Ultradian to circadian transcriptome re-wiring underlies liver aging

项目摘要/摘要 除了昼夜节律(~24小时振荡)外，还存在超常节律(周期小于24小时)， 其中，12小时节律普遍存在于多种物种中，从旋涡虫海洋动物，到 线虫、线虫和哺乳动物，如老鼠、狒狒，甚至人类。我们小组最近发现了一种 哺乳动物的12小时钟，在进化上是保守的，细胞自主的，独立于 生物钟，但依赖于未折叠的蛋白反应转录因子XBP1s。肝脏特异性 XBP1s的全球缺失会损害小鼠的12h转录组，但不会影响体内的昼夜节律。XBP1- 依赖的肝脏12h转录组在黎明和黄昏时优先达到峰值，并显著富含 调节先天免疫功能、内质网和高尔基体的途径 动态平衡，包括翻译调控，内质网和高尔基体中蛋白质的加工和分类，蛋白质质量 控制神经鞘脂脂和甘油脂代谢。这些通路在衰老过程中通常是不受调控的 与衰老相关的疾病。虽然最近已经确定24小时的昼夜节律普遍存在 衰老过程中的重新编程，12小时时钟失调是否也与衰老和/或衰老有关- 相关疾病的定义仍然不明确。非常耐人寻味的是，初步数据显示，全球 在小鼠肝脏老化期间，12h循环转录组重新编程为24小时昼夜节律，这是 进一步与12h肝脏XBP1s振荡向24小时昼夜振荡的转换有关。基于 这些发现，我们假设12小时到24小时(昼夜节律)的重新编程可以加速肝脏老化。我们会 建立小鼠肝脏12小时至24小时重编程模型。广泛的表型实验将是 以确定基因诱导的12小时至24小时的重编程是否足以推动肝脏老化 老鼠。我们将进一步进行临时RNA-Seq和肝脏分泌组图谱来鉴定分子 这种重新编程背后的机制。因此，这项工作将把12小时不规律作为一种新的 这是衰老的标志，并表明旨在防止这种12小时至24小时重新编程的新疗法可能 有效地改善人类的健康状况。

Project Summary/Abstract In addition to the circadian rhythms (~24h oscillation), ultradian rhythms (with period smaller than 24h) also exist, among which 12h rhythms were prevalently found in multiple species ranging from circatidal marine animals, to nematode C. elegans and mammals like mouse, baboon and even humans. Our group recently discovered a mammalian 12h-clock that is evolutionarily conserved, cell-autonomous and established independently from the circadian clock but dependent on the unfolded protein response transcription factor XBP1s. Liver-specific deletion of XBP1s globally impairs the murine 12h transcriptome, but not circadian rhythms in vivo. XBP1s- dependent hepatic 12h transcriptome preferentially peaks at dawn and dusk, and is remarkably enriched in pathways regulating innate immune functions and endoplasmic reticulum (ER) and the Golgi apparatus homeostasis, including translation regulation, protein processing and sorting in ER and Golgi, protein quality control and sphingolipid and glycerolipid metabolism. These pathways are often dysregulated during aging and aging-related diseases. While it has been recently established that the 24h circadian rhythms undergo prevalent reprogramming during aging, whether the 12h-clock dysregulation is also causally linked to aging and/or aging- related diseases remains ill defined. Very intriguingly, preliminary data revealed a very robust global reprogramming of 12h-cycling transcriptome to 24h circadian rhythms during aging in mouse liver, which is further associated with a conversion of 12h hepatic XBP1s oscillation to 24h circadian oscillation. Based upon these findings, we hypothesize that 12h-to-24h (circadian) reprogramming can accelerate liver aging. We will generate mouse models of hepatic 12h-to-24h reprogramming. Extensive phenotyping experiments will be performed to determine if genetically-induced 12h-to-24h reprogramming is sufficient to drive hepatic aging in mice. We will further perform temporal RNA-Seq and hepatic secretome profiling to identify the molecular mechanism underlying this reprogramming. This work will therefore establish 12h-clock dysregulation as a novel hallmark of aging and suggest that new therapeutics aimed at preventing this 12h-to-24h reprogramming could be effective at improving health span in humans.