Kruppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)
Kruppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)
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DOI：
10.1074/jbc.m116.715748
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发表时间：
2016-07-29
影响因子：
4.8
通讯作者：
Quinlan, Kate G. R.
中科院分区：
文献类型：
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作者：
Knights, Alexander J.;Yik, Jinfen J.;Quinlan, Kate G. R.
Lgals3基因编码一种多功能的β -半乳糖苷结合蛋白——半乳糖凝集素-3。半乳糖凝集素-3参与了从趋化和炎症到纤维化和细胞凋亡的广泛生物学过程。半乳糖凝集素-3作为炎症调节剂的作用已被深入研究，最近的证据表明，它可能是肥胖和其他代谢紊乱的保护因素。尽管对半乳糖凝集素-3有相当大的兴趣，但对其在转录水平上的生理调节知之甚少。通过基因敲除小鼠、染色质免疫沉淀、细胞和分子分析，我们发现锌指转录因子kruppel样因子3 （KLF3）直接抑制半乳糖凝集素-3的转录。我们发现半乳糖凝集素-3在KLF3缺陷小鼠组织中广泛上调，KLF3占据Lgals3基因的调控区域，KLF3直接结合半乳糖凝集素-3启动子中的同源元件（CACCC盒），并在细胞实验中抑制其激活。我们还提供了Lgals3调控的机制见解，证明c端结合蛋白（CtBP）是驱动最佳klf3介导沉默的必要条件。这些发现有助于增强我们对炎症调节剂半乳糖凝集素-3的表达是如何被控制的理解，为未来潜在的治疗干预开辟了道路。
The Lgals3 gene encodes a multifunctional beta-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Kruppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future.