Non-transcriptional processes in circadian rhythm generation

Abstract

'Biological clocks' orchestrate mammalian biology to a daily rhythm. Whilst 'clock gene' transcriptional circuits impart rhythmic regulation to myriad cellular systems, our picture of the biochemical mechanisms that determine their circadian (∼24 hour) period is incomplete. Here we consider the evidence supporting different models for circadian rhythm generation in mammalian cells in light of evolutionary factors. We find it plausible that the circadian timekeeping mechanism in mammalian cells is primarily protein-based, signalling biological timing information to the nucleus by the post-translational regulation of transcription factor activity, with transcriptional feedback imparting robustness to the oscillation via hysteresis. We conclude by suggesting experiments that might distinguish this model from competing paradigms.

Figure 1

Models for circadian rhythm generation. (a) Biological clocks consist of a timekeeping mechanism whose phase, period and amplitude may be regulated by various inputs. Outputs of the clock control rhythmic metabolism, physiology and behaviour of organisms, and some of these may in turn feedback to modulate the timekeeping mechanism itself, thus also acting as inputs. Rhythmic input regulation is not essential for circadian rhythm generation however. (b) TTFL-based model for cellular circadian timekeeping: the TTFL itself can sustain oscillations, with the 24-hour period conferred by a post-translational delay-timer. The clock-controlled genes are direct outputs of the TTFL, and result in rhythmic cell function. Some of these outputs can feed back to regulate TTFL function. (c) Post-translational model for cellular circadian timekeeping: a self-sustained post-translational timekeeping mechanism is sufficient to sustain ∼24h rhythms in enzyme activity. The TTFL acts as a signal transducer, receiving timing information from this biochemical oscillation through post-translational modification of TTFL components, to differentially regulate transcription of clock and clock-controlled genes. The TTFL may confer robustness upon the post-translational oscillation by amplifying timing information and also by differentially regulating the activity of the enzymes that post-translationally modify clock proteins.

Figure 2

Comparing the circadian cycle to the cell cycle G1/S transition. A critical point for both the cell cycle and the circadian cycle is the activation of key transcription factors. This is achieved in both cases by the relief of repression by a negative regulator. The mechanism for this is phosphorylation: of Rb by cyclin-dependent kinases for the cell cycle, and of PER by CK1δ/ε for the circadian cycle. Hence the de-repression of crucial activating transcription factors via kinase activity is a common network motif for the temporal regulation of cellular processes.