VDR-RXR and TCF4/β-Catenin Cistromes in Colonic Cells of Colorectal Tumor Origin: Impact on c-FOS and c-MYC Gene Expression
VDR-RXR and TCF4/β-Catenin Cistromes in Colonic Cells of Colorectal Tumor Origin: Impact on c-FOS and c-MYC Gene Expression
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DOI：
10.1210/me.2011-1109
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Pike, J. Wesley
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文献类型：
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作者：
Meyer, Mark B.;Goetsch, Paul D.;Pike, J. Wesley
1α,25-二羟基维生素 D-3 [1,25-(OH)(2)D-3] 在肠和结肠中的许多转录和生长调节活性在人结直肠癌细胞 LS180 中得到了重现。因此，我们将该细胞系与染色质免疫沉淀-seq 和基因表达分析结合使用，以鉴定维生素 D 受体 (VDR)/类视黄醇 X 受体 (RXR) 和转录因子 7 样 2 (TCF7L2/TCF4)/β-连环蛋白顺反子及其调节的基因。 VDR 和 RXR 以很大程度上依赖于配体的方式共定位于主要启动子远端、含有维生素 D 反应元件的位点。这些调控位点控制已知和新型 1,25-(OH)(2)D-3 靶基因的表达。 TCF4 和 β-连环蛋白顺反子部分重叠，包含 TCF/淋巴增强子结合因子共有元件，并且仅受 1,25-(OH)(2)D-3 的适度影响。然而，这两个异二聚体复合物共定位于一组有限基因（包括 c-FOS 和 c-MYC）附近的位点；两个基因的表达均受 1,25-(OH)(2)D-3 调节。在 c-FOS 基因处，VDR/RXR 和 TCF4/β-连环蛋白均与位于转录起始位点上游 24 kb 的单个远端增强子结合。然而，在 c-MYC 基因座上，在 -139 和 -165 kb 之间的一组位点以及位于上游 -335 kb 的位点处注意到结合。作为分离的增强子片段进行检查，这些区域表现出基础活性和 1,25-(OH)(2)D-3 诱导活性，这些活性与 VDR 和 β-连环蛋白激活相互关联。这些数据揭示了 1,25-(OH)(2)D-3 调节靶基因的额外复杂性，并支持 VDR 和 TCF4/β-连环蛋白调节复合物对 c-FOS 和 c-MYC 的直接作用。 (分子内分泌学 26: 37-51, 2012)
Many of the transcriptional and growth regulating activities of 1 alpha,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] in the intestine and colon are recapitulated in the human colorectal cancer cell LS180. We therefore used this line together with chromatin immunoprecipitation-seq and gene expression analyses to identify the vitamin D receptor (VDR)/retinoid X receptor (RXR) and transcription factor 7-like 2 (TCF7L2/TCF4)/beta-catenin cistromes and the genes that they regulate. VDR and RXR colocalized to predominantly promoter distal, vitamin D response element-containing sites in a largely ligand-dependent manner. These regulatory sites control the expression of both known as well as novel 1,25-(OH)(2)D-3 target genes. TCF4 and beta-catenin cistromes partially overlapped, contained TCF/lymphoid enhancer-binding factor consensus elements, and were only modestly influenced by 1,25-(OH)(2)D-3. However, the two heterodimer complexes colocalized at sites near a limited set of genes that included c-FOS and c-MYC; the expression of both genes was modulated by 1,25-(OH)(2)D-3. At the c-FOS gene, both VDR/RXR and TCF4/beta-catenin bound to a single distal enhancer located 24 kb upstream of the transcriptional start site. At the c-MYC locus, however, binding was noted at a cluster of sites between -139 and -165 kb and at a site located -335 kb upstream. Examined as isolated enhancer fragments, these regions exhibited basal and 1,25-(OH)(2)D-3-inducible activities that were interlinked to both VDR and beta-catenin activation. These data reveal additional complexity in the regulation of target genes by 1,25-(OH)(2)D-3 and support a direct action of both VDR and the TCF4/beta-catenin regulatory complex at c-FOS and c-MYC. (Molecular Endocrinology 26: 37-51, 2012)