Regulatory properties of transcription factors with diverse mechanistic function

• Published in: PLoS computational biology 2024-06, Vol.20 (6), p.e1012194
• Main Authors: Ali, Md Zulfikar, Guharajan, Sunil, Parisutham, Vinuselvi, Brewster, Robert C
• Format: Article
• Language: English
• Subjects: Acceleration; Analysis; Binding sites; Biology and Life Sciences; Computational Biology; Computer and Information Sciences; DNA binding proteins; DNA-Directed RNA Polymerases - genetics; DNA-Directed RNA Polymerases - metabolism; Dynamic response; Equilibrium; Gene expression; Gene Expression Regulation - genetics; Genes; Genetic aspects; Genetic regulation; Genetic research; Kinetics; Models, Genetic; Noise sensitivity; Physical Sciences; Promoter Regions, Genetic - genetics; Promoters; Response time; RNA polymerase; RNA polymerases; State regulations; Steady state; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription initiation; Transcription, Genetic - genetics
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1012194

Transcription factors (TFs) regulate the process of transcription through the modulation of different kinetic steps. Although models can often describe the observed transcriptional output of a measured gene, predicting a TFs role on a given promoter requires an understanding of how the TF alters each step of the transcription process. In this work, we use a simple model of transcription to assess the role of promoter identity, and the degree to which TFs alter binding of RNAP (stabilization) and initiation of transcription (acceleration) on three primary characteristics: the range of steady-state regulation, cell-to-cell variability in expression, and the dynamic response time of a regulated gene. We find that steady state regulation and the response time of a gene behave uniquely for TFs that regulate incoherently, i.e that speed up one step but slow the other. We also find that incoherent TFs have dynamic implications, with one type of incoherent mode configuring the promoter to respond more slowly at intermediate TF concentrations. We also demonstrate that the noise of gene expression for these TFs is sensitive to promoter strength, with a distinct non-monotonic profile that is apparent under stronger promoters. Taken together, our work uncovers the coupling between promoters and TF regulatory modes with implications for understanding natural promoters and engineering synthetic gene circuits with desired expression properties.