Epigenetic regulation during 1,25-dihydroxyvitamin D-dependent gene transcription.

Multiple evidence accumulated over the years, demonstrates that vitamin D-dependent physiological control in vertebrates occurs primarily through the regulation of target gene transcription. In addition, there has been an increasing appreciation of the role of the chromatin organization of the genome on the ability of the active form of vitamin D, 1,25(OH)D, and its specific receptor VDR to regulate gene expression. Chromatin structure in eukaryotic cells is principally modulated through epigenetic mechanisms including, but not limited to, a wide number of post-translational modifications of histone proteins and ATP-dependent chromatin remodelers, which are operative in different tissues during response to physiological cues.

Ezh2-dependent H3K27me3 modification dynamically regulates vitamin D3-dependent epigenetic control of CYP24A1 gene expression in osteoblastic cells.

Epigenetic control is critical for the regulation of gene transcription in mammalian cells. Among the most important epigenetic mechanisms are those associated with posttranslational modifications of chromosomal histone proteins, which modulate chromatin structure and increased accessibility of promoter regulatory elements for competency to support transcription. A critical histone mark is trimethylation of histone H3 at lysine residue 27 (H3K27me3), which is mediated by Ezh2, the catalytic subunit of the polycomb group complex PRC2 to repress transcription.

Switches in histone modifications epigenetically control vitamin D3-dependent transcriptional upregulation of the CYP24A1 gene in osteoblastic cells.

In bone cells vitamin D dependent regulation of gene expression principally occurs through modulation of gene transcription. Binding of the active vitamin D metabolite, 1,25-dihydroxy vitamin D3 (1,25(OH) D ) to the vitamin D receptor (VDR) induces conformational changes in its C-terminal domain enabling competency for interaction with physiologically relevant coactivators, including SRC-1. Consequently, regulatory complexes can be assembled that support intrinsic enzymatic activities with competency to posttranslationally modify chromatin histones at target genomic sequences to epigenetically alter transcription.

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway.

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified.

Recruitment and subnuclear distribution of the regulatory machinery during 1alpha,25-dihydroxy vitamin D3-mediated transcriptional upregulation in osteoblasts.

The architectural organization of the genome and regulatory proteins within the nucleus supports gene expression in a physiologically regulated manner. In osteoblastic cells ligand activation induces a nuclear punctate distribution of the 1alpha,25-dihydroxy vitamin D3 (1alpha,25(OH)2D3) receptor (VDR) and promotes its interaction with transcriptional coactivators such as SRC-1, NCoA-62/Skip, and DRIP205. Here, we discuss evidence demonstrating that in osteoblastic cells VDR binds to the nuclear matrix fraction in a 1alpha,25(OH)2D3-dependent manner.