Publications about 'transcriptional networks' |
Articles in journal or book chapters |
A design for genetically-encoded counters is proposed via repressor-based circuits. An N-bit counter reads sequences of input pulses and displays the total number of pulses, modulo $2^N$. The design is based on distributed computation, with specialized cell types allocated to specific tasks. This allows scalability and bypasses constraints on the maximal number of circuit genes per cell due to toxicity or failures due to resource limitations. The design starts with a single-bit counter. The N-bit counter is then obtained by interconnecting (using diffusible chemicals) a set of N single-bit counters and connector modules. An optimization framework is used to determine appropriate gate parameters and to compute bounds on admissible pulse widths and relaxation (inter-pulse) times, as well as to guide the construction of novel gates. This work can be viewed as a step toward obtaining circuits that are capable of finite-automaton computation, in analogy to digital central processing units. |
This paper deals with the analysis of the dynamics of chemical reaction networks, developing a theoretical framework based only on graphical knowledge and applying regardless of the particular form of kinetics. This paper introduces a class of networks that are "structurally (mono) attractive", by which we mean that they are incapable of exhibiting multiple steady states, oscillation, or chaos by the virtue of their reaction graphs. These networks are characterized by the existence of a universal energy-like function which we call a Robust Lyapunov function (RLF). To find such functions, a finite set of rank-one linear systems is introduced, which form the extremals of a linear convex cone. The problem is then reduced to that of finding a common Lyapunov function for this set of extremals. Based on this characterization, a computational package, Lyapunov-Enabled Analysis of Reaction Networks (LEARN), is provided that constructs such functions or rules out their existence. An extensive study of biochemical networks demonstrates that LEARN offers a new unified framework. We study basic motifs, three-body binding, and transcriptional networks. We focus on cellular signalling networks including various post-translational modification cascades, phosphotransfer and phosphorelay networks, T-cell kinetic proofreading, ERK signaling, and the Ribosome Flow Model. |
Starting in the early 2000s, sophisticated technologies have been developed for the rational construction of synthetic genetic networks that implement specified logical functionalities. Despite impressive progress, however, the scaling necessary in order to achieve greater computational power has been hampered by many constraints, including repressor toxicity and the lack of large sets of mutually-orthogonal repressors. As a consequence, a typical circuit contains no more than roughly seven repressor-based gates per cell. A possible way around this scalability problem is to distribute the computation among multiple cell types, which communicate among themselves using diffusible small molecules (DSMs) and each of which implements a small sub-circuit. Examples of DSMs are those employed by quorum sensing systems in bacteria. This paper focuses on systematic ways to implement this distributed approach, in the context of the evaluation of arbitrary Boolean functions. The unique characteristics of genetic circuits and the properties of DSMs require the development of new Boolean synthesis methods, distinct from those classically used in electronic circuit design. In this work, we propose a fast algorithm to synthesize distributed realizations for any Boolean function, under constraints on the number of gates per cell and the number of orthogonal DSMs. The method is based on an exact synthesis algorithm to find the minimal circuit per cell, which in turn allows us to build an extensive database of Boolean functions up to a given number of inputs. For concreteness, we will specifically focus on circuits of up to 4 inputs, which might represent, for example, two chemical inducers and two light inputs at different frequencies. Our method shows that, with a constraint of no more than seven gates per cell, the use of a single DSM increases the total number of realizable circuits by at least 7.58-fold compared to centralized computation. Moreover, when allowing two DSM's, one can realize 99.995\% of all possible 4-input Boolean functions, still with at most 7 gates per cell. The methodology introduced here can be readily adapted to complement recent genetic circuit design automation software. |
In this paper, we introduce a topological redundancy measure for labeled directed networks that is formal, computationally efficient and applicable to a variety of directed networks such as cellular signaling, metabolic and social interaction networks. We demonstrate the computational efficiency of our measure by computing its value and statistical significance on a number of biological and social networks with up to several thousands of nodes and edges. Our results suggest a number of interesting observations: (1) social networks are more redundant that their biological counterparts, (2) transcriptional networks are less redundant than signaling networks, (3) the topological redundancy of the C. elegans metabolic network is largely due to its inclusion of currency metabolites, and (4) the redundancy of signaling networks is highly (negatively) correlated with monotonicity of their dynamics. |
Modularity plays a fundamental role in the prediction of the behavior of a system from the behavior of its components, guaranteeing that the properties of individual components do not change upon interconnection. Just as electrical, hydraulic, and other physical systems often do not display modularity, nor do many biochemical systems, and specifically, genetic networks. Here, we study the effect of interconnections on the input/output dynamic characteristics of transcriptional components, focusing on a property, which we call "retroactivity," that plays a role analogous to non-zero output impedance in electrical systems. In transcriptional networks, retroactivity is large when the amount of transcription factor is comparable to, or smaller than, the amount of promoter binding sites, or when the affinity of such binding sites is high. In order to attenuate the effect of retroactivity, we propose a feedback mechanism inspired by the design of amplifiers in electronics. We introduce, in particular, a mechanism based on a phosphorylation/dephosphorylation cycle. This mechanism enjoys a remarkable insulation property, due to the fast time scales of the phosphorylation and dephosphorylation reactions. Such a mechanism, when viewed as a signal transduction system, has thus an inherent capacity to provide insulation and hence to increase the modularity of the system in which it is placed. |
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