Jeong, E. M. | Search bioRxiv

bioRxiv2023

Robust Ultrasensitive Transcriptional Switch in Noisy Cellular Environments

Ultrasensitive transcriptional switches enable sharp transitions between on and off states of transcription and are essential for cells to respond to environmental cues precisely. However, conventional switches, relying on direct repressor-DNA binding, are extremely sensitive to noise. Here, we discovered an alternative design combining three indirect transcriptional repression mechanisms, sequestration, blocking, and displacement, to generate a noise-resilient ultrasensitive switch. Although sequestration alone can generate an ultrasensitive switch, it remains sensitive to noise because the unintended transcriptional state induced by noise can persist for long periods. However, by jointly utilizing blocking and displacement, these noise-induced transitions can be rapidly restored to the original transcriptional state. Because this transcriptional switch is effective in noisy cellular contexts, it goes beyond previous synthetic transcriptional switches utilizing direct repression mechanisms, making it particularly valuable for robust synthetic system design. Our findings also provide insights into the evolution of robust ultrasensitive switches in real cells. Specifically, the concurrent use of seemingly redundant indirect repression mechanisms in diverse biological systems appears to be a strategy to achieve noise-resilience of ultrasensitive switches. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/553401v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@e6f1e6org.highwire.dtl.DTLVardef@1369deorg.highwire.dtl.DTLVardef@8b9f19org.highwire.dtl.DTLVardef@7a2fec_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2022

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

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-{kappa}B 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.

systems biology↗