Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor
Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor
复制标题
DOI：
10.1016/j.bbagrm.2017.07.002
复制
发表时间：
2017-09-01
影响因子：
4.7
通讯作者：
Carlberg, Carsten
中科院分区：
文献类型：
--
作者：
Neme, Antonio;Seuter, Sabine;Carlberg, Carsten
转录因子维生素D受体（VDR）是维生素D（1，25（OH）（2）D-3）生物活性形式的唯一核靶点。在THP-1人单核细胞中，我们在2和24小时配体刺激后获得了高度准确的VDR顺式组，其包含> 11，600个基因组基因座，其中78%仅在24小时后检测到。相比之下，一组510个持续性VDR位点发生在所有条件下，约2100个VDR位点仅短暂占用。机器学习和统计分析以及与重新分析的B细胞VDR顺式组的比较表明了339个高度保守的持续VDR位点的亚组，其最适合于描述维生素D触发的基因调控情况。THP-1细胞的1，25（OH）（2）D-3依赖性转录组包含587个基因，其中311个基因是免疫系统中的主要功能靶基因，97%以上的靶基因位于1，25（OH）（2）D-3调节的拓扑相关结构域（TADs）内。持续性和短暂性VDR位点的数量被认为是将这些TADs分为五类的主要原因，这些TADs携带参与不同生物过程的维生素D靶基因。总之，维生素D对生物过程的特异性调节取决于时间依赖性VDR结合的差异。
The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)(2)D-3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24 h ligand stimulation comprising > 11,600 genomic loci, 78% of which were detected exclusively after 24 h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re -analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D -triggered gene regulatory scenarios. The 1,25(OH)(2)D-3-dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system.More than 97% of the latter genes were located within 1,25(OH)(2)D-3-modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding.