RELATCH: relative optimality in metabolic networks explains robust metabolic and regulatory responses to perturbations.
Ontology highlight
ABSTRACT:
SUBMITTER: Kim J
PROVIDER: S-EPMC3506949 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:An important goal of whole-cell computational modeling is to integrate detailed biochemical information with biological intuition to produce testable predictions. Based on the premise that prokaryotes such as Escherichia coli have maximized their growth performance along evolution, flux balance analysis (FBA) predicts metabolic flux distributions at steady state by using linear programming. Corroborating earlier results, we show that recent intracellular flux data for wild-type E. coli JM101 display excellent agreement with FBA predictions. Although the assumption of optimality for a wild-type bacterium is justifiable, the same argument may not be valid for genetically engineered knockouts or other bacterial strains that were not exposed to long-term evolutionary pressure. We address this point by introducing the method of minimization of metabolic adjustment (MOMA), whereby we test the hypothesis that knockout metabolic fluxes undergo a minimal redistribution with respect to the flux configuration of the wild type. MOMA employs quadratic programming to identify a point in flux space, which is closest to the wild-type point, compatibly with the gene deletion constraint. Comparing MOMA and FBA predictions to experimental flux data for E. coli pyruvate kinase mutant PB25, we find that MOMA displays a significantly higher correlation than FBA. Our method is further supported by experimental data for E. coli knockout growth rates. It can therefore be used for predicting the behavior of perturbed metabolic networks, whose growth performance is in general suboptimal. MOMA and its possible future extensions may be useful in understanding the evolutionary optimization of metabolism.
| S-EPMC137552 | biostudies-literature
Project description:Transcriptional motifs are small regulatory interaction patterns that regulate biological functions in highly-interacting cellular networks. Recently, attempts have been made to explain the significance of transcriptional motifs through dynamic function. However, fundamental questions remain unanswered. Why are certain transcriptional motifs with similar dynamic function abundant while others occur rarely? What are the criteria for topological generalization of these motifs into complex networks? Here, we present a novel paradigm that combines non-equilibrium thermodynamics with multiobjective-optimality for network analysis. We found that energetic cost, defined herein as specific dissipation energy, is minimal at the optimal environmental conditions and it correlates inversely with the abundance of the network motifs obtained experimentally for E. coli and S. cerevisiae. This yields evidence that dissipative energetics is the underlying criteria used during evolution for motif selection and that biological systems during transcription tend towards evolutionary selection of subgraphs which produces minimum specific heat dissipation under optimal conditions, thereby explaining the abundance/rare occurrence of some motifs. We show that although certain motifs had similar dynamical functionality, they had significantly different energetic cost, thus explaining the abundance/rare occurrence of these motifs. The presented insights may establish global thermodynamic analysis as a backbone in designing and understanding complex networks systems, such as metabolic and protein interaction networks.
| S-EPMC3964374 | biostudies-literature
Project description:Design and implementation of robust network modules is essential for construction of complex biological systems through hierarchical assembly of 'parts' and 'devices'. The robustness of gene regulatory networks (GRNs) is ascribed chiefly to the underlying topology. The automatic designing capability of GRN topology that can exhibit robust behavior can dramatically change the current practice in synthetic biology. A recent study shows that Darwinian evolution can gradually develop higher topological robustness. Subsequently, this work presents an evolutionary algorithm that simulates natural evolution in silico, for identifying network topologies that are robust to perturbations. We present a Monte Carlo based method for quantifying topological robustness and designed a fitness approximation approach for efficient calculation of topological robustness which is computationally very intensive. The proposed framework was verified using two classic GRN behaviors: oscillation and bistability, although the framework is generalized for evolving other types of responses. The algorithm identified robust GRN architectures which were verified using different analysis and comparison. Analysis of the results also shed light on the relationship among robustness, cooperativity and complexity. This study also shows that nature has already evolved very robust architectures for its crucial systems; hence simulation of this natural process can be very valuable for designing robust biological systems.
| S-EPMC4304830 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, "undetermined"). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations ("undetermined") harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.ConclusionStratification of intrahepatic cholangiocarcinoma patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (Hepatology 2018).
| S-EPMC6599967 | biostudies-literature
Project description:Progress in systems biology depends on accurate descriptions of biological networks. Connections in a regulatory network are identified as correlations of gene expression across a set of environmental or genetic perturbations. To use this information to predict system behavior, we must test how the nature of perturbations affects topologies of networks they reveal. To probe this question, we focused on metabolism of Drosophila melanogaster. Our source of perturbations is a set of crosses among 92 wild-derived lines from five populations, replicated in a manner permitting separate assessment of the effects of genetic variation and environmental fluctuation. We directly assayed activities of enzymes and levels of metabolites. Using a multivariate Bayesian model, we estimated covariance among metabolic parameters and built fine-grained probabilistic models of network topology. The environmental and genetic co-regulation networks are substantially the same among five populations. However, genetic and environmental perturbations reveal qualitative differences in metabolic regulation, suggesting that environmental shifts, such as diet modifications, produce different systemic effects than genetic changes, even if the primary targets are the same.
