Simplifications and approximations in a single-gene circuit modeling

TL;DR

This paper shows how simplifications in modeling gene circuits can lead to different biological outcomes, highlighting the importance of considering molecular details.

Contribution

The study reveals that different modeling assumptions about gene regulation can produce conflicting results, even when based on the same biological principles.

Findings

Models with detailed molecular processes can show instabilities and oscillations not seen in simplified models.

Different cooperative binding mechanisms compatible with the same regulatory function can lead to distinct phenotypes.

Phenomenological assumptions may mask important system behaviors, affecting biological interpretation.

Abstract

The absence of detailed knowledge about regulatory interactions makes the use of phenomenological assumptions mandatory in cell biology modeling. Furthermore, the challenges associated with the analysis of these models compel the implementation of mathematical approximations. However, the constraints these methods introduce to biological interpretation are sometimes neglected. Consequently, understanding these restrictions is a very important task for systems biology modeling. In this article, we examine the impact of such simplifications, taking the case of a single-gene autoinhibitory circuit; however, our conclusions are not limited solely to this instance. We demonstrate that models grounded in the same biological assumptions but described at varying levels of detail can lead to different outcomes, that is, different and contradictory phenotypes or behaviors. Indeed, incorporating specific molecular processes like translation and elongation into the model can introduce instabilities and oscillations not seen when these processes are assumed to be instantaneous. Furthermore, incorporating a detailed description of promoter dynamics, usually described by a phenomenological regulatory function, can lead to instability, depending on the cooperative binding mechanism that is acting. Consequently, although the use of a regulating function facilitates model analysis, it may mask relevant aspects of the system’s behavior. In particular, we observe that the two cooperative binding mechanisms, both compatible with the same sigmoidal function, can lead to different phenotypes, such as transcriptional oscillations with different oscillation frequencies.

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