title: An intensity ratio of interlocking loops determines circadian period length.
abstract: Circadian clocks allow organisms to orchestrate the daily rhythms in physiology and behaviors, and disruption of circadian rhythmicity can profoundly affect fitness. The mammalian circadian oscillator consists of a negative primary feedback loop and is associated with some 'auxiliary' loops. This raises the questions of how these interlocking loops coordinate to regulate the period and maintain its robustness. Here, we focused on the REV-ERBα/Cry1 auxiliary loop, consisting of Rev-Erbα/ROR-binding elements (RORE) mediated Cry1 transcription, coordinates with the negative primary feedback loop to modulate the mammalian circadian period. The silicon simulation revealed an unexpected rule: the intensity ratio of the primary loop to the auxiliary loop is inversely related to the period length, even when post-translational feedback is fixed. Then we measured the mRNA levels from two loops in 10-mutant mice and observed the similar monotonic relationship. Additionally, our simulation and the experimental results in human osteosarcoma cells suggest that a coupling effect between the numerator and denominator of this intensity ratio ensures the robustness of circadian period and, therefore, provides an efficient means of correcting circadian disorders. This ratio rule highlights the contribution of the transcriptional architecture to the period dynamics and might be helpful in the construction of synthetic oscillators.
authors.affiliation: Center for Systems Biology, Soochow University, Suzhou 215006, China MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Shi
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xing
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Qu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Center for Systems Biology, Soochow University, Suzhou 215006, China School of Mathematical Sciences, Soochow University, Suzhou 215006, China yingxu@suda.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Center for Systems Biology, Soochow University, Suzhou 215006, China MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200433, China yingxu@suda.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000235:genetics*; D056931:Cryptochromes / Q000096:biosynthesis / Q000235:genetics; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins