Modeling circadian variability of core-clock and clock-controlled genes in four tissues of the rat.

Circadian clocks, present in almost all cells of the body, are entrained to rhythmic changes in the environment (e.g. light/dark cycles). Genes responsible for this timekeeping are named core-clock genes, which through transcriptional feedback interactions mediated by transcription factor binding to Ebox/RRE/Dbox elements can generate oscillatory activity of their expression. By regulating the transcription of other clock-controlled genes (CCGs) circadian information is transmitted to tissue and organ levels. Recent studies have indicated that there is a considerable variability of clock-controlled gene expression between tissues both with respect to the circadian genes that are regulated and to their phase lags. In this work, a mathematical model was adapted to explore the dynamics of core-clock and clock-controlled genes measured in four tissues of the rat namely liver, muscle, adipose, and lung. The model efficiently described the synchronous rhythmicity of core-clock genes and further predicted that their phases are mainly regulated by Per2 and Cry1 transcriptional delays and Rev-Erba and Cry1 degradation rates. Similarly, after mining databases for potential Ebox/RRE/Dbox elements in the promoter region of clock-controlled genes, the phase variabilities of the same genes between different tissues were described. The analysis suggests that inter-tissue circadian variability of the same clock-controlled genes is an inherent component of homeostatic function and may arise due to different transcription factor activities on Ebox/RRE/Dbox elements.