Circadian timekeeping and output mechanisms in animals

Abstract

Daily rhythms in animal behavior, physiology and metabolism are driven by cell-autonomous clocks that are synchronized by environmental cycles, but maintain ~24 hours rhythms even in the absence of environmental cues. These clocks keep time and control overt rhythms via interlocked transcriptional feedback loops, making it imperative to define the mechanisms that drive rhythmic transcription within these loops and on a genome-wide scale. Recent work identifies novel post-transcriptional and post-translational mechanisms that govern progression through these feedback loops to maintain a period of ~24 hours. Likewise, new microarray and deep sequencing studies reveal interplay among clock activators, chromatin remodeling and RNA Pol II binding to set the phase of gene transcription and drive post-transcriptional regulatory systems that may greatly increase the proportion of genes that are under clock control. Despite great progress, gaps in our understanding of how feedback loop transcriptional programs maintain ~24 hours cycles and drive overt rhythms remain.

Day–night cycles and the sleep-promoting factor, Sleepless, affect stem cell activity in the Drosophila testis

“…Although synchronized to the periodic environment, rhythms controlled by the circadian clock can persist for prolonged periods of time, even when the cycling of light or other environmental signals is abolished (i.e., in a constant environment) (19). In contrast, those biological cycles that are not supported by the endogenous clock mechanism dampen rapidly in the dark [12:12-h dark-dark (DD) cycle].…”

Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock

“…The circadian rhythm is the cyclic change in biochemical, physiological, and behavioral functions of organisms with a periodicity of ;24 h. In mammalian organisms, this cell-autonomous and self-sustained rhythm is generated by a transcription-translation feedback loop (TTFL) (Reppert and Weaver 2002;Hardin and Panda 2013;Partch et al 2014). According to the commonly accepted model (''canonical model''), the core clock circuitry is composed of four genes/proteins and their paralogs (Clock [Npas2], Bmal1, Cry [Cry1 and Cry2], and Per [Per1 and Per2]), which generate rhythmicity in the following manner: CLOCK and BMAL1 transcriptional activators bind to E-box sequences in the promoters of Cry and Per genes and activate their transcription; CRY and PER proteins then accumulate in the cytoplasm and, after a time delay, enter the nucleus as a heterodimer and inhibit their own transcription (Kume et al 1999;Vitaterna et al 1999;Zheng et al 1999Zheng et al , 2001Shearman et al 2000) as well as the transcription of other output genes controlled by CLOCK-BMAL1 ( Fig.…”

Mammalian Period represses and de-represses transcription by displacing CLOCK–BMAL1 from promoters in a Cryptochrome-dependent manner

“…In mammals, CLOCK, BMAL1, Cryptochrome (CRY), and Period (PER) proteins and their paralogs are essential for generating rhythmicity (1)(2)(3)(4). Rhythmicity is the product of a transcription-translation feedback loop (TTFL): The circadian locomotor output cycles kaput (CLOCK)-brain and muscle Arnt-like protein-1 (BMAL1) heterodimer binds to E-boxes in the promoters of Cry1, Cry2, Per1, and Per2 genes and activates their transcription.…”