Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Abstract

Transcriptional repression can occur via various mechanisms, such as blocking, sequestration, and displacement. For instance, the repressors can hold the activators to prevent binding with DNA or can bind to the DNA-bound activators to block their transcriptional activity. Although the transcription can be completely suppressed with a single mechanism, multiple repression mechanisms are utilized together to inhibit transcriptional activators in many systems, such as circadian clocks and NF-κB oscillators. This raises the question of what advantages arise if seemingly redundant repression mechanisms are combined. Here, by deriving equations describing the multiple repression mechanisms, we find that their combination can synergistically generate a sharply ultrasensitive transcription response and thus strong oscillations. This rationalizes why the multiple repression mechanisms are used together in various biological oscillators. The critical role of such combined transcriptional repression for strong oscillations is further supported by our analysis of formerly identified mutations disrupting the transcriptional repression of the mammalian circadian clock. The hitherto unrecognized source of the ultrasensitivity, the combined transcriptional repressions, can lead to robust synthetic oscillators with a previously unachievable simple design.

Cell cycle oscillations driven by two interlinked bistable switches

“…Indeed, measurements have shown that fast cell cycle oscillations persist after the first cell cycle despite the fact that (cyclin B, active Cdk1) bistability is absent Tsai et al (2014). Recent work on circadian clocks and NF-κB oscillators driven by a transcriptional negative feedback loop also showed that combinations of multiple (potentially redundant) repression mechanisms are used to generate strong oscillations (sharper responses) Jeong et al (2022). Our results are consistent with those findings and they are also in line with our previous work on combining multiple different functional motifs De Boeck et al (2021).…”

Time-keeping and decision-making in living cells: Part I

“…Burckard et al [20] provide new results on the synchronization of peripheral circadian clocks by intercellular communication between two cells or in small clusters of cells. In the final contribution, Jeong et al [21] investigate the role of multiple modes of transcriptional repression in generating many of these rhythms. By modelling three mechanisms of transcriptional repression—repressor R may bind to activator A on promoter P to block transcription (R:A:P is transcriptionally inactive), R binding to A may displace A from the promoter (R + A:P → R:A:P → R:A + P) and R binding to A may sequester A from P (R:A prevents A from binding to P)—they show that synergistic interactions of the three modes generate ultrasensitive transcriptional responses and robust oscillations.…”

Time-keeping and decision-making in living cells: Part II

“…Burckard et al [3] provided new results on the synchronization of peripheral circadian clocks by intercellular communication between two cells or in small clusters of cells. And Jeong et al [4] investigated the role of multiple modes of transcriptional repression in generating many of these rhythms.…”