VDR ChIP-seq in human monocytic THP-1 cell line. Homo sapiens

Treatment with calcitriol, a specific VDR agonist, augmented the heterodimerization between VDR and RXR. We also wanted to investigate its impact on VDR binding to genomic regions. ChIP-seq experiments were carried out with the human monocytic THP-1 cell line under either vehicle (1:1 DMSO-ethanol) or calcitriol (100 nM) treatment conditions. Our finding is that calcitriol may have both a stimulatory or an inhibitory effect on VDR binding depending on the presence of its specific response element (VDRE), a less specific nuclear receptor (NR) half-site or absence thereof ("None"). Upon calcitriol activation, VDRE-containing genomic regions showed considerably higher occupancies on average than in the control, vehicle-treated sample. A similar induction, but to a much lesser extent, was detected for the NR half-site-containing regions. In contrast, genomic regions not containing any of these specific response elements did not show any induction upon calcitriol treatment; they rather showed a decrease of binding in promoter regions. We can conclude that ligand-induced heterodimerization and binding of the NR to its response elements are correlated events.

采用特异性维生素D受体（VDR, Vitamin D Receptor）激动剂骨化三醇（calcitriol）进行处理，可增强VDR与类视黄醇X受体（RXR, Retinoid X Receptor）之间的异二聚化水平。本研究拟探究骨化三醇对VDR结合基因组区域的调控作用。我们以人类单核细胞THP-1细胞系为实验模型，分别设置溶媒对照（1:1体积比的二甲基亚砜-乙醇混合液）与100纳摩尔浓度骨化三醇处理组，开展染色质免疫共沉淀测序（ChIP-seq, Chromatin Immunoprecipitation sequencing）实验。研究结果显示，骨化三醇对VDR基因组结合的调控作用存在双向性：其效果取决于靶基因组区域是否存在其特异性反应元件VDRE（维生素D反应元件, Vitamin D Response Element）、特异性较低的核受体（NR, Nuclear Receptor）半位点，抑或两者均不存在（标注为"None"）。经骨化三醇激活后，携带VDRE的基因组区域的平均VDR结合占有率显著高于溶媒处理的对照组；携带核受体半位点的区域虽也出现类似的结合诱导效应，但诱导幅度大幅降低。与之形成对比的是，未携带上述任一反应元件的基因组区域在骨化三醇处理后未出现结合水平的诱导上升，反而在启动子区域呈现出结合程度的下降。综上，配体诱导的核受体异二聚化过程，与其结合靶反应元件的行为存在显著相关性。