Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays

Abstract

Feedback inhibition of gene expression is a widespread phenomenon in which the expression of a gene is downregulated by its protein product. Feedback in eukaryotic cells involves time delays resulting from transcription, transcript splicing and processing, and protein synthesis. In principle, such delays can result in oscillatory mRNA and protein expression. However, experimental evidence of such delay-driven oscillations has been lacking. Using mathematical modeling informed by recent data, I show that the observed oscillatory expression and activity of three proteins is most likely to be driven by transcriptional delays. Each protein (Hes1, p53, and NF-kappaB) is a component of a short feedback inhibition loop. The oscillatory period is determined by the delay and the protein and mRNA half-lives, but it is robust to changes in the rates of transcription and protein synthesis. In contrast to nondelayed models, delayed models do not require additional components in the feedback loop. These results provide direct evidence that transcriptional delays can drive oscillatory gene activity and highlight the importance of considering delays when analyzing genetic regulatory networks, particularly in processes such as developmental pattern formation, where short half-lives and feedback inhibition are common.