Emergence of activation or repression in transcriptional control under a fixed molecular context
Open accessPreprint — published as 10.1073/pnas.2413715122
Abstract
For decades, studies have noted that transcription factors (TFs) can behave as either activators or repressors of different target genes. More recently, evidence suggests TFs can act on transcription simultaneously in positive and negative ways. Here we use biophysical models of gene regulation to define, conceptualize and explore these two aspects of TF action: “duality”, where TFs can be overall both activators and repressors at the level of the transcriptional response, and “coherent and incoherent” modes of regulation, where TFs act mechanistically on a given target gene either as an activator or a repressor (coherent) or as both (incoherent). For incoherent TFs, the overall response depends on three kinds of features: the TF’s mechanistic effects, the dynamics and effects of additional regulatory molecules or the transcriptional machinery, and the occupancy of the TF on DNA. Therefore, activation or repression can be tuned by just the TF-DNA binding affinity, or the number of TF binding sites, given an otherwise fixed molecular context. Moreover, incoherent TFs can cause non-monotonic transcriptional responses, increasing over a certain concentration range and decreasing outside the range, and we clarify the relationship between non-monotonicity and common assumptions of gene regulation models. Using the mammalian SP1 as a case study and well controlled, synthetically designed target sequences, we find experimental evidence for incoherent action and activation, repression or non-monotonicity tuned by affinity. Our work highlights the importance of moving from a TF-centric view to a systems view when reasoning about transcriptional control.
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These observations can quantitatively be explained by a biophysical model where a TF activates a rate-limiting step in transcriptional activation and represses other steps, such that a second step becomes rate limiting once a certain TF occupancy is exceeded.
“These observations can quantitatively be explained by a biophysical model46 where a TF activates a rate-limiting step in transcriptional activation and represses other steps, such that a second step becomes rate limiting once a certain TF occupancy is exceeded (Figures 3H and 3I; see STAR Methods, section biophysical models).”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [46]
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Experimental — accuracy not yet measuredUnder common biophysical assumptions, increases in motif number and affinity lead to higher TF occupancy.
“Under common biophysical assumptions, increases in these two quantities lead to higher TF occupancy.46,47”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [46]
Non-monotonous effects of a transcription factor with respect to binding site affinity can arise when gene regulation is limited at multiple steps and the transcription factor acts incoherently on those steps, promoting transcription at some steps and hindering it at others.
“In that work, we show that non-monotonous effects of a TF with respect to binding site affinity can arise when gene regulation is limited at multiple steps, and a TF acts incoherently on those steps, such that it acts on one or more steps to promote transcription, and on other steps to hinder it.”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [46]
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Design principles of cell-state-specific enhancers in hematopoiesis
Frömel, R., Rühle, J., Bernal Martinez, A., Szu-Tu, C., Pacheco Pastor, F., Martinez-Corral, R., & Velten, L. (2025) · Cell · doi:10.1016/j.cell.2025.04.017 · Cited by 29 · see citing works
Self-citation
- Authors
- Martinez-Corral, R., Friedrich, D., Frömel, R., Velten, L., Gunawardena, J., & DePace, A. H.
- Affiliations
- Harvard University (US)
- Universitat Pompeu Fabra (ES)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Martinez-Corral, Rosa
- DePace, Angela H.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- openRxiv
- Published
- 2024-06-02
- Volume
- 122
- Issue
- 39
- Pages
- e2413715122-e2413715122
- ISSN
- 0027-8424 (ISSN-L)
- PMC
- PMC11160767
- OpenAlex
- W4414384778
- Cited by
- 18
- References
- 67
- Citations by year
- 2026: 12 · 2025: 6
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc)
- Funders
- National Science Foundation (1715184, CAREER, 1452557)
- Howard Hughes Medical Institute
- European Molecular Biology Organization (ALTF683-2019)
- European Molecular Biology Laboratory
- Ministerio de Ciencia, Innovación y Universidades (PID2019‐108082GA‐I00, PID2022-142210NA-I00, PID2019, CEX2020-001049-S MCIN/AEI /10.13039/501100011033, RYC2021-033860-I, .13039/501100011033, 501100011033)
- Centres de Recerca de Catalunya (501100011033)
- European Commission (13039/501100011033, 501100011033)
- Generalitat de Catalunya (501100011033, PID2019)
- Ministerio de Ciencia e Innovación (MCIN/AEI/10, .13039/501100011033, RYC2021-033860-I, / AEI/10, PID2019, 501100011033, CEX2020-001049-S, RYC2021, PID2022)
- National Institutes of Health
- Agencia Estatal de Investigación (501100011033, 13039, .13039/501100011033, AEI/10, PID2019)
- National Institute of General Medical Sciences (R01GM122928)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Sp1, transcriptional regulation
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