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.

Figure 1

Interlocked feedback loops that keep circadian time. Genetic architecture of the core and interlocked feedback loops of Drosophila (a) and mice (b). Gene, protein and regulatory element names are as defined in the text. Sinusoidal lines represent rhythmic mRNAs; arrows depict the synthesis, assembly and/or localization of clock proteins; blocked line denotes repression; gray background indicates events in the nucleus; white background indicates events in the cytoplasm.

Figure 2

Regulatory events in the core loop of Drosophila that control 24 hours periodicity. Gene, protein and regulatory element names are as defined in the text. CLKK represents kinases that phosphorylate CLK; CLKP denotes phosphatases that dephosphorylate CLK; stippled proteins indicate degradation; black sinusoidal lines represent active transcription; gray sinusoidal lines represent repressed transcription; arrows depict the synthesis, assembly and/or localization of clock proteins; dashed lines denote the action of regulatory proteins; lines marked with pppG and AAAA depict mature mRNAs; P depicts phosphorylation, G indicates O-GlcNAcylation; U represents ubiquitylation; gray background indicates events in the nucleus; white background indicates events in the cytoplasm.

Figure 3

Transcriptional regulation of circadian gene expression. Protein and regulatory element names are as defined in the text. Arrows, sequence of events triggered by CLOCK–BMAL1 binding to E-boxes; dashed lines, influence of transcription factors; chromatin remodeling factors, factors that alter chromatin structure; phase variation, regulation of nascent RNA cycling phase; parentheses, possible explanation for phenomena. See text for detailed description.