Department of Biochemistry, University of Wisconsin at Madison, 433 Babcock Dr., Madison, WI 53706, USA.
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):136-41. doi: 10.1016/j.jsbmb.2010.02.011. Epub 2010 Feb 18.
The vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in target cells and tissues by orchestrating the expression of gene networks responsible for vitamin D-induced phenotypes. The molecular mechanisms of these regulatory systems have been studied for decades under the principle that transcriptional regulation occurs near the transcriptional start site of the gene. However, this now appears to be an outdated view of transcriptional control. In this study, we examined the genome-wide chromatin immunoprecipitation on microarray (ChIP-chip) across pre-osteoblastic cells for VDR, retinoid X receptor (RXR), RNA polymerase II, and histone H4 acetylation (H4ac). We uncovered potential regulatory mechanisms for genes important to osteoblast biology as well as skeletal formation under the control of 1,25(OH)2D3. We found that VDR, along with RXR and H4ac, binds to distal regions 43% of the time; and within gene introns and exons 44%, leaving only 13% of activation at traditional promoter regions. Here, we briefly summarize our findings for all the VDR/RXR cis-acting transcriptional elements (VDR/RXR cistrome) in pre-osteoblastic cells, MC3T3-E1, provide a few examples of this dynamic control by VDR and 1,25(OH)2D3, and demonstrate that distal transcriptional control contributes to the majority of vitamin D3-mediated transcription.
维生素 D 受体 (VDR) 通过协调负责维生素 D 诱导表型的基因网络的表达，介导 1,25-二羟维生素 D3(1,25(OH)2D3)在靶细胞和组织中的作用。几十年来，人们一直根据转录调控发生在基因转录起始位点附近的原理，研究这些调节系统的分子机制。然而，这似乎是一种过时的转录控制观点。在这项研究中，我们在预成骨细胞中检测了 VDR、视黄酸受体 (RXR)、RNA 聚合酶 II 和组蛋白 H4 乙酰化 (H4ac)的全基因组染色质免疫沉淀微阵列 (ChIP-chip)。我们揭示了 1,25(OH)2D3 控制下对成骨细胞生物学和骨骼形成很重要的基因的潜在调节机制。我们发现 VDR 与 RXR 和 H4ac 一起绑定到远端区域的频率为 43%；在基因内含子和外显子中的频率为 44%，只有 13%的激活发生在传统启动子区域。在这里，我们简要总结了我们在预成骨细胞 MC3T3-E1 中的所有 VDR/RXR 顺式作用转录元件 (VDR/RXR 顺式作用组)的发现，提供了一些 VDR 和 1,25(OH)2D3 这种动态控制的例子，并证明了远端转录控制有助于维生素 D3 介导的转录的大部分。
