Impact of vitamin D deficiency on defective endometrial decidualization and the repressive role of VDR in the epigenomic network

The identification of the factors regulating female reproduction is critical to understanding how the environment and nutrition impact female fertility and reproductive health. Vitamin D and its cognate receptor, VDR, are recognized for their role in calcium homeostasis; however, their broader impact on female reproduction remains underexplored. Here, we demonstrate that vitamin D and VDR are involved in the hormonal induction of uterine stromal cell differentiation, known as decidualization. Mice fed a vitamin D-deficient diet displayed an impaired hormonally induced decidual response. In a human endometrial stromal cell line, T-HESC, VDR decreases during decidualization. siRNA knockdown of VDR in T-HESC enhanced decidualization, while overexpression of VDR inhibited decidualization. Chromatin accessibility and histone modification analyses revealed that VDR functions as a chromatin regulator, restricting accessibility and maintaining transcriptional repression in specific genomic regions. Transcriptomic analyses confirmed that VDR broadly modulates gene expression, with most ligand-mediated effects dependent on its presence. These findings identify VDR as a key regulator of transcriptional and chromatin landscapes in endometrial stromal cells, offering novel insights into vitamin D signaling in reproduction. This study highlights the potential of targeting vitamin D pathways to treat uterine disorders associated with impaired decidualization.