Epigenomics of vitamin D

Since some 30 years Carsten Carlberg is investigating the role of the transcription factor vitamin D receptor (VDR), its ligand 1,25(OH)2D3 and their primary target genes. This resulted in some 160 original publications and some 50 review articles. Some 10 years ago the interests focused on the function of vitamin D in human hematopoietic cells, such as 1,25(OH)2D3 -stimulated THP-1 human monocytic leukemia cells and peripheral blood mononuclear cells (PBMCs) isolated from human donors that received a vitamin D3 bolus.

Recently, the team investigated in THP-1 cells the role of pioneer transcription factors, such as PU.1, on vitamin D signaling and described how VDR and its ligand influences topologically associated domains (TADs), via affecting the binding of the chromatin organizer CTCF. This resulted in the chromatin model of vitamin D signaling, which is based on the team’s high quality genome-wide data on time-dependent VDR binding, PU.1 and CTCF binding, chromatin opening and the transcriptome. This chromatin model explains the response of some 300 primary vitamin D target genes, many of which have a key role in cellular metabolism, such as glycolysis.

The key to the understanding of the pleiotropic action of vitamin D is the spatio-temporal VDR binding profile. We challenged this model with PBMCs of healthy donors in the short-term vitamin D intervention study VitDbol (NCT02063334). This allowed extrapolating insight in vitamin D signaling from in vitro to in vivo. The study subjects showed a personalized response to vitamin D and could be distinguished into high, mid and low responders and led to the concept of a personalized vitamin D response index. The latter is of high impact in Nordic countries, where seasonal deficiency in sunlight exposure leads to largely insufficient vitamin D levels in winter times. In conclusion, vitamin D and its metabolites have a direct effect on the human epigenome and transcriptome and affect the expression of a large variation of target genes, many of which relate to cellular energy homeostasis and other physiological processes.