A multiscale model of the mammalian liver circadian clock supports synchronization of autonomous oscillations by intercellular communication

Abstract

Expression of core circadian clock genes in hepatocytes across the liver lobule is temporally synchronized despite cell-autonomous oscillations in gene expression. This spatial synchronization has been attributed to an unknown intercellular coupling mechanism. Here we have developed multicellular computational models of the murine liver lobule with and without intercellular coupling to investigate the role of synchronization in circadian gene expression. Our models demonstrated that intercellular coupling was needed to generate sustained circadian oscillations with a near 24-hour period. Without coupling the simulated period was variable within the 21-28-hour range. Further model analysis revealed that a robust near-24-hour oscillation period can be generated with a wide range of circadian protein degradation rates. In contrast, only a small window of circadian gene transcription rates was able to generate realistic oscillatory periods. The coupled model accurately captured the temporal dynamics of circadian genes derived from single-nuclei transcriptomic data. Overall, this study provides novel insights into the mammalian hepatic circadian clock through modeling of spatial and temporal gene expression patterns and data-driven analysis.