreciation the physiological impact of the nuclear hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Genome-wide analysis of lipopolysaccharide (LPS)-polarized THP-1 human monocytic leukemia cells via chromatin immunoprecipitation sequencing (ChIP-seq) resulted in 1,318 high-confidence VDR binding sites, of which 789 and 364 occurred uniquely with and without 1,25(OH)2D3 stimulation, while only 165 were common. We re-analyzed five public VDR ChIP-seq datasets with identical peak calling settings (MACS, version 2) and found, using a novel consensus summit identification strategy, in total 23,409 non-overlapping VDR binding sites, 75% of which are unique within the six analyzed cellular models. LPS-differentiated THP-1 cells have 22% more genomic VDR locations than undifferentiated cells and both cell types display more overlap in their VDR locations than the other investigated cell types. In general, the intersection of VDR binding profiles of ligand-stimulated cells is higher than those of unstimulated cells. De novo binding site searches and HOMER screening for binding motifs formed by direct repeats spaced by three nucleotides (DR3) suggest for all six VDR ChIP-seq datasets that these sequences are found preferentially at highly ligand responsive VDR loci. Importantly, all VDR ChIP-seq datasets display the same relationship between the VDR occupancy and the percentage of DR3-type sequences below the peak summits. The comparative analysis of six VDR ChIP-seq datasets demonstrated that the mechanistic basis for the action of the VDR is independent of the cell type. Only the minority of genome-wide VDR binding sites contains a DR3-type sequence. Moreover, the total number of identified VDR binding sites in each ligand-stimulated cell line inversely correlates with the percentage of peak summits with DR3 sites.
Highlights
The nuclear receptor vitamin D receptor (VDR) belongs to a transcription factor superfamily, members of which have the unique property to be directly activated by small lipophilic compounds [1]
The genome-wide location of VDR is an essential information for understanding the pleiotropic physiological action of 1,25(OH)2D3
This study represents the first meta-analysis of VDR ChIP-seq data from six different cell types and sets the basis for a compendium of all VDR binding sites genome-wide
Summary
The nuclear receptor VDR belongs to a transcription factor superfamily, members of which have the unique property to be directly activated by small lipophilic compounds [1]. The specific high-affinity ligand of VDR is the biologically most active vitamin D compound, 1,25(OH)2D3 [2]. In monocytes 1,25(OH)2D3 reduces the up-regulation of cytokines, such as tumor necrosis factor a and interleukins 1 and 6 [6,7], i.e. VDR ligands can counteract pro-inflammatory signal transduction pathways, such as that of the transcription factor NF-kB [8]. Cells of the hematopoietic system, such as monocytes and macrophages, are important targets of 1,25(OH)2D3 [9], in which, for example, the expression of anti-bacterial proteins, such as cathelicidin antimicrobial peptide (CAMP), is promoted [10]
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