The impact of the vitamin D-modulated epigenome on VDR target gene regulation.

The micronutrient vitamin D significantly modulates the human epigenome via enhancing genome-wide the rate of accessible chromatin and vitamin D receptor (VDR) binding. This study focuses on histone marks of active chromatin at promoter and enhancer regions and investigates, whether these genomic loci are sensitive to vitamin D. The epigenome of THP-1 human monocytes contains nearly 23,000 sites with H3K4me3 histone modifications, 550 of which sites are significantly (p < 0.05) modulated by stimulation with the VDR ligand 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). H3K27ac histone modifications mark active chromatin and 2473 of 45,500 sites are vitamin D sensitive. The two types of ligand-dependent histone marks allow to distinguish promoter and enhancer regulation by vitamin D, respectively. Transcription start site overlap is the prime attribute of ligand-dependent H3K4me3 marks, while VDR co-location is the top ranking parameter describing 1,25(OH)2D3-sensitive H3K27ac marks at enhancers. A categorization of 1,25(OH)2D3-sensitive histone marks by machine learning algorithms - using the attributes overall peak strength and ligand inducibility - highlights 260 and 287 regions with H3K4me3 and H3K27ac modifications, respectively. These loci are found at the promoter regions of 59 vitamin D target genes and their associated enhancers. In this way, ligand-dependent histone marks provide a link of the effects of 1,25(OH)2D3 on the epigenome with previously reported mRNA expression changes of vitamin D target genes. In conclusion, the human epigenome responds also on the level of histone modifications to 1,25(OH)2D3 stimulation. This allows a more detailed understanding of vitamin D target gene regulation.