Emergence of activation or repression in transcriptional control under a fixed molecular context

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• dc.contributor.author Martinez-Corral, Rosa
• dc.contributor.author Friedrich, Dhana
• dc.contributor.author Frömel, Robert
• dc.contributor.author Velten, Lars
• dc.contributor.author Gunawardena, Jeremy
• dc.contributor.author DePace, Angela H.
• dc.date.accessioned 2025-10-15T15:00:42Z
• dc.date.available 2025-10-15T15:00:42Z
• dc.date.issued 2025
• dc.description.abstract Transcription factors (TFs) can be both activators and repressors of gene transcription. This can manifest as "duality," where the transcriptional response increases (activation) with TF concentration in one context but decreases (repression) in another context, or as "nonmonotonicity," where, in the same context, the response increases in part of the concentration range and decreases outside that range. Here we use biophysical models of gene regulation to investigate how duality and nonmonotonicity relate to the interactions between a TF, Polymerase and the regulatory DNA. We distinguish two modes of TF action on Polymerase: "coherent," with interactions either positive or negative, and "incoherent," where interactions are a mix of both. For TFs that act incoherently from a single TF-DNA binding site, nonmonotonicity can arise, but only under nonequilibrium models. For single-site models, we show that nonmonotonicity can never happen under the common thermodynamic models of gene regulation, which consider equilibrium conditions and ignore the dissipative nature of the transcription process. Moreover, we show that merely changing the TF-DNA binding affinity, while keeping other features fixed, can tune the response between activation and repression, with responses either evaluated as a function of TF concentration or site number. Using the mammalian Sp1 as a case study and synthetically designed target sequences, we find experimental evidence for nonmonotonicity, and activation or repression tuned by affinity, which we interpret as evidence of incoherent action. Our work highlights the importance of moving from a TF-centric view to a systems view when reasoning about transcriptional control.
• dc.description.sponsorship This work was supported by the Howard Hughes Medical Institute (A.H.D.), NSF grant MCB-1715184 (D.F. and A.H.D.), NIH grant R01GM122928 (J.G. and A.H.D.), NSF CAREER IOS-1452557 (A.H.D.), the Lynch Foundation (D.F.), European Molecular Biology Organisation (EMBO) Fellowship ALTF683-2019 (R.M.-C.), RYC2021-033860-I funded by MCIN/AEI/10.13039/501100011033 and by European Union NextGenerationEU/PRTR (R.M.-C.), PID2022-142210NA-I00 (R.M.-C.), and PID2019-108082GA-I00 (L.V.) by the Spanish Ministry of Science, Innovation and Universities (MCIU/AEI/FEDER, UE). L.V. also acknowledges support of the Spanish Ministry of Science and Innovation to the European Molecular Biology Laboratory (EMBL) partnership. R.M.-C., L.V., and R.F. acknowledge support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033) and the Generalitat de Catalunya through the Centres de Recerca de Catalunya (CERCA) programme and are grateful to the Center for Genomic Regulation Core Technologies Programme for their support and assistance in this work. Research for this publication has been partially carried out in the Barcelona Collaboratorium. A.H.D. is a Senior Director - Scientific Program Officer of the HHMI.
• dc.format.mimetype application/pdf
• dc.identifier.citation Martinez-Corral R, Friedrich D, Frömel R, Velten L, Gunawardena J, DePace AH. Emergence of activation or repression in transcriptional control under a fixed molecular context. Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2413715122. DOI: 10.1073/pnas.2413715122
• dc.identifier.doi http://dx.doi.org/10.1073/pnas.2413715122
• dc.identifier.issn 0027-8424
• dc.identifier.uri http://hdl.handle.net/10230/71518
• dc.language.iso eng
• dc.publisher National Academy of Sciences
• dc.relation.ispartof Proceedings of the National Academy of Sciences of the United States of America. 2025 Sep 30;122(39):e2413715122
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-142210NA-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108082GA-I00
• dc.rights Copyright © 2025 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Duality
• dc.subject.keyword Gene regulation
• dc.subject.keyword Nonequilibrium regulation
• dc.subject.keyword Nonmonotonicity
• dc.subject.keyword Transcription factor
• dc.title Emergence of activation or repression in transcriptional control under a fixed molecular context
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion