Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-86032-5
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Funding
- Projekt DEAL
- Deutsche Forschungsgemeinschaft [437173059, SFB1039 TPA01, EXS2026]
- DZHK
- Goethe University, Frankfurt
- Academy of Finland [267067]
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This study demonstrated the essential role of VDR in mediating the genome-wide transcriptional effects of 1,25(OH)(2)D-3. Predicted primary VDR target genes play a crucial role in the complex vitamin D signaling cascade, with potential mediation of secondary responses by transcription factors.
The transcription factor vitamin D receptor (VDR) is the high affinity nuclear target of the biologically active form of vitamin D-3 (1,25(OH)(2)D-3). In order to identify pure genomic transcriptional effects of 1,25(OH)(2)D-3, we used VDR cistrome, transcriptome and open chromatin data, obtained from the human monocytic cell line THP-1, for a novel hierarchical analysis applying three bioinformatics approaches. We predicted 75.6% of all early 1,25(OH)(2)D-3-responding (2.5 or 4 h) and 57.4% of the late differentially expressed genes (24 h) to be primary VDR target genes. VDR knockout led to a complete loss of 1,25(OH)(2)D-3-induced genome-wide gene regulation. Thus, there was no indication of any VDR-independent non-genomic actions of 1,25(OH)(2)D-3 modulating its transcriptional response. Among the predicted primary VDR target genes, 47 were coding for transcription factors and thus may mediate secondary 1,25(OH)(2)D-3 responses. CEBPA and ETS1 ChIP-seq data and RNA-seq following CEBPA knockdown were used to validate the predicted regulation of secondary vitamin D target genes by both transcription factors. In conclusion, a directional network containing 47 partly novel primary VDR target transcription factors describes secondary responses in a highly complex vitamin D signaling cascade. The central transcription factor VDR is indispensable for all transcriptome-wide effects of the nuclear hormone.
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