FTO is a transcriptional repressor to auto-regulate its own gene and potentially associated with homeostasis of body weight
FTO is a transcriptional repressor to auto-regulate its own gene and potentially associated with homeostasis of body weight
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FTO 是一种转录抑制因子，可自动调节自身基因，并可能与体重稳态相关
DOI：
10.1093/jmcb/mjy028
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发表时间：
2019-02-01
影响因子：
5.5
通讯作者：
Long, Yue-Sheng
中科院分区：
文献类型：
--
作者：
Liu, Shu-Jing;Tang, Hui-Ling;Long, Yue-Sheng
脂肪量和肥胖相关 (FTO) 蛋白是一种亚铁离子 (Fe2+)/2-酮戊二酸 (2-OG) 依赖性去甲基酶，优先催化 RNA 中的 m6A 位点。 FTO基因在下丘脑中高表达，并响应各种营养条件而波动，被认为参与全身代谢的控制。然而，人们对不同营养线索的潜在机制仍知之甚少。在这里，我们发现生酮饮食衍生的酮体 β-羟基丁酸 (BHB) 会短暂增加小鼠下丘脑和培养细胞中 FTO 的表达。有趣的是，FTO 蛋白抑制 Fto 启动子活性，这可以被 BHB 抵消。然后我们证明 FTO 与其自身的基因启动子结合，而 Fe2+（而非 2-OG）会阻碍这种结合并增加 FTO 表达。 BHB 诱导的 FTO 占据启动子会影响基础转录机制的组装。重要的是，功能丧失的 FTO 突变体 (I367F) 可在 FTOI367F 小鼠中诱导瘦表型，表现出增强的结合力和更高的抑制启动子的效力。此外，FTO 无法与其自身的启动子结合，该启动子可促进高脂饮食诱导的肥胖和 48 小时禁食小鼠的下丘脑中 FTO 的表达，这表明该基因的稳定表达受到破坏。总而言之，这项研究揭示了 FTO 作为 Fe2+ 敏感转录抑制因子的新功能，指示其自身的基因开关形成可能与下丘脑体重控制相关的自动调节环路。
Fat mass and obesity-associated (FTO) protein is a ferrous ion (Fe2+)/2-oxoglutarate (2-OG)-dependent demethylase preferentially catalyzing m6A sites in RNA. The FTO gene is highly expressed in the hypothalamus with fluctuation in response to various nutritional conditions, which is believed to be involved in the control of whole body metabolism. However, the underlying mechanism in response to different nutritional cues remains poorly understood. Here we show that ketogenic diet-derived ketone body β-hydroxybutyrate (BHB) transiently increases FTO expression in both mouse hypothalamus and cultured cells. Interestingly, the FTO protein represses Fto promoter activity, which can be offset by BHB. We then demonstrate that FTO binds to its own gene promoter, and Fe2+, but not 2-OG, impedes this binding and increases FTO expression. The BHB-induced occupancy of the promoter by FTO influences the assembly of the basal transcriptional machinery. Importantly, a loss-of-function FTO mutant (I367F), which induces a lean phenotype in FTOI367F mice, exhibits augmented binding and elevated potency to repress the promoter. Furthermore, FTO fails to bind to its own promoter that promotes FTO expression in the hypothalamus of high-fat diet-induced obese and 48-h fasting mice, suggesting a disruption of the stable expression of this gene. Taken together, this study uncovers a new function of FTO as a Fe2+-sensitive transcriptional repressor dictating its own gene switch to form an auto-regulatory loop that may link with the hypothalamic control of body weight.