System-level identification of transcriptional circuits underlying mammalian circadian clocks

  title={System-level identification of transcriptional circuits underlying mammalian circadian clocks},
  author={Hiroki R. Ueda and Satoko Hayashi and Wenbin Chen and Motoaki Sano and Masayuki Machida and Yasufumi Shigeyoshi and Masamitsu Iino and Seiichi Hashimoto},
  journal={Nature Genetics},
Mammalian circadian clocks consist of complexly integrated regulatory loops, making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits. Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional… 

Mammalian circadian clock: the roles of transcriptional repression and delay.

Experimental verification of the roles of each motif as well as post-transcriptional regulation of the circadian oscillator will be the next challenges.

The Interplay of cis-Regulatory Elements Rules Circadian Rhythms in Mouse Liver

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.

Accurate timekeeping is controlled by a cycling activator in Arabidopsis

It is demonstrated that a related Myb-like protein, REVEILLE8 (RVE8), is a direct transcriptional activator of EE-containing clock and output genes, suggesting that the plant clock consists of a highly interconnected, complex regulatory network rather than of coupled morning and evening feedback loops.

Distinct Roles of DBHS Family Members in the Circadian Transcriptional Feedback Loop

The data suggest that all of the DBHS family members serve overlapping or redundant roles as transcriptional cofactors at circadian clock-regulated genes.

Molecular modulators of the circadian clock: lessons from flies and mice

The current knowledge of circadian clock regulation—from transcriptional to post-translational—drawing from literature pertaining to the Drosophila and murine circadian systems is summarized.

CLOCK-Controlled Polyphonic Regulation of Circadian Rhythms through Canonical and Noncanonical E-Boxes

7,978 CLOCK-binding sites in mouse liver are identified by chromatin immunoprecipitation-sequencing (ChIP-Seq), and a newly developed bioinformatics method, motif centrality analysis of ChIP- Seq (MOCCS), revealed a genome-wide distribution of previously unappreciated noncanonical E-boxes targeted by CLOCK.

Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals

It is demonstrated that the RRE-mediated feedback regulation of Bmal1 underpins the E-box-mediated rhythm in cooperation with CRY1-dependent posttranslational regulation of BMAL1 protein, thereby conferring the perturbation-resistant oscillation and chronologically-organized output of the circadian clock.

Periodicity, repression, and the molecular architecture of the mammalian circadian clock

The argument that shared protein interfaces within the clockwork are critical for both the generation of rhythmicity and timing of the clock is made.

Functional D-box sequences reset the circadian clock and drive mRNA rhythms

The role of the D-box genomic element in the circadian clockwork is investigated and 1490 D- box-containing regions that are bound by DBP and E4BP4 in the mouse liver are identified.



A transcription factor response element for gene expression during circadian night

The role of the Rev-ErbA/ROR response element in gene expression during circadian night is demonstrated, which is in phase with Bmal1 and in antiphase to Per2 oscillations.

Dec1 and Dec2 are regulators of the mammalian molecular clock

Dec1 and Dec2 are regulators of the mammalian molecular clock, and form a fifth clock-gene family that repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein–protein interactions with Bmal1 and/or competition for E-box elements.

Role of the CLOCK protein in the mammalian circadian mechanism.

CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.

Interacting molecular loops in the mammalian circadian clock.

Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal 1 loop.

Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus.

A superfamily gene which encodes a bHLH (basic helix-loop-helix)/PAS transcription factor, BMAL1, was cloned and sequenced from rat cDNA and possibly plays a critical role in the clock mechanism generating the circadian oscillation in rats.

Circadian oscillation of a mammalian homologue of the Drosophila period gene

The human and mouse genes (hPER and mPer, respectively) encoding PAS-domain (PAS, a dimerization domain present in Per, Amt and Sim)-containing polypeptides that are highly homologous to dPer are identified.