title: The interplay of cis-regulatory elements rules circadian rhythms in mouse liver.
abstract: The mammalian circadian clock is driven by cell-autonomous transcriptional feedback loops that involve E-boxes, D-boxes, and ROR-elements. In peripheral organs, circadian rhythms are additionally affected by systemic factors. We show that intrinsic combinatorial gene regulation governs the liver clock. With a temporal resolution of 2 h, we measured the expression of 21 clock genes in mouse liver under constant darkness and equinoctial light-dark cycles. Based on these data and known transcription factor binding sites, we develop a six-variable gene regulatory network. The transcriptional feedback loops are represented by equations with time-delayed variables, which substantially simplifies modelling of intermediate protein dynamics. Our model accurately reproduces measured phases, amplitudes, and waveforms of clock genes. Analysis of the network reveals properties of the clock: overcritical delays generate oscillations; synergy of inhibition and activation enhances amplitudes; and combinatorial modulation of transcription controls the phases. The agreement of measurements and simulations suggests that the intrinsic gene regulatory network primarily determines the circadian clock in liver, whereas systemic cues such as light-dark cycles serve to fine-tune the rhythms.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Korenčič
authors.forename: Grigory
authors.initials: G
authors.lastname: Bordyugov
authors.forename: Rok
authors.initials: R
authors.lastname: Košir
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
authors.forename: Marko
authors.initials: M
authors.lastname: Goličnik
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D057906:Circadian Clocks; D002940:Circadian Rhythm; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D024721:E-Box Elements; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D056950:Period Circadian Proteins / Q000235:genetics; D017440:Photoperiod; D014157:Transcription Factors / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D056925:Circadian Rhythm Signaling Peptides and Proteins; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors