Temporal stratification of promoter-proximal versus enhancer VDR binding directs vitamin D-responsive transcription.
Level 5 - mechanism / opinion, no new human data
In vitro laboratory study in a human cell line
PubMed 42071256 · doi:10.1186/s13072-026-00677-y
What was done
Human THP-1 monocytic cells were stimulated with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) across a time course of 40 minutes, 4 hours, 8 hours, and 24 hours. The authors performed time-resolved VDR ChIP-seq integrated with matched transcriptome profiling to characterize VDR binding dynamics and downstream transcription. Gene targets were classified as promoter-proximal versus enhancer-dominated architectures using distance- and topologically associated domain-informed genomic assignments.
What was found
Time-resolved ChIP-seq identified >22,000 total VDR binding sites, including >5,100 ligand-inducible sites that expanded over 24 hours. Early vitamin D target genes were characterized by direct promoter-proximal VDR binding at transcription start sites, higher basal expression, and greater transcriptional responsiveness. Late-responsive target genes were predominantly associated with distal enhancers or lacked direct assignable VDR binding.
Why it matters
This study defines a temporal hierarchy for vitamin D signaling in monocytes, showing that rapid core responses rely on promoter-proximal VDR binding while late transcriptional diversification is driven by distal enhancers and indirect mechanisms.
Limits
The findings are derived solely from an in vitro human monocytic cell line (THP-1) and may not fully represent primary human immune cells in vivo. Specific gene counts, statistical fold-changes, and functional validation (such as targeted enhancer perturbations) are not detailed in the abstract.
Cited by
- supports Vitamin D response elements are present in more than 5% of the protein-encoding human genome.