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Transcriptional architecture of the mammalian circadian clock

Key Points

  • The mammalian circadian clock mechanism is cell autonomous and composed of a transcription–translation negative-feedback loop. These clocks are distributed throughout the body and regulate tissue-specific rhythmic functions.

  • The core circadian transcriptional regulators drive gene expression rhythms in thousands of genes. The targets of the CLOCK–BMAL1 complex in the mouse liver regulate genes in all fundamental metabolic pathways, thus indicating that the clock system is closely embedded in cellular metabolism.

  • Circadian activators and repressors recruit a wide array of chromatin modifiers that mediate dynamic changes in the poising of the genome with time of day.

  • RNA polymerase II is recruited and initiated genome-wide in a circadian manner in the mouse liver, leading to genome-wide circadian changes in histone modifications.

  • Circadian CLOCK–BMAL1 gene targets are directly linked to metabolism, immune function, cell proliferation, cancer and signalling.

Abstract

Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription–translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.

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Figure 1: Circadian rhythms are adaptations of organismal physiology to resonate with the daily solar energetic cycle on earth.
Figure 2: The circadian gene network in mammals.
Figure 3: The circadian cistrome of the mouse liver.
Figure 4: Whole-transcriptome RNA sequencing analysis of circadian gene expression in the mouse liver.
Figure 5: Circadian chromatin states in the mouse liver.
Figure 6: Circadian transcriptional landscape in the mouse liver.
Figure 7: Circadian transcriptional regulation at enhancer and promoter sites during the CLOCK–BMAL1 activation phase during the daytime.

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Acknowledgements

The author thanks three anonymous reviewers for their constructive comments. Apologies to those whose work was not cited owing to content and length constraints. The author thanks N. Koike and T.-K. Kim for critical contributions to the research presented here. This work was supported by the Howard Hughes Medical Institute and US National Institutes of Health (NIH) grants R01AG045795 (to J.S.T.) and R21MH107672 (to G. Konopka and J.S.T.).

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Correspondence to Joseph S. Takahashi.

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The author is a co-founder and scientific advisory board member of Reset Therapeutics.

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Glossary

Convergent evolution

The process by which unrelated organisms independently evolve similar traits as a result of adapting to similar environments or selective pressures.

Network motif

As defined by Uri Alon, a small set of recurring regulatory patterns in a network.

Oscillations

Repetitive variations of variables over time with a stable frequency or period.

E-boxes

Also known as enhancer boxes, these are short DNA regulatory elements in some eukaryotic promoters that act as binding sites for transcription factors and have thus been found to regulate gene expression. For CLOCK–BMAL1, the consensus sequence for this cis-regulatory element is CACGTG.

RevDR2 and retinoic acid-related orphan receptor (ROR)-binding elements

(ROREs). The cis-regulatory elements for the nuclear receptors REV-ERB and ROR. The consensus sequence of RevDR2/RORE motifs involve RGGTCA half-sites preceded by an (A/T)-rich region.

D-boxes

Short cis-regulatory elements for the PAR-zip transcription factors DBP (D-box binding protein), HLF (hepatic leukaemia factor) and TEF (thyrotroph embryonic factor). The common sequence of a D-box is TTATG(C/T)AA.

Phases of expression

The time of the day when peak gene expression occurs.

Period

The length of the circadian rhythm measured from specific phase points in each cycle; for example, the peak-to-peak interval.

Phosphoswitch

In the case of the PER2 protein, a phosphoswitch model is proposed whereby two competing phosphorylation sites (one for the FASPD site and one for the β-TrCP binding site) determine whether PER2 has a fast or slow degradation rate.

Cistrome

The in vivo genome-wide location of transcription factor-binding sites.

'Kamikaze' model of transcriptional activation

Describes the ubiquitin-dependent proteolysis of transcriptional activators, which suggests a role for activator degradation in RNA polymerase II elongation and the requirement for reloading of newly synthesized activators.

Circadian time

(CT). A standard of time based on the free-running period of a rhythm (oscillation). By convention, CT0 is the beginning of the subjective day and CT12 is the beginning of the subjective night.

Global Run-On sequencing

(GRO-seq). A nuclear run-on assay method that captures nascent transcripts from initiated RNA polymerase II followed by next-generation sequencing.

Zeitgeber time

(ZT). A standard of time based on the period of an environmental synchronizer or zeitgeber, such as the 24-hour diurnal cycle of light and darkness. Under standard light–dark cycles, the time of 'lights on' usually defines zeitgeber time zero (ZT0) for diurnal organisms and the time of 'lights off' defines ZT12 for nocturnal animals.

Nascent-seq

Next-generation sequencing of nascent RNA transcripts based on chromatin-associated RNA transcripts, nuclear run-on global transcripts, such as GRO-seq or PRO-seq, or RNA sequencing of transcripts immunoprecipitated with RNA polymerase II.

Laplacian analysis

A framework used in many disciplines to quantify topologies in which autonomous entities reach a consensus without a central direction. In the 4D nucleome, it is used to describe the underlying topology of genome-wide chromosome conformation capture interactions in the genome.

Lamina-associated domains

Regions of condensed chromatin that are bound by the nuclear lamina and are enriched for repressive histone marks such as H3K9me2.

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Takahashi, J. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 18, 164–179 (2017). https://doi.org/10.1038/nrg.2016.150

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