Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms.
Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms.
复制标题
时钟蛋白调节时钟基因的时空组织以控制昼夜节律。
DOI：
10.1073/pnas.2019756118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Yadlapalli,Swathi
中科院分区：
文献类型：
--
作者：
Xiao,Yangbo;Yuan,Ye;Jimenez,Mariana;Soni,Neeraj;Yadlapalli,Swathi
昼夜节律钟调节基因表达、行为和生理中的~ 24小时振荡。虽然昼夜节律的遗传和分子机制已经得到了很好的表征，但对昼夜节律钟组成部分的细胞内动力学以及它们如何影响昼夜节律仍然知之甚少。在这里，我们阐明了核心时钟蛋白和基因的时空组织和动态如何影响果蝇时钟神经元的昼夜节律。利用高分辨率成像和dna荧光原位杂交技术，我们证明了果蝇时钟蛋白（PERIOD和CLOCK）在昼夜节律抑制阶段在核膜上被组织成几个离散的焦点，并在核心时钟基因的亚核定位中发挥重要作用，以控制昼夜节律。具体来说，我们发现核心时钟基因（periodandtimeless）在抑制阶段被PERIOD蛋白定位在靠近核外周的位置，这表明核心时钟基因的亚核定位可能在其节律性基因表达中发挥关键作用。最后，我们发现核包膜蛋白Lamin B受体的缺失会导致PER病灶和基因外周定位的破坏，并导致昼夜节律缺陷。这些结果表明，时钟蛋白在核心时钟基因的亚核重组中发挥了迄今为止意想不到的作用，以控制昼夜节律，揭示了时钟在亚细胞水平上的功能。我们的研究结果进一步表明，时钟蛋白焦点可能调节时钟调控基因在抑制阶段的动态聚类和空间重组，从而控制行为和生理的昼夜节律。
Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms inDrosophilaclock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate thatDrosophilaclock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes,periodandtimeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci andpergene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.