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Designing sequential transcription logic: a simple genetic circuit for conditional memory.

ABSTRACT: The ability to learn and respond to recurrent events depends on the capacity to remember transient biological signals received in the past. Moreover, it may be desirable to remember or ignore these transient signals conditioned upon other signals that are active at specific points in time or in unique environments. Here, we propose a simple genetic circuit in bacteria that is capable of conditionally memorizing a signal in the form of a transcription factor concentration. The circuit behaves similarly to a "data latch" in an electronic circuit, i.e. it reads and stores an input signal only when conditioned to do so by a "read command." Our circuit is of the same size as the well-known genetic toggle switch (an unconditional latch) which consists of two mutually repressing genes, but is complemented with a "regulatory front end" involving protein heterodimerization as a simple way to implement conditional control. Deterministic and stochastic analysis of the circuit dynamics indicate that an experimental implementation is feasible based on well-characterized genes and proteins. It is not known, to which extent molecular networks are able to conditionally store information in natural contexts for bacteria. However, our results suggest that such sequential logic elements may be readily implemented by cells through the combination of existing protein-protein interactions and simple transcriptional regulation.

SUBMITTER: Fritz G

PROVIDER: S-EPMC2533522 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Designing sequential transcription logic: a simple genetic circuit for conditional memory.

Fritz Georg G Buchler Nicolas E NE Hwa Terence T Gerland Ulrich U

Systems and synthetic biology 20070401 2

The ability to learn and respond to recurrent events depends on the capacity to remember transient biological signals received in the past. Moreover, it may be desirable to remember or ignore these transient signals conditioned upon other signals that are active at specific points in time or in unique environments. Here, we propose a simple genetic circuit in bacteria that is capable of conditionally memorizing a signal in the form of a transcription factor concentration. The circuit behaves sim ...[more]

PMID: 19003438

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Project description:Multicellularity, the coordinated collective behavior of cell populations, gives rise to the emergence of self-organized phenomena at many different spatio-temporal scales. At the genetic scale, oscillators are ubiquitous in regulation of multicellular systems, including during their development and regeneration. Synthetic biologists have successfully created simple synthetic genetic circuits that produce oscillations in single cells. Studying and engineering synthetic oscillators in a multicellular chassis can therefore give us valuable insights into how simple genetic circuits can encode complex multicellular behaviors at different scales. Here we develop a study of the coupling between the repressilator synthetic genetic ring oscillator and constraints on cell growth in colonies. We show in silico how mechanical constraints generate characteristic patterns of growth rate inhomogeneity in growing cell colonies. Next, we develop a simple one-dimensional model which predicts that coupling the repressilator to this pattern of growth rate via protein dilution generates traveling waves of gene expression. We show that the dynamics of these spatio-temporal patterns are determined by two parameters; the protein degradation and maximum expression rates of the repressors. We derive simple relations between these parameters and the key characteristics of the traveling wave patterns: firstly, wave speed is determined by protein degradation and secondly, wavelength is determined by maximum gene expression rate. Our analytical predictions and numerical results were in close quantitative agreement with detailed individual based simulations of growing cell colonies. Confirming published experimental results we also found that static ring patterns occur when protein stability is high. Our results show that this pattern can be induced simply by growth rate dilution and does not require transition to stationary phase as previously suggested. Our method generalizes easily to other genetic circuit architectures thus providing a framework for multi-scale rational design of spatio-temporal patterns from genetic circuits. We use this method to generate testable predictions for the synthetic biology design-build-test-learn cycle.

Project description:BACKGROUND: Cellular signaling involves a sequence of events from ligand binding to membrane receptors through transcription factors activation and the induction of mRNA expression. The transcriptional-regulatory system plays a pivotal role in the control of gene expression. A novel computational approach to the study of gene regulation circuits is presented here. METHODOLOGY: Based on the concept of finite state machine, which provides a discrete view of gene regulation, a novel sequential logic model (SLM) is developed to decipher control mechanisms of dynamic transcriptional regulation of gene expressions. The SLM technique is also used to systematically analyze the dynamic function of transcriptional inputs, the dependency and cooperativity, such as synergy effect, among the binding sites with respect to when, how much and how fast the gene of interest is expressed. PRINCIPAL FINDINGS: SLM is verified by a set of well studied expression data on endo16 of Strongylocentrotus purpuratