Genomic regions occupied by both RARα and VDR are involved in the convergence and cooperation of retinoid and vitamin D signaling pathways.

Abstract

Retinoic acid receptors (RARs) and the vitamin D receptor (VDR) regulate distinct but overlapping gene sets in multiple cell types. The abundance and characteristics of regulatory regions, occupied by both RARs and VDR are largely unexplored. We used global approaches (ChIP-seq, RNA-seq, and ATAC-seq) and bioinformatics tools to map and characterize common binding regions of RARα and VDR in differentiated human THP-1 cells. We found that the cistromes of ligand-activated RARα and VDR largely overlapped, and their agonists (AM580 and calcitriol) co-regulated several genes, often cooperatively. Common binding regions were frequently (but not exclusively) annotated with co-regulated genes and exhibited increased MED1 occupancy upon ligand stimulation, suggesting their involvement in gene regulation. Chromatin accessibility was typically higher in the common regions than in regions occupied exclusively by RARα or VDR. DNA response elements for RARα (DR1/2/5) and VDR (DR3) were enriched in the common regions, albeit the co-occurrence of the two types of canonical motifs was low (8.4%), suggesting that "degenerate" DR1/2/5 and DR3 motifs or other sequences could mediate the binding. In summary, common binding regions of RARα and VDR are at the crossroads of the retinoid and vitamin D pathways, playing important roles in their convergence and cooperation.