Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

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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 used 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.
Publisher
ROYAL SOC
Issue Date
2022-04
Language
English
Article Type
Article
Citation

INTERFACE FOCUS, v.12, no.3

ISSN
2042-8898
DOI
10.1098/rsfs.2021.0084
URI
http://hdl.handle.net/10203/295854
Appears in Collection
MA-Journal Papers(저널논문)
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