Transcriptomics

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Coactivator-independent vitamin D receptor signaling impairs intestinal calcium transport in mice, leading to severe rickets, which is not prevented by a diet high in calcium, phosphate, and lactose.


ABSTRACT: The vitamin D receptor (VDR) plays a critical role in the regulation of mineral and bone homeostasis. Upon binding of 1α,25-dihydroxyvitamin D3 to the VDR, the activation function 2 (AF2) domain repositions and recruits coactivators for the assembly of the transcriptional machinery required for gene transcription. In contrast to coactivator-induced transcriptional activation, the functional effects of coactivator-independent VDR signaling remain unclear. In humans, mutations in the AF2 domain are associated with hereditary vitamin D-resistant rickets, a genetic disorder characterized by impaired bone mineralization and growth. In the present study, we used mice with a systemic or conditional deletion of the VDR-AF2 domain (VdrΔAF2) to study coactivator-independent VDR signaling. We confirm that ligand-induced transcriptional activation was disabled because the mutant VDRΔAF2 protein was unable to interact with coactivators. Systemic VdrΔAF2 mice developed short, undermineralized bones with enlarged growth plates, a bone phenotype that was more pronounced than that of systemic Vdr knockout (Vdr-/-) mice. Interestingly, a rescue diet that is high in calcium, phosphate, and lactose, normalized this phenotype in Vdr-/-, but not in VdrΔAF2 mice. Our findings in osteoblast- and osteoclast-specific VdrΔAF2 mice did not recapitulate this bone phenotype indicating coactivator-independent VDR effects are more important in other organs. On the other hand, RNA-seq analysis of duodenum and kidney revealed a repression of VDR target genes in systemic VdrΔAF2 mice, which was not observed in Vdr-/- mice. These genes could provide new insights in the compensaory (re)absorption of minerals that are crucial for bone homeostasis. In summary, coactivator-independent VDR effects contribute to mineral and bone homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE260988 | GEO | 2024/03/20

REPOSITORIES: GEO

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