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Supplemental data for "Stochastic Gene Expression in a Lentiviral Positive Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity" [q-bio.MN/0608002, Cell. 2005 Jul 29;122(2):169-82].
In this work, a machine learning approach for identifying the multi-omics metabolic regulatory control circuits inside the pathways is described. Therefore, the identification of bacterial metabolic pathways that are more regulated than others in term of their multi-omics follows from the analysis of these circuits . This is a consequence of the alternation of the omic values of codon usage and protein abundance along with the circuits. In this work, the E.Coli's Glycolysis and its multi-omic circuit features are shown as an example.
RNA 3D motifs are recurrent substructures, modelled as networks of base pair interactions, which are crucial for understanding structure-function relationships. The task of automatically identifying such motifs is computationally hard, and remains a key challenge in the field of RNA structural biology and network analysis. State of the art methods solve special cases of the motif problem by constraining the structural variability in occurrences of a motif, and narrowing the substructure search space. Here, we relax these constraints by posing the motif finding problem as a graph representation learning and clustering task. This framing takes advantage of the continuous nature of graph representations to model the flexibility and variability of RNA motifs in an efficient manner. We propose a set of node similarity functions, clustering methods, and motif construction algorithms to recover flexible RNA motifs. Our tool, VeRNAl can be easily customized by users to desired levels of motif flexibility, abundance and size. We show that VeRNAl is able to retrieve and expand known classes of motifs, as well as to propose novel motifs.
The multisite phosphorylation-dephosphorylation cycle is a motif repeatedly used in cell signaling. This motif itself can generate a variety of dynamic behaviors like bistability and ultrasensitivity without direct positive feedbacks. In this paper, we study the number of positive steady states of a general multisite phosphorylation-dephosphorylation cycle, and how the number of positive steady states varies by changing the biological parameters. We show analytically that (1) for some parameter ranges, there are at least n+1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2n-1 steady states (in particular, this implies that for n=2, including single levels of MAPK cascades, there are at most three steady states); (3) for parameters near the standard Michaelis-Menten quasi-steady state conditions, there are at most n+1 steady states; and (4) for parameters far from the standard Michaelis-Menten quasi-steady state conditions, there is at most one steady state.
We have built an open-source software system for the modeling of biomolecular reaction networks, SloppyCell, which is written in Python and makes substantial use of third-party libraries for numerics, visualization, and parallel programming. We highlight here some of the powerful features that Python provides that enable SloppyCell to do dynamic code synthesis, symbolic manipulation, and parallel exploration of complex parameter spaces.
Transcription regulation typically involves the binding of proteins over long distances on multiple DNA sites that are brought close to each other by the formation of DNA loops. The inherent complexity of the assembly of regulatory complexes on looped DNA challenges the understanding of even the simplest genetic systems, including the prototypical lac operon. Here we implement a scalable quantitative computational approach to analyze systems regulated through multiple DNA sites with looping. Our approach applied to the lac operon accurately predicts the transcription rate over five orders of magnitude for wild type and seven mutants accounting for all the combinations of deletions of the three operators. A quantitative analysis of the model reveals that the presence of three operators provides a mechanism to combine robust repression with sensitive induction, two seemingly mutually exclusive properties that are required for optimal functioning of metabolic switches.
Schroedinger's book 'What is Life?' is widely credited for having played a crucial role in development of molecular and cellular biology. My essay revisits the issues raised by this book from the modern perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of epigenetic stability: 'epigenetic templating' and 'systems biology' approaches, and consider them from the point of view expressed by Schroedinger. I also discuss how quantum entanglement, a nonclassical feature of quantum mechanics, can help to address the 'problem of small numbers' that lead Schroedinger to promote the idea of molecular code-script for explanation of stability of biological order.
The classical approach to protein folding inspired by statistical mechanics avoids the high dimensional structure of the conformation space by using effective coordinates. Here we introduce a network approach to capture the statistical properties of the structure of conformation spaces. Conformations are represented as nodes of the network, while links are transitions via elementary rotations around a chemical bond. Self-avoidance of a polypeptide chain introduces degree correlations in the conformation network, which in turn lead to energy landscape correlations. Folding can be interpreted as a biased random walk on the conformation network. We show that the folding pathways along energy gradients organize themselves into scale free networks, thus explaining previous observations made via molecular dynamics simulations. We also show that these energy landscape correlations are essential for recovering the observed connectivity exponent, which belongs to a different universality class than that of random energy models. In addition, we predict that the exponent and therefore the structure of the folding network fundamentally changes at high temperatures, as verified by our simulations on the AK peptide.
