Browsing by Author "Gedeon, Tomáš"

Now showing 1 - 9 of 9

Experimental guidance for discovering genetic networks through hypothesis reduction on time series
(Public Library of Science, 2022-10) Cummins, Breschine; Motta, Francis C.; Moseley, Robert C.; Deckard, Anastasia; Campione, Sophia; Gedeon, Tomáš; Mischaikow, Konstantin; Haase, Steven B.
Large programs of dynamic gene expression, like cell cyles and circadian rhythms, are controlled by a relatively small “core” network of transcription factors and post-translational modifiers, working in concerted mutual regulation. Recent work suggests that system-independent, quantitative features of the dynamics of gene expression can be used to identify core regulators. We introduce an approach of iterative network hypothesis reduction from time-series data in which increasingly complex features of the dynamic expression of individual, pairs, and entire collections of genes are used to infer functional network models that can produce the observed transcriptional program. The culmination of our work is a computational pipeline, Iterative Network Hypothesis Reduction from Temporal Dynamics (Inherent dynamics pipeline), that provides a priority listing of targets for genetic perturbation to experimentally infer network structure. We demonstrate the capability of this integrated computational pipeline on synthetic and yeast cell-cycle data.
Extremal event graphs: A (stable) tool for analyzing noisy time series data
(American Institute of Mathematical Sciences, 2023-01) Belton, Robin; Cummins, Bree; Gedeon, Tomáš; Fasy, Brittany Terese
Local maxima and minima, or extremal events, in experimental time series can be used as a coarse summary to characterize data. However, the discrete sampling in recording experimental measurements suggests uncertainty on the true timing of extrema during the experiment. This in turn gives uncertainty in the timing order of extrema within the time series. Motivated by applications in genomic time series and biological network analysis, we construct a weighted directed acyclic graph (DAG) called an extremal event DAG using techniques from persistent homology that is robust to measurement noise. Furthermore, we define a distance between extremal event DAGs based on the edit distance between strings. We prove several properties including local stability for the extremal event DAG distance with respect to pairwise distances between functions in the time series data. Lastly, we provide algorithms, publicly free software, and implementations on extremal event DAG construction and comparison.
Joint realizability of monotone Boolean functions
(Elsevier BV, 2022-06) Crawford-Kahrl, Peter; Cummins, Bree; Gedeon, Tomáš
The study of monotone Boolean functions (MBFs) has a long history. We explore a connection between MBFs and ordinary differential equation (ODE) models of gene regulation, and, in particular, a problem of the realization of an MBF as a function describing the state transition graph of an ODE. We formulate a problem of joint realizability of finite collections of MBFs by establishing a connection between the parameterized dynamics of a class of ODEs and a collection of MBFs. We pose a question of what collections of MBFs can be realized by ODEs that belong to nested classes defined by increased algebraic complexity of their right-hand sides. As we progressively restrict the algebraic form of the ODE, we show by a combination of theory and explicit examples that the class of jointly realizable functions strictly decreases. Our results impact the study of regulatory network dynamics, as well as the classical area of MBFs. We conclude with a series of potential extensions and conjectures.
Lattice structures that parameterize regulatory network dynamics
(Elsevier BV, 2024-08) Gedeon, Tomáš
We consider two types of models of regulatory network dynamics: Boolean maps and systems of switching ordinary differential equations. Our goal is to construct all models in each category that are compatible with the directed signed graph that describe the network interactions. This leads to consideration of lattice of monotone Boolean functions (MBF), poset of non-degenerate MBFs, and a lattice of chains in these sets. We describe explicit inductive construction of these posets where the induction is on the number of inputs in MBF. Our results allow enumeration of potential dynamic behavior of the network for both model types, subject to practical limitation imposed by the size of the lattice of MBFs described by the Dedekind number.
Modeling Transport Regulation in Gene Regulatory Networks
(Springer Science and Business Media LLC, 2022-07) Fox, Erika; Cummins, Bree; Duncan, William; Gedeon, Tomáš
A gene regulatory network summarizes the interactions between a set of genes and regulatory gene products. These interactions include transcriptional regulation, protein activity regulation, and regulation of the transport of proteins between cellular compartments. DSGRN is a network modeling approach that builds on traditions of discrete-time Boolean models and continuous-time switching system models. When all interactions are transcriptional, DSGRN uses a combinatorial approximation to describe the entire range of dynamics that is compatible with network structure. Here we present an extension of the DGSRN approach to transport regulation across a boundary between compartments, such as a cellular membrane. We illustrate our approach by searching a model of the p53-Mdm2 network for the potential to admit two experimentally observed distinct stable periodic cycles.
Network topology and interaction logic determine states it supports
(Springer Science and Business Media LLC, 2024-08) Gedeon, Tomáš
In this review paper we summarize a recent progress on the problem of describing range of dynamics supported by a network. We show that there is natural connection between network models consisting of collections of multivalued monotone boolean functions and ordinary differential equations models. We show how to construct such collections and use them to answer questions about prevalence of cellular phenotypes that correspond to equilibria of network models.
Operon dynamics with state dependent transcription and/or translation delays
(Springer Science and Business Media LLC, 2022-01) Gedeon, Tomáš; Humphries, Antony R.; Mackey, Michael C.; Walther, Hans-Otto; Wang, Zhao
Transcription and translation retrieve and operationalize gene encoded information in cells. These processes are not instantaneous and incur significant delays. In this paper we study Goodwin models of both inducible and repressible operons with state-dependent delays. The paper provides justification and derivation of the model, detailed analysis of the appropriate setting of the corresponding dynamical system, and extensive numerical analysis of its dynamics. Comparison with constant delay models shows significant differences in dynamics that include existence of stable periodic orbits in inducible systems and multistability in repressible systems. A combination of parameter space exploration, numerics, analysis of steady state linearization and bifurcation theory indicates the likely presence of Shilnikov-type homoclinic bifurcations in the repressible operon model.
Rational design of complex phenotype via network models
(Public Library of Science, 2021-07) Gameiro, Marcio; Gedeon, Tomáš; Kepley, Shane; Mischaikow, Konstantin
We demonstrate a modeling and computational framework that allows for rapid screening of thousands of potential network designs for particular dynamic behavior. To illustrate this capability we consider the problem of hysteresis, a prerequisite for construction of robust bistable switches and hence a cornerstone for construction of more complex synthetic circuits. We evaluate and rank most three node networks according to their ability to robustly exhibit hysteresis where robustness is measured with respect to parameters over multiple dynamic phenotypes. Focusing on the highest ranked networks, we demonstrate how additional robustness and design constraints can be applied. We compare our results to more traditional methods based on specific parameterization of ordinary differential equation models and demonstrate a strong qualitative match at a small fraction of the computational cost.
Rational design of complex phenotype via network models
(Public Library of Science, 2021-07) Gameiro, Marcio; Gedeon, Tomáš; Kepley, Shane; Mischaikow, Konstantin
We demonstrate a modeling and computational framework that allows for rapid screening of thousands of potential network designs for particular dynamic behavior. To illustrate this capability we consider the problem of hysteresis, a prerequisite for construction of robust bistable switches and hence a cornerstone for construction of more complex synthetic circuits. We evaluate and rank most three node networks according to their ability to robustly exhibit hysteresis where robustness is measured with respect to parameters over multiple dynamic phenotypes. Focusing on the highest ranked networks, we demonstrate how additional robustness and design constraints can be applied. We compare our results to more traditional methods based on specific parameterization of ordinary differential equation models and demonstrate a strong qualitative match at a small fraction of the computational cost.