PT  - JOURNAL ARTICLE
AU  - J Patrick Pett
AU  - Matthew Kondoff
AU  - Grigory Bordyugov
AU  - Achim Kramer
AU  - Hanspeter Herzel
TI  - Co-existing feedback loops generate tissue-specific circadian rhythms
AID  - 10.26508/lsa.201800078
DP  - 2018 Jun 01
TA  - Life Science Alliance
PG  - e201800078
VI  - 1
IP  - 3
4099  - https://www.life-science-alliance.org/content/1/3/e201800078.short
4100  - https://www.life-science-alliance.org/content/1/3/e201800078.full
SO  - Life Sci. Alliance2018 Jun 01; 1
AB  - 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.