We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Transcription factor competition facilitates self-sustained oscillations in single gene genetic circuits.
- Authors
Landman, Jasper; Verduyn Lunel, Sjoerd M.; Kegel, Willem K.
- Abstract
Genetic feedback loops can be used by cells to regulate internal processes or to keep track of time. It is often thought that, for a genetic circuit to display self-sustained oscillations, a degree of cooperativity is needed in the binding and unbinding of actor species. This cooperativity is usually modeled using a Hill function, regardless of the actual promoter architecture. Furthermore, genetic circuits do not operate in isolation and often transcription factors are shared between different promoters. In this work we show how mathematical modelling of genetic feedback loops can be facilitated with a mechanistic fold-change function that takes into account the titration effect caused by competing binding sites for transcription factors. The model shows how the titration effect facilitates self-sustained oscillations in a minimal genetic feedback loop: a gene that produces its own repressor directly without cooperative transcription factor binding. The use of delay-differential equations leads to a stability contour that predicts whether a genetic feedback loop will show self-sustained oscillations, even when taking the bursty nature of transcription into account. Author summary: Cells keep track of time by genetic feedback loops—transcription factor proteins that repress their own production and whose availability oscillates regularly in time. For oscillations to occur, the amount of transcription factor that is produced should be extremely sensitive to the amount of transcription factor that is present in the cell. In some genetic circuits, sensitivity comes from the fact that multiple transcription factors need to bind to the gene simultaneously to successfully inhibit its production, but it is also possible to generate this sensitivity when multiple binding sites compete for the same pool of transcription factors. In this work we show how to mathematically model this competition effect, and predict under which circumstances stable oscillations occur.
- Subjects
GENE regulatory networks; TRANSCRIPTION factors; OSCILLATIONS; BINDING sites; GENETIC models
- Publication
PLoS Computational Biology, 2023, Vol 19, Issue 9, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1011525