Integrating regulatory information via combinatorial control of the transcription cycle

Combinatorial regulation of gene expression by multiple transcription factors (TFs) enables cells to carry out sophisticated computations that are key to cellular decision-making. How is the information contained in multiple TF binding sites integrated to dictate the rate of transcription? The dominant model is that direct or indirect physical interactions between TFs enable them to combinatorially recruit each other and RNA polymerase to the promoter. Here we develop a quantitative framework to explore an alternative model, where combinatorial gene regulation can result from TFs working on different kinetic steps of the transcription cycle. Our results clarify the null hypotheses for independent action of TFs and show that combinatorial control of the transcription cycle can generate a wide range of analog and Boolean computations without requiring the input regulators to be simultaneously co-localized in the nucleus. This work emphasizes the importance of deciphering TF function beyond activation and repression, highlights the role of the basal promoter in processing regulatory information and suggests qualitative explanations for the flexibility of regulatory evolution.