Nuclear envelope protein MAN1 regulates clock through BMAL1.
Nuclear envelope protein MAN1 regulates clock through BMAL1.
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作者：
Lin ST;Zhang L;Lin X;Zhang LC;Garcia VE;Tsai CW;Ptáček L;Fu YH
生物钟作为内部起搏器，影响许多基本的体内平衡过程；因此，它们组成部分的表达和功能受到复杂的反馈回路网络的严格调节，这些反馈回路网络对昼夜节律过程进行了微调。我们对这些成分和途径的了解远非详尽无遗。近几十年来，尽管核膜在昼夜节律调节中的作用尚未被探索，但它已成为全球基因调控机器。我们报道了核心时钟成分BMAL1的转录受到核膜蛋白MAN1的正调控，MAN1直接结合BMAL1启动子并增强其转录。我们的研究结果在核外围和昼夜节律之间建立了一种新的联系，因此连接了两个调节身体功能各个方面的全球调节系统。DOI: http://dx.doi.org/10.7554/eLife.02981.001如果啮齿类动物，或者实际上是人类，在连续几天的黑暗中，它们会继续表现出大约每24小时重复一次的睡眠和清醒模式。这种内在的“昼夜节律”控制着动物生理的许多方面，包括体温、血压和激素水平。它通过调节关键基因的表达来实现这一点：这意味着这些基因编码的蛋白质的活性也会随着昼夜节律而变化。人体用于大规模协调基因表达的第二种机制需要对细胞核周围的膜进行调整。这个“核膜”主要由脂质组成，但它也含有结合DNA的蛋白质。这些蛋白质通过控制其他激活或抑制基因的蛋白质进入特定DNA序列的难易程度来调节基因表达。Lin等人现在揭示了这些机制协同工作。第一个证据是发现三种特定核膜蛋白的水平影响昼夜节律，并受昼夜节律的影响。特别是，其中两种蛋白质控制着第三种蛋白质的活性，即所谓的MAN1。这种蛋白质反过来会触发一种名为BMAL1的基因的表达，BMAL1是少数负责产生内部昼夜节律的“时钟基因”之一。这项研究不仅增加了我们对昼夜节律生物学和核膜的了解，还揭示了细胞能够协调大量基因表达的机制。这种机制允许广泛的生理和行为过程得到协调。DOI: http://dx.doi.org/10.7554/eLife.02981.002
Circadian clocks serve as internal pacemakers that influence many basic homeostatic processes; consequently, the expression and function of their components are tightly regulated by intricate networks of feedback loops that fine-tune circadian processes. Our knowledge of these components and pathways is far from exhaustive. In recent decades, the nuclear envelope has emerged as a global gene regulatory machine, although its role in circadian regulation has not been explored. We report that transcription of the core clock component BMAL1 is positively modulated by the inner nuclear membrane protein MAN1, which directly binds the BMAL1 promoter and enhances its transcription. Our results establish a novel connection between the nuclear periphery and circadian rhythmicity, therefore bridging two global regulatory systems that modulate all aspects of bodily functions. DOI: http://dx.doi.org/10.7554/eLife.02981.001 If rodents, or indeed humans, are kept in constant darkness for a number of days, they continue to show patterns of sleep and wakefulness that repeat roughly every 24 hr. This internal ‘circadian rhythm’ controls many aspects of animal physiology, including body temperature, blood pressure, and hormone levels. It does so by regulating the expression of key genes: this means that the activity of the proteins encoded by these genes also varies in accordance with the circadian rhythm. A second mechanism used by the body to coordinate gene expression on a large scale entails making adjustments to the membrane that surrounds the cell nucleus. This ‘nuclear envelope’ consists mainly of lipids, but it also contains proteins that bind DNA. These proteins regulate gene expression by controlling how easy it is for other proteins that activate or repress genes to gain access to specific DNA sequences. Lin et al. now reveal that these mechanisms work together. The first evidence for this was the discovery that the levels of three specific nuclear envelope proteins influence, and are influenced by, circadian rhythms. In particular, two of these proteins control the activity of the third, which is known as MAN1. This protein in turn triggers the expression of a gene called BMAL1, which is one of the small number of ‘clock genes’ that are responsible for generating the internal circadian rhythm. As well as adding to our knowledge of circadian biology and the nuclear envelope, this study reveals a mechanism by which cells can orchestrate the expression of large numbers of genes. Such mechanisms allow a wide range of physiological and behavioral processes to be co-ordinated. DOI: http://dx.doi.org/10.7554/eLife.02981.002