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bioRxiv · 10.1101/2025.11.14.688535

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

Yi, M.·Montague Redecke, S. G.·Wang, T.·Bell-Hensley, A.·Li, S.·Massri, A. J.·Jukic, A. M. Z.·DeMayo, F. J.
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Abstract

Identifying the factors that regulate female reproduction is crucial to understanding how the environment affects female reproductive health. The vitamin D receptor (VDR) and its ligands (primarily 1,25(OH)2D3) have a recognized role in calcium homeostasis; however, their broader impact on female reproduction remains underexplored. We demonstrate that the VDR and its ligands are involved in the hormonal induction of uterine decidualization. Mice fed a vitamin D-deficient diet displayed an impaired hormonally induced decidual response. In a human telomerase reverse transcriptase-immortalized human endometrial stromal cell line (T-HESC), VDR decreased during in vitro decidualization. Small interfering RNA (siRNA) knockdown of VDR in T-HESC enhanced in vitro decidualization, while overexpression of VDR inhibited it. Chromatin accessibility and histone modification analyses revealed that VDR functions as a chromatin regulator, restricting accessibility and repressing transcription in specific genomic regions. Transcriptomic analyses confirmed that VDR broadly modulates gene expression, with most ligand-mediated effects occurring through the VDR. These findings identify VDR as a key regulator of transcriptional and chromatin landscapes in human 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 and reduced fertility. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/688535v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@6b048org.highwire.dtl.DTLVardef@11f7b4corg.highwire.dtl.DTLVardef@1d7dbfaorg.highwire.dtl.DTLVardef@ab3894_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Yi, M., Montague Redecke, S. G., Wang, T., Bell-Hensley, A., Li, S., Massri, A. J., Jukic, A. M. Z., DeMayo, F. J.. 2025-11-15. Impact of vitamin D deficiency on defective endometrial decidualization and the repressive role of vitamin D receptor (VDR) in the epigenomic network. https://doi.org/10.1101/2025.11.14.688535

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