TY - JOUR T1 - Co-existing feedback loops generate tissue-specific circadian rhythms JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800078 VL - 1 IS - 3 SP - e201800078 AU - J Patrick Pett AU - Matthew Kondoff AU - Grigory Bordyugov AU - Achim Kramer AU - Hanspeter Herzel Y1 - 2018/06/01 UR - https://www.life-science-alliance.org/content/1/3/e201800078.abstract N2 - 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. ER -