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Abstract
Gene regulatory feedback loops generate autonomous circadian rhythms in mammalian tissues. The well-studied core clock network contains many negative and positive regulations. Multiple feedback loops have been discussed as primary rhythm generators but the design principles of the core clock and differences between tissues are still under debate. Here we use global optimization techniques to fit mathematical models to circadian gene expression profiles for different mammalian tissues. It turns out that for every investigated tissue multiple model parameter sets reproduce the experimental data. We extract for all model versions the most essential feedback loops and find auto-inhibitions of period and cryptochrome genes, Bmal1-Rev-erb-α loops, and repressilator motifs as possible rhythm generators. Interestingly, the essential feedback loops differ between tissues, pointing to specific design principles within the hierarchy of mammalian tissue clocks. Self-inhibitions of Per and Cry genes are characteristic for models of suprachiasmatic nucleus clocks, whereas in liver models many loops act in synergy and are connected by a repressilator motif. Tissue-specific use of a network of co-existing synergistic feedback loops could account for functional differences between organs.
Highlights
Many organisms have evolved a circadian (~24 h) clock to adapt to the 24-h period of the day/night cycle [1]
Circadian rhythms are generated in a cell-autonomous manner by transcriptional/translational feedback loops [7] and can be monitored even in individual neurons [8] or fibroblasts [9]
There are the early E-box targets Per1, Per2, Per3, and Cry2 and the late gene Cry1. We model this complicated modulation by three representative genes: Bmal1 as the main activator and Per2 and Cry1 as the early and late E-box target, respectively
Summary
Many organisms have evolved a circadian (~24 h) clock to adapt to the 24-h period of the day/night cycle [1]. Ukai and Ueda [10] depict the mammalian core clock as a network of 20 transcriptional regulators (10 activators and 10 inhibitors) acting via enhancer elements in their promoters such as E-boxes, D-boxes, and retinoic acid receptor-related orphan receptor elements (RREs). Because many of these regulators have similar phases of expression and DNA binding [11, 12], the complex gene regulatory network has been reduced by Korencicet al [6] to just five regulators representing groups of genes: the activators Bmal and Dbp and the inhibitors Per, Cry, and Rev-Erba (Fig 1A and B)
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