Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

Abstract

Mammals have evolved an internal timing system, the circadian clock, which synchronizes physiology and behavior to the daily light and dark cycles of the Earth. The master clock, located in the suprachiasmatic nucleus (SCN) of the brain, takes fluctuating light input from the retina and synchronizes other tissues to the same internal rhythm. The molecular clocks that drive these circadian rhythms are ticking in nearly all cells in the body. Efforts in systems chronobiology are now being directed at understanding, on a comprehensive scale, how the circadian clock controls different layers of gene regulation to provide robust timing cues at the cellular and tissue level. In this review, we introduce some basic concepts underlying periodicity of gene regulation, and then highlight recent genome-wide investigations on the propagation of rhythms across multiple regulatory layers in mammals, all the way from chromatin conformation to protein accumulation.

Figure 1.

Constraints on transmission of rhythmic information across multiple gene regulatory layers. (A) Rhythmic accumulation of gene products. In the stationary state, rhythmic synthesis s(t) leads to rhythmic accumulation of gene product X(t). Assuming that the lifetime of X (lifetime = tau = 1/k = half-life/ln(2)) is independent of time, a longer lifetime of X damps amplitudes and induces longer delays (ΔT) (top right) compared with shorter lifetimes (bottom right). (B) Damping (left) and delays (right) of X(t) as a function of half-life of X(t). With increasing half-life, relative amplitudes (or fold change) are damped and X(t) is delayed up to a maximum of 6 hours. Tau = 1/k; e_s = relative amplitude of synthesis. (C) Simple model for protein expression. Transcription s(t) produces pre-mRNA (p), which can be processed into mature mRNA (m). Proteins are synthesized at a rate proportional to the accumulation of mRNA. In the simplest model, the half-life of each gene product is assumed to be independent of time. (D) Damping (left) and delays (right) of rhythms in short-lived versus long-lived mRNAs and proteins. Gene products with shorter half-lives preserve rhythmic information more efficiently than those with longer half-lives. Initial fold change of s(t) was chosen as 9 to illustrate damping of amplitude.

Figure 2.

Circadian regulation of gene expression. (A) Circadian rhythms can impact gene expression at virtually any step between transcription to translation. In mammals, although many steps of gene regulation such as transcription, mRNA, and protein accumulation are known to fluctuate over the day, the role of the clock in other steps such as splicing and mRNA transport is less understood. Recent advances have highlighted other levels of regulation involving the circadian clock, such as chromatin structure and translation. (B) Recent advances highlighted the role of chromatin conformation in regulating circadian genes. For instance, rhythmic contacts between distal genomic regulatory sequences and gene promoters contribute to circadian gene expression. (C) By measuring translation rate around the clock, ribosome-profiling experiments found that translation efficiency fluctuates over the diurnal cycle. Thus, although TOP and TISU motif mRNAs accumulate constantly in mouse liver, the rhythmic translation rate of these mRNAs allows fluctuating protein synthesis encoding ribosomal (TOP) and mitochondrial (TISU) functions.