Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor

摘要

Abstract The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH) 2 D 3 ). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24 h ligand stimulation comprising 11,600 genomic loci, 78% of which were detected exclusively after 24 h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios. The 1,25(OH) 2 D 3 -dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system. More than 97% of the latter genes were located within 1,25(OH) 2 D 3 -modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding. Highlights ? There are 510 persistent VDR sites in 1,25(OH) 2 D 3 -stimulated THP-1 cells. ? 311 of 587 vitamin D target genes are primary. ? 97% of the primary vitamin D target genes are located within 1,25(OH) 2 D 3 -modulated TADs. ? There are TAD classes carrying vitamin D target genes involved in distinct biological processes.