Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity
Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity
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DOI：
10.1038/s41467-019-10532-2
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发表时间：
2019-06-12
影响因子：
16.6
通讯作者：
Okamura, Hitoshi
中科院分区：
文献类型：
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作者：
Doi, Masao;Shimatani, Hiroyuki;Okamura, Hitoshi
非编码顺式调控元件是发育的基本决定因素，但它们对成年人行为和生理的确切影响仍然难以捉摸。基于顺式元件的转录调控被认为是在行为和生理中产生昼夜节律的关键。然而，支持这一模型的遗传证据是基于时钟基因蛋白质编码序列的突变。在这里，我们报告了仅在核心时钟基因PER2启动子区域的E‘-box顺式元件处携带突变的突变小鼠的生成。PER2E‘-box突变取消了可持续的分子时钟振荡，使昼夜活动和体温节律不稳定。如果没有E‘盒，PER2信使RNA和蛋白质的表达保持在中高水平。我们的工作将PER2E‘盒描述为维持持续的细胞自主昼夜节律的关键节点元件，并揭示了非编码顺式元件在日常维持动物运动活动和体温节律性方面的影响程度。
Non-coding cis-regulatory elements are essential determinants of development, but their exact impacts on behavior and physiology in adults remain elusive. Cis-element-based transcriptional regulation is believed to be crucial for generating circadian rhythms in behavior and physiology. However, genetic evidence supporting this model is based on mutations in the protein-coding sequences of clock genes. Here, we report generation of mutant mice carrying a mutation only at the E'-box cis-element in the promoter region of the core clock gene Per2. The Per2 E'-box mutation abolishes sustainable molecular clock oscillations and renders circadian locomotor activity and body temperature rhythms unstable. Without the E'-box, Per2 messenger RNA and protein expression remain at mid-to-high levels. Our work delineates the Per2 E'-box as a critical nodal element for keeping sustainable cell-autonomous circadian oscillation and reveals the extent of the impact of the non-coding cis-element in daily maintenance of animal locomotor activity and body temperature rhythmicity.