Renal and extrarenal production of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), is catalyzed by CYP27B1, an enzyme also called 1-α-hydroxylase. The overproduction of 1,25(OH)2D has been described in granulomatous diseases. High circulating concentrations of 1,25(OH)2D can lead to hypercalcemia. The aim of this work was to characterize the transcriptional regulation of CYP27B1 in human mononuclear phagocytes exposed to LPS due to its relevance to understanding the hypercalcemia and ectopic calcifications associated with chronic inflammatory diseases such as tuberculosis and other granulomatous diseases. The human CYP27B1 promoter analysis identified binding sites for published TF, SNPs, novel putative TFBS and conserved sites compared to mice. Then, using microarray data, a meta-analysis was performed to obtain a global view of the gene expression in LPS-challenged dendritic cells, monocytes and macrophages. Finally, two experiments, GSE40885 and time series GSE19765, were analyzed in-depth using differential expression analysis which permitted the identification of TF co-expressed with CYP27B1. This work allowed us to formulate a CYP27B1 transcriptional regulation model for LPS-challenged monocytes/macrophages. The importance of two TF families, NFKB and CEBPB, was confirmed. Data also suggests that PLAGL2 and STAT4 which are novel TF could participate in the CYP27B1 transcriptional regulation in cells exposed to LPS. These TF, in turn, would be interacting with regions that present polymorphisms in the general population which might explain the pathological phenotypes associated with altered vitamin D metabolism.

中文翻译：

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在计算机上鉴定与LPS攻击的单核吞噬细胞中CYP27B1转录调控相关的新型转录因子。

肾脏和肾外产生维生素D的活性形式1,25-二羟基维生素D（1,25（OH）2D）被CYP27B1催化，该酶也称为1-α-羟化酶。在肉芽肿性疾病中已描述了1,25（OH）2D的过量生产。1,25（OH）2D的高循环浓度可导致高钙血症。这项工作的目的是表征CYP27B1在暴露于LPS的人单核吞噬细胞中的转录调控，这是由于其与了解与慢性炎性疾病（如结核病和其他肉芽肿性疾病）相关的高钙血症和异位钙化具有相关性。与小鼠相比，人类CYP27B1启动子分析确定了已发表TF，SNP，新型推定TFBS和保守位点的结合位点。然后，使用微阵列数据，进行了荟萃分析，以全面了解LPS攻击的树突状细胞，单核细胞和巨噬细胞中基因的表达。最后，使用差异表达分析法深入分析了两个实验GSE40885和时间序列GSE19765，从而可以鉴定与CYP27B1共表达的TF。这项工作使我们能够为LPS攻击的单核细胞/巨噬细胞建立CYP27B1转录调控模型。证实了两个TF家族NFKB和CEBPB的重要性。数据还表明，新型TF的PLAGL2和STAT4可以参与暴露于LPS的细胞中CYP27B1的转录调控。这些TF反过来会与普通人群中呈现多态性的区域相互作用，这可能解释了与维生素D代谢改变有关的病理表型。