Higher-Order Chromatin Regulation and Differential Gene Expression in the Human Tumor Necrosis Factor/Lymphotoxin Locus in Hepatocellular Carcinoma Cells
Higher-Order Chromatin Regulation and Differential Gene Expression in the Human Tumor Necrosis Factor/Lymphotoxin Locus in Hepatocellular Carcinoma Cells
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DOI：
10.1128/mcb.06478-11
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发表时间：
2012-04-01
影响因子：
5.3
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
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作者：
Watanabe, Takehisa;Ishihara, Ko;Nakao, Mitsuyoshi
内源染色体区域的三维背景可能通过影响转录调控元件之间的相互作用来促进基因簇的调控。在这项研究中，我们研究了肿瘤坏死因子（TNF）信号传导对人肿瘤坏死因子（TNF）/淋巴毒素（LT）基因座中时空增强子-启动子相互作用的影响，该相互作用由CCTCC结合因子（CTCF）依赖性染色质绝缘体介导。细胞因子基因 LT α、TNF 和 LT β 在炎症和致癌反应中受到 NF-κ B 信号传导的差异调节。我们在 TNF/LT 基因座中鉴定出至少四个具有增强子阻断活性的 CTCF 富集位点和 TNF 响应性 TE2 增强子。 CTCF 富集位点之一位于早期诱导型 LT α/TNF 启动子和晚期诱导型 LT β 启动子之间。 CTCF 的消耗减少了 TNF 的表达并加速了 LT β 的诱导。 TNF 刺激后，通过染色体内动力学，这些绝缘子介导增强子和 LT α/TNF 启动子之间的相互作用，然后与 LT β 启动子相互作用。这些结果表明绝缘子介导 TNF/LT 基因簇中增强子-启动子关联的时空控制。
The three-dimensional context of endogenous chromosomal regions may contribute to the regulation of gene clusters by influencing interactions between transcriptional regulatory elements. In this study, we investigated the effects of tumor necrosis factor (TNF) signaling on spatiotemporal enhancer-promoter interactions in the human tumor necrosis factor (TNF)/lymphotoxin (LT) gene locus, mediated by CCCTC-binding factor (CTCF)-dependent chromatin insulators. The cytokine genes LT alpha, TNF, and LT beta are differentially regulated by NF-kappa B signaling in inflammatory and oncogenic responses. We identified at least four CTCF-enriched sites with enhancer-blocking activities and a TNF-responsive TE2 enhancer in the TNF/LT locus. One of the CTCF-enriched sites is located between the early-inducible LT alpha/TNF promoters and the late-inducible LT beta promoter. Depletion of CTCF reduced TNF expression and accelerated LT beta induction. After TNF stimulation, via intrachromosomal dynamics, these insulators mediated interactions between the enhancer and the LT alpha/TNF promoters, followed by interaction with the LT beta promoter. These results suggest that insulators mediate the spatiotemporal control of enhancer-promoter associations in the TNF/LT gene cluster.