Temporal control of physiology requires the interplay between gene networks involved in daily timekeeping and tissue function across different organs. How the circadian clock interweaves with tissue-specific transcriptional programs is poorly understood. Here, we dissected temporal and tissue-specific regulation at multiple gene regulatory layers by examining mouse tissues with an intact or disrupted clock over time. Integrated analysis uncovered two distinct regulatory modes underlying tissue-specific rhythms: tissue-specific oscillations in transcription factor (TF) activity, which were linked to feeding-fasting cycles in liver and sodium homeostasis in kidney; and colocalized binding of clock and tissue-specific transcription factors at distal enhancers. Chromosome conformation capture (4C-seq) in liver and kidney identified liver-specific chromatin loops that recruited clock-bound enhancers to promoters to regulate liver-specific transcriptional rhythms. Furthermore, this looping was remarkably promoter-specific on the scale of less than 10 kilobases (kb). Enhancers can contact a rhythmic promoter while looping out nearby nonrhythmic alternative promoters, confining rhythmic enhancer activity to specific promoters. These findings suggest that chromatin folding enables the clock to regulate rhythmic transcription of specific promoters to output temporal transcriptional programs tailored to different tissues.

生理学的时间控制需要涉及不同器官的日常计时和组织功能的基因网络之间的相互作用。人们对生物钟如何与组织特异性转录程序交织在一起知之甚少。在这里，我们通过检查随时间变化的时钟完整或破坏的小鼠组织，剖析了多个基因调控层的时间和组织特异性调控。综合分析揭示了组织特异性节律的两种不同的调节模式：转录因子（TF）活性的组织特异性振荡，与肝脏中的进食-禁食周期和肾脏中的钠稳态有关；以及时钟和组织特异性转录因子在远端增强子处的共定位结合。肝脏和肾脏中的染色体构象捕获 (4C-seq) 鉴定了肝脏特异性染色质环，该环将时钟结合增强子招募到启动子以调节肝脏特异性转录节律。此外，这种循环在小于 10 千碱基 (kb) 的规模上具有显着的启动子特异性。增强子可以接触节律启动子，同时环出附近的非节律替代启动子，将节律增强子活性限制在特定启动子上。这些发现表明，染色质折叠使时钟能够调节特定启动子的节律转录，以输出适合不同组织的时间转录程序。