Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Author:

Jeong Eui Min12,Song Yun Min12,Kim Jae Kyoung12ORCID

Affiliation:

1. Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea

2. Biomedical Mathematics Group, Institute for Basic Science, Daejeon 34126, Republic of Korea

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 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.

Funder

National Research Foundation of Korea, Ministry of Science and ICT

Institute for Basic Science

Human Frontier Science Program

Publisher

The Royal Society

Subject

Biomedical Engineering,Biomaterials,Biochemistry,Bioengineering,Biophysics,Biotechnology

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