| S-EPMC3738848 | biostudies-other
Project description:BackgroundComputational modeling and analysis of metabolic networks has been successful in metabolic engineering of microbial strains for valuable biochemical production. Limitations of currently available computational methods for metabolic engineering are that they are often based on reaction deletions rather than gene deletions and do not consider the regulatory networks that control metabolism. Due to the presence of multi-functional enzymes and isozymes, computational designs based on reaction deletions can sometimes result in strategies that are genetically complicated or infeasible. Additionally, strains might not be able to grow initially due to regulatory restrictions. To overcome these limitations, we have developed a new approach (OptORF) for identifying metabolic engineering strategies based on gene deletion and overexpression.ResultsHere we propose an effective method to systematically integrate transcriptional regulatory networks and metabolic networks. This allows for the formulation of linear optimization problems that search for metabolic and/or regulatory perturbations that couple biomass and biochemical production, thus proposing adaptive evolutionary strain designs. Using genome-scale models of Escherichia coli, we have implemented the OptORF algorithm (which considers gene deletions and transcriptional regulation) and compared its metabolic engineering strategies for ethanol production to those found using OptKnock (which considers reaction deletions). Our results found that the reaction-based strategies often require more gene deletions to remove the identified reactions (2 more genes than reactions), and result in lethal growth phenotypes when transcriptional regulation is considered (162 out of 200 cases). Finally, we present metabolic engineering strategies for producing ethanol and higher alcohols (e.g. isobutanol) in E. coli using our OptORF approach. We have found common genetic modifications such as deletion of pgi and overexpression of edd, as well as chemical specific strategies for producing different alcohols.ConclusionsBy taking regulatory effects into account, OptORF can propose changes such as the overexpression of metabolic genes or deletion of transcriptional factors, in addition to the deletion of metabolic genes, that may lead to faster evolutionary trajectories. While biofuel production in E. coli is evaluated here, the developed OptORF approach is general and can be applied to optimize the production of different compounds in other biological systems.
| S-EPMC2887412 | biostudies-literature
Project description:BACKGROUND:Gene regulatory networks (GRNs) can be inferred from both gene expression data and genetic perturbations. Under different conditions, the gene data of the same gene set may be different from each other, which results in different GRNs. Detecting structural difference between GRNs under different conditions is of great significance for understanding gene functions and biological mechanisms. RESULTS:In this paper, we propose a Bayesian Fused algorithm to jointly infer differential structures of GRNs under two different conditions. The algorithm is developed for GRNs modeled with structural equation models (SEMs), which makes it possible to incorporate genetic perturbations into models to improve the inference accuracy, so we name it BFDSEM. Different from the naive approaches that separately infer pair-wise GRNs and identify the difference from the inferred GRNs, we first re-parameterize the two SEMs to form an integrated model that takes full advantage of the two groups of gene data, and then solve the re-parameterized model by developing a novel Bayesian fused prior following the criterion that separate GRNs and differential GRN are both sparse. CONCLUSIONS:Computer simulations are run on synthetic data to compare BFDSEM to two state-of-the-art joint inference algorithms: FSSEM and ReDNet. The results demonstrate that the performance of BFDSEM is comparable to FSSEM, and is generally better than ReDNet. The BFDSEM algorithm is also applied to a real data set of lung cancer and adjacent normal tissues, the yielded normal GRN and differential GRN are consistent with the reported results in previous literatures. An open-source program implementing BFDSEM is freely available in Additional file 1.
| S-EPMC6953167 | biostudies-literature
Project description:A high level of robustness against gene deletion is observed in many organisms. However, it is still not clear which biochemical features underline this robustness and how these are acquired during evolution. One hypothesis, specific to metabolic networks, is that robustness emerges as a byproduct of selection for biomass production in different environments. To test this hypothesis we performed evolutionary simulations of metabolic networks under stable and fluctuating environments. We find that networks evolved under the latter scenario can better tolerate single gene deletion in specific environments. Such robustness is underlined by an increased number of independent fluxes and multifunctional enzymes in the evolved networks. Observed robustness in networks evolved under fluctuating environments was "apparent," in the sense that it decreased significantly as we tested effects of gene deletions under all environments experienced during evolution. Furthermore, when we continued evolution of these networks under a stable environment, we found that any robustness they had acquired was completely lost. These findings provide evidence that evolution under fluctuating environments can account for the observed robustness in metabolic networks. Further, they suggest that organisms living under stable environments should display lower robustness in their metabolic networks, and that robustness should decrease upon switching to more stable environments.
| S-EPMC2928748 | biostudies-literature
Project description:Gene regulation is an intrinsically noisy process, which is subject to intracellular and extracellular noise perturbations and environment fluctuations. In this paper, we consider the robust stability analysis problem of genetic regulatory networks with time-varying delays and stochastic perturbation. Different from other papers, the genetic regulate system considers not only stochastic perturbation but also parameter disturbances, it is in close proximity to the real gene regulation process than determinate model. Based on the Lyapunov functional theory, sufficient conditions are given to ensure the stability of the genetic regulatory networks. All the stability conditions are given in terms of LMIs which are easy to be verified. Illustrative examples are presented to show the effectiveness of the obtained results.
| S-EPMC2727162 | biostudies-other
Project description:Predicting the sign of press perturbation responses in ecological networks is challenging, due to the poor knowledge of the strength of the direct interactions among the species, and to the entangled coexistence of direct and indirect effects. We show in this paper that, for a class of networks that includes mutualistic and monotone networks, the sign of press perturbation responses can be qualitatively determined based only on the sign pattern of the community matrix, without any knowledge of parameter values. For other classes of networks, we show that a semi-qualitative approach yields sufficient conditions for community matrices with a given sign pattern to exhibit mutualistic responses to press perturbations; quantitative conditions can be provided as well for community matrices that are eventually nonnegative. We also present a computational test that can be applied to any class of networks so as to check whether the sign of the responses to press perturbations is constant in spite of parameter variations.
| S-EPMC5596000 | biostudies-literature