We report a first in modeling and simulation of the effects of the HIV proteins on the (caspase dependent) apoptotic pathway in infected cells. This work is novel and is an extension on the recent reports and clarifications on the FAS apoptotic pathway from the literature. We have gathered most of the reaction rates and initial conditions from the literature, the rest of the constants have been computed by fitting our model to the experimental results reported. Using the model obtained we have then run the simulations for the infected memory T cells, called also latent T cells, which, at the moment, represent the major obstacle to finding a cure for HIV. We can now report that the infected latent T cells have an estimated lifetime of about 42 hours from the moment they are re-activated. As far as we know this is the first result of this type obtained for the infected memory T cells.
The metabolic networks are very well characterized for a large set of organisms, a unique case in within the large-scale biological networks. For this reason they provide a a very interesting framework for the construction of analytically tractable statistical mechanics models. In this paper we introduce a solvable model for the distribution of fluxes in the metabolic network. We show that the effect of the topology on the distribution of fluxes is to allow for large fluctuations of their values, a fact that should have implications on the robustness of the system.
The problem of reconstructing and identifying intracellular protein signaling and biochemical networks is of critical importance in biology today. We sought to develop a mathematical approach to this problem using, as a test case, one of the most well-studied and clinically important signaling networks in biology today, the epidermal growth factor receptor (EGFR) driven signaling cascade. More specifically, we suggest a method, augmented sparse reconstruction, for the identification of links among nodes of ordinary differential equation (ODE) networks from a small set of trajectories with different initial conditions. Our method builds a system of representation by using a collection of integrals of all given trajectories and by attenuating block of terms in the representation itself. The system of representation is then augmented with random vectors, and minimization of the 1-norm is used to find sparse representations for the dynamical interactions of each node. Augmentation by random vectors is crucial, since sparsity alone is not able to handle the large error-in-variables in the representation. Augmented sparse reconstruction allows to consider potentially very large spaces of models and it is able to detect with high accuracy the few relevant links among nodes, even when moderate noise is added to the measured trajectories. After showing the performance of our method on a model of the EGFR protein network, we sketch briefly the potential future therapeutic applications of this approach.
Pathways are integral to systems biology. Their classical representation has proven useful but is inconsistent in the meaning assigned to each arrow (or edge) and inadvertently implies the isolation of one pathway from another. Conversely, modern high-throughput experiments give rise to standardized networks facilitating topological calculations. Combining these perspectives, we can embed classical pathways within large-scale networks and thus demonstrate the crosstalk between them. As more diverse types of high-throughput data become available, we can effectively merge both perspectives, embedding pathways simultaneously in multiple networks. However, the original problem still remains - the current edge representation is inadequate to accurately convey all the information in pathways. Therefore, we suggest that a standardized, well-defined, edge ontology is necessary and propose a prototype here, as a starting point for reaching this goal.
In this paper, we consider the statistical analysis of a protein interaction network. We propose a Bayesian model that uses a hierarchy of probabilistic assumptions about the way proteins interact with one another in order to: (i) identify the number of non-observable functional modules; (ii) estimate the degree of membership of proteins to modules; and (iii) estimate typical interaction patterns among the functional modules themselves. Our model describes large amount of (relational) data using a relatively small set of parameters that we can reliably estimate with an efficient inference algorithm. We apply our methodology to data on protein-to-protein interactions in saccharomyces cerevisiae to reveal proteins' diverse functional roles. The case study provides the basis for an overview of which scientific questions can be addressed using our methods, and for a discussion of technical issues.
