The circadian clock times post-transcriptional and immunometabolic processes in the innate immune system

Abstract

Within each cell of our bodies, and in that of plants, animals, and bacteria, a molecular clock ticks, keeping important biological and cellular processes running on time and efficiently. This circadian clock is tuned by the 24-hour cycles of light and dark on earth. The core circadian clock uses a transcription-translation negative feedback loop to keep time: an activating arm composed of transcription factors stimulates expression of ”clock-controlled genes”, including its repressors.The repressive arm proteins then bind together, are transported to the nucleus, and inhibit the action of the activating arm. Extensive phosphorylation ultimately target the negative arm for degradation. One loop of this cycle takes approximately 24-hours in mammals. One cell type that is controlled by the circadian clock system is the macrophage, the sentinel of the immune system. The circadian clock regulates multiple aspects of macrophage homeostatic function that are involved in central metabolism and immune pathways, a system termed immunometabolism. Intriguingly, many clock-controlled genes within macrophages are subject to post-transcriptional regulation by largely unknown mechanisms, but which may play roles in macrophage activation. Additionally, although the clock is known to heavily regulate immunometabolism, and macrophage responses involve multi-level cellular responses, only small-scale studies have examined the bidirectional relationship between the circadian clock and macrophage responses to pathogens. Utilizing multi-omic analyses and new circadian rhythm analysis tools, we described different post-transcriptional mechanisms that are used by the clock to regulate gene expression and protein translation, namely non-coding RNAs and the spliceosome. Additionally, we examined multiple cellular levels of the macrophage response to an antigen–SARS-CoV spike proteins–at different times over the circadian day, utilizing multi-omic and cellular assays. Our work sheds light on the extent to which the circadian clock in macrophages regulates cellular homeostasis as well as pathogen responses. We hope this work will encourage the broadening of the scope of circadian cellular studies to create a fuller picture of how the clock regulates whole-cell processes.