Circadian Regulation of Vitamin D Target Genes Reveals a Network Shaped by Individual Responsiveness

In humans, vitamin D₃ synthesis follows a day-night rhythm due to its UV-B-dependent production.

As part of the VitDHiD intervention study, we identified 87 in vivo vitamin D target genes with circadian expression patterns in immune cells, forming a regulatory network centered on transcription factors and membrane receptors. These genes exhibit a narrow basal expression range, with 80% downregulated upon vitamin D₃ supplementation. Clustering analysis revealed six distinct gene groups, with the two most prominent clusters driven by the transcription factor CSRNP1 (cysteine- and serine-rich nuclear protein 1) and GAS7 (growth arrest-specific 7), a known differentiation inducer. Among the 25 VitDHiD study participants, we identified two subgroups distinguished by significant differences in the responsiveness of 14 in vivo vitamin D target genes. These genes encode transcription factors like CSRNP1, as well as metabolic enzymes and transporters, including NAMPT (nicotinamide phosphoribosyltransferase), PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), and SLC2A3 (solute carrier family 2 member 3). Notably, all 14 genes possess a vitamin D receptor-binding enhancer within a reasonable distance of their transcription start site.

These findings highlight a novel link between vitamin D signaling and circadian gene regulation, with potential implications for personalized supplementation strategies.