article published yes Benjamin Zoller author Thomas Gregor author Gašper Tkačik author 3D494DCA-F248-11E8-B48F-1D18A9856A871 GaTk department Biophysics of information processing in gene regulation project Models of transcriptional regulation that assume equilibrium binding of transcription factors have been less successful at predicting gene expression from sequence in eukaryotes than in bacteria. This could be due to the non-equilibrium nature of eukaryotic regulation. Unfortunately, the space of possible non-equilibrium mechanisms is vast and predominantly uninteresting. The key question is therefore how this space can be navigated efficiently, to focus on mechanisms and models that are biologically relevant. In this review, we advocate for the normative role of theory—theory that prescribes rather than just describes—in providing such a focus. Theory should expand its remit beyond inferring mechanistic models from data, towards identifying non-equilibrium gene regulatory schemes that may have been evolutionarily selected, despite their energy consumption, because they are precise, reliable, fast, or otherwise outperform regulation at equilibrium. We illustrate our reasoning by toy examples for which we provide simulation code. https://research-explorer.ista.ac.at/download/12156/12362/2022_CurrentBiology_Zoller.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ Elsevier2022 eng Applied MathematicsComputer Science ApplicationsDrug DiscoveryGeneral BiochemistryGenetics and Molecular BiologyModeling and Simulation 2452-3100 3659007210.1016/j.coisb.2022.100435 319 B. Zoller, T. Gregor, and G. Tkačik, “Eukaryotic gene regulation at equilibrium, or non?,” <i>Current Opinion in Systems Biology</i>, vol. 31, no. 9. Elsevier, 2022. Zoller B, Gregor T, Tkačik G. 2022. Eukaryotic gene regulation at equilibrium, or non? Current Opinion in Systems Biology. 31(9), 100435. Zoller B, Gregor T, Tkačik G. Eukaryotic gene regulation at equilibrium, or non? <i>Current Opinion in Systems Biology</i>. 2022;31(9). doi:<a href="https://doi.org/10.1016/j.coisb.2022.100435">10.1016/j.coisb.2022.100435</a> B. Zoller, T. Gregor, G. Tkačik, Current Opinion in Systems Biology 31 (2022). Zoller, Benjamin, Thomas Gregor, and Gašper Tkačik. “Eukaryotic Gene Regulation at Equilibrium, or Non?” <i>Current Opinion in Systems Biology</i>. Elsevier, 2022. <a href="https://doi.org/10.1016/j.coisb.2022.100435">https://doi.org/10.1016/j.coisb.2022.100435</a>. Zoller, Benjamin, et al. “Eukaryotic Gene Regulation at Equilibrium, or Non?” <i>Current Opinion in Systems Biology</i>, vol. 31, no. 9, 100435, Elsevier, 2022, doi:<a href="https://doi.org/10.1016/j.coisb.2022.100435">10.1016/j.coisb.2022.100435</a>. Zoller, B., Gregor, T., &#38; Tkačik, G. (2022). Eukaryotic gene regulation at equilibrium, or non? <i>Current Opinion in Systems Biology</i>. Elsevier. <a href="https://doi.org/10.1016/j.coisb.2022.100435">https://doi.org/10.1016/j.coisb.2022.100435</a> 121562023-01-12T12:08:51Z2025-06-11T13:47:43Z