The important task of determining the connectivity of gene networks, and at a more detailed level even the kind of interaction existing between genes, can nowadays be tackled by microarraylike technologies. Yet, there is still a large amount of unknowns with respect to the amount of data provided by a single microarray experiment, and therefore reliable gene network retrieval procedures must integrate all of the available biological knowledge, even if coming from different sources and of different nature. In this paper we present a reverse engineering algorithm able to reveal the underlying gene network by using time-series dataset on gene expressions considering the system response to different perturbations. The approach is able to determine the sparsity of the gene network, and to take into account possible {\it a priori} biological knowledge on it. The validity of the reverse engineering approach is highlighted through the deduction of the topology of several {\it simulated} gene networks, where we also discuss how the performance of the algorithm improves enlarging the amount of data or if any a priori knowledge is considered. We also apply the algorithm to experimental data on a nine gene network in {\it Escherichia coli
Cells store information in DNA and in stable programs of gene expression, which thereby implement forms of long-term cellular memory. Cells must also possess short-term forms of information storage, implemented post-translationally, to transduce and interpret external signals. CaMKII, for instance, is thought to implement a one-bit (bistable) short-term memory required for learning at post-synaptic densities. Here we show by mathematical analysis that multisite protein phosphorylation, which is ubiquitous in all eukaryotic signalling pathways, exhibits multistability for which the maximal number of steady states increases with the number of sites. If there are n sites, the maximal information storage capacity is at least log_2 (n+2)/2 bits when n is even and log_2 (n+1)/2 bits when n is odd. Furthermore, when substrate is in excess, enzyme saturation together with an alternating low/high pattern in the site-specific relative catalytic efficiencies, enriches for multistability. That is, within physiologically plausible ranges for parameters, multistability becomes more likely than monostability. We discuss the experimental challenges in pursuing these predictions and in determining the biological role of short-term information storage.
A probabilistic structure on sequential dynamical systems is introduced here, the new model will be called Probabilistic Sequential Network, PSN. The morphisms of Probabilistic Sequential Networks are defined using two algebraic conditions. It is proved here that two homomorphic Probabilistic Sequential Networks have the same equilibrium or steady state probabilities if the morphism is either an epimorphism or a monomorphism. Additionally, the proof of the set of PSN with its morphisms form the category PSN, having the category of sequential dynamical systems SDS, as a full subcategory is given. Several examples of morphisms, subsystems and simulations are given.
Sequence alignment forms the basis of many methods for functional annotation by phylogenetic comparison, but becomes unreliable in the `twilight' regions of high sequence divergence and short gene length. Here we perform a cross-species comparison of two herpesviruses, VZV and KSHV, with a hybrid method called graph alignment. The method is based jointly on the similarity of protein interaction networks and on sequence similarity. In our alignment, we find open reading frames for which interaction similarity concurs with a low level of sequence similarity, thus confirming the evolutionary relationship. In addition, we find high levels of interaction similarity between open reading frames without any detectable sequence similarity. The functional predictions derived from this alignment are consistent with genomic position and gene expression data.
The lac operon of Escherichia coli exhibits bistability. Early studies showed that bistability occurs during growth on TMG/succinate and lactose + glucose, but not during growth on lactose. More recent studies with lacGFP-transfected cells show bistability with TMG/succinate, but not with lactose and lactose + glucose. In the literature, these results are attributed to variations of the positive feedback generated by induction. Specifically, during growth on TMG/succinate, induction generates positive feedback because the permease stimulates the accumulation of TMG, which, in turn, promotes the synthesis of more permease. This positive feedback is attenuated during growth on lactose because hydrolysis of lactose by galactosidase suppresses the stimulatory effect of the permease. But the stabilizing effect of dilution also changes dramatically as a function of the medium composition. For instance, during growth on TMG/succinate, the dilution rate of the permease is proportional to its activity, $e$, because the specific growth rate is independent of $e$. However, during growth on lactose, the permease dilution rate is proportional to $e^2$ because the specific growth rate is proportional to the specific lactose uptake rate, which in turn, proportional to $e$. Here, we show that: (a) This dependence on $e^2$ creates such a strong stabilizing effect that bistability is virtually impossible during growth on lactose, even in the face of positive feedback. (b) This stabilizing effect is weakened during growth on lactose + glucose because the specific growth rate on glucose is independent of $e$, so that the dilution rate once again contains a term that is proportional to $e$. We discuss the experimental data in the light of these results.