Department of Biosciences, University of Eastern Finland, FIN-70210 Kuopio, Finland.
Nucleic Acids Res. 2011 Nov;39(21):9181-93. doi: 10.1093/nar/gkr654. Epub 2011 Aug 16.
A global understanding of the actions of the nuclear hormone 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) and its vitamin D receptor (VDR) requires a genome-wide analysis of VDR binding sites. In THP-1 human monocytic leukemia cells we identified by ChIP-seq 2340 VDR binding locations, of which 1171 and 520 occurred uniquely with and without 1α,25(OH)(2)D(3) treatment, respectively, while 649 were common. De novo identified direct repeat spaced by 3 nucleotides (DR3)-type response elements (REs) were strongly associated with the ligand-responsiveness of VDR occupation. Only 20% of the VDR peaks diminishing most after ligand treatment have a DR3-type RE, in contrast to 90% for the most growing peaks. Ligand treatment revealed 638 1α,25(OH)(2)D(3) target genes enriched in gene ontology categories associated with immunity and signaling. From the 408 upregulated genes, 72% showed VDR binding within 400 kb of their transcription start sites (TSSs), while this applied only for 43% of the 230 downregulated genes. The VDR loci showed considerable variation in gene regulatory scenarios ranging from a single VDR location near the target gene TSS to very complex clusters of multiple VDR locations and target genes. In conclusion, ligand binding shifts the locations of VDR occupation to DR3-type REs that surround its target genes and occur in a large variety of regulatory constellations.
要全面了解核激素 1α,25-二羟维生素 D(3)（1α,25(OH)(2)D(3)）及其维生素 D 受体（VDR）的作用，需要对 VDR 结合位点进行全基因组分析。在 THP-1 人单核白血病细胞中，我们通过 ChIP-seq 鉴定了 2340 个 VDR 结合位置，其中 1171 个和 520 个分别是在有和没有 1α,25(OH)(2)D(3)处理的情况下唯一发生的，而 649 个是共同发生的。新鉴定的直接重复间隔 3 个核苷酸（DR3）型反应元件（RE）与 VDR 占据的配体反应性密切相关。只有 20%的 VDR 峰在配体处理后大部分减少时有 DR3 型 RE，而对于增长最多的峰则为 90%。配体处理揭示了 638 个 1α,25(OH)(2)D(3)靶基因，这些基因富集在与免疫和信号转导相关的基因本体类别中。在 408 个上调基因中，有 72%的基因在其转录起始位点（TSS）的 400 kb 范围内显示出 VDR 结合，而在 230 个下调基因中，这一比例仅为 43%。VDR 基因座在基因调控场景中表现出相当大的变化，从靶基因 TSS 附近的单个 VDR 位置到多个 VDR 位置和靶基因的非常复杂的簇。总之，配体结合将 VDR 占据的位置转移到围绕其靶基因的 DR3 型 RE 上，并发生在多种调节构象中。
