A robust ultrasensitive transcriptional switch in noisy cellular environments

Abstract

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