M. Ali Al-Radhawi, Krishna Manoj, Dhruv D. Jatkar, Alon Duvall, Domitilla Del Vecchio, Eduardo D. Sontag
{"title":"Competition for binding targets results in paradoxical effects for simultaneous activator and repressor action -- Extended Version","authors":"M. Ali Al-Radhawi, Krishna Manoj, Dhruv D. Jatkar, Alon Duvall, Domitilla Del Vecchio, Eduardo D. Sontag","doi":"arxiv-2403.14820","DOIUrl":null,"url":null,"abstract":"In the context of epigenetic transformations in cancer metastasis, a puzzling\neffect was recently discovered, in which the elimination (knock-out) of an\nactivating regulatory element leads to increased (rather than decreased)\nactivity of the element being regulated. It has been postulated that this\nparadoxical behavior can be explained by activating and repressing\ntranscription factors competing for binding to other possible targets. It is\nvery difficult to prove this hypothesis in mammalian cells, due to the large\nnumber of potential players and the complexity of endogenous intracellular\nregulatory networks. Instead, this paper analyzes this issue through an\nanalogous synthetic biology construct which aims to reproduce the paradoxical\nbehavior using standard bacterial gene expression networks. The paper first\nreviews the motivating cancer biology work, and then describes a proposed\nsynthetic construct. A mathematical model is formulated, and basic properties\nof uniqueness of steady states and convergence to equilibria are established,\nas well as an identification of parameter regimes which should lead to\nobserving such paradoxical phenomena (more activator leads to less activity at\nsteady state). A proof is also given to show that this is a steady-state\nproperty, and for initial transients the phenomenon will not be observed. This\nwork adds to the general line of work of resource competition in synthetic\ncircuits.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":"21 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"arXiv - QuanBio - Molecular Networks","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/arxiv-2403.14820","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
In the context of epigenetic transformations in cancer metastasis, a puzzling
effect was recently discovered, in which the elimination (knock-out) of an
activating regulatory element leads to increased (rather than decreased)
activity of the element being regulated. It has been postulated that this
paradoxical behavior can be explained by activating and repressing
transcription factors competing for binding to other possible targets. It is
very difficult to prove this hypothesis in mammalian cells, due to the large
number of potential players and the complexity of endogenous intracellular
regulatory networks. Instead, this paper analyzes this issue through an
analogous synthetic biology construct which aims to reproduce the paradoxical
behavior using standard bacterial gene expression networks. The paper first
reviews the motivating cancer biology work, and then describes a proposed
synthetic construct. A mathematical model is formulated, and basic properties
of uniqueness of steady states and convergence to equilibria are established,
as well as an identification of parameter regimes which should lead to
observing such paradoxical phenomena (more activator leads to less activity at
steady state). A proof is also given to show that this is a steady-state
property, and for initial transients the phenomenon will not be observed. This
work adds to the general line of work of resource competition in synthetic
circuits.