Author/Editor		Korenčič, Anja; Bordyugov, Grigory; Košir, Rok; Rozman, Damjana; Goličnik, Marko; Herzel, Hanspeter
Title		The interplay of cis-regulatory elements rules circadian rhythms in mouse liver
Type		članek
Source		Plos one
Vol. and No.		Letnik 7, št. 11
Publication year		2012
Volume		str. 1-13
Language		eng
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.
Descriptors		CIRCADIAN RHYTHM LIVER TRANSCRIPTION FACTORS GENE EXPRESSION MODELS, GENETIC MICE