A hierarchical regulatory network analysis of the vitamin D induced transcriptome reveals novel regulators and complete VDR dependency in monocytes
- The transcription factor vitamin D receptor (VDR) is the high affinity nuclear target of the biologically active form of vitamin D3 (1,25(OH)2D3). In order to identify pure genomic transcriptional effects of 1,25(OH)2D3, 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)2D3-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)2D3–induced genome-wide gene regulation. Thus, there was no indication of any VDR-independent non-genomic actions of 1,25(OH)2D3 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)2D3 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.
Author: | Timothy WarwickORCiDGND, Marcel Holger SchulzORCiDGND, Stefan GüntherORCiD, Ralf GilsbachORCiDGND, Antonio NemeORCiD, Carsten CarlbergORCiDGND, Ralf BrandesORCiDGND, Sabine SeuterORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-636810 |
DOI: | https://doi.org/10.1038/s41598-021-86032-5 |
ISSN: | 2045-2322 |
Parent Title (English): | Scientific reports |
Publisher: | Macmillan Publishers Limited, part of Springer Nature |
Place of publication: | [London] |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2021/03/22 |
Date of first Publication: | 2021/03/22 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2022/12/27 |
Tag: | Endocrinology; Epigenetics; Gene expression; Gene regulation; Sequencing |
Volume: | 11 |
Issue: | art. 6518 |
Page Number: | 16 |
First Page: | 1 |
Last Page: | 16 |
Note: | Open Access funding enabled and organized by Projekt DEAL. This work was supported by Deutsche Forschungsgemeinschaft (project 437173059 to SS, SFB1039 TPA01 to RPB, EXS2026 “CPI – Cardiopulmonary institute”), the DZHK, the Goethe University, Frankfurt and the Academy of Finland (grant 267067 to CC). |
Institutes: | Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | ![]() |