The ASAP2 gene is a primary target of 1,25-dihydroxyvitamin D3 in human monocytes and macrophages

A genome-wide data set on vitamin D receptor (VDR) binding sites in human THP-1 cells (monocytes) led us to the genomic region around the ASAP2 (Arf-GAP with SH3 domain, ankyrin repeat and PH domain 2) gene, whose product is involved in the regulation of vesicular transport, cellular migration and autophagy. Using ENCODE data, we demonstrated that the ASAP2 gene is flanked by conserved binding sites of the insulating transcription factor CTCF. These sites define different chromosomal domains containing the ASAP2 gene, up to six additional genes and three VDR binding sites. In human monocytes (THP-1 cells) the ASAP2 gene is more weakly expressed but more and faster inducible by the biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), than in M2-type macrophages (phorbol ester-differentiated THP-1 cells). Within the investigated genomic region, the basal mRNA expressions of the neighboring genes are comparably high in both monocytes and macrophages, but the ASAP2 gene is the only primary 1,25(OH)2D3 target. The three VDR binding sites located 54, 436 and 574 kb downstream of the ASAP2 transcription start site each carry a sequence formed by a direct repeat with three intervening nucleotides (DR3). Ligand-inducible VDR binding was confirmed to all three genomic sites in monocytes and macrophages. Taken together, the region around the ASAP2 gene is genome-wide highlighted as a special attraction point for the VDR, but the presently sole known functional consequence of the binding of VDR to three sites within this chromosomal region is that ASAP2 is a primary 1,25(OH)2D3 target gene in monocytes and macrophages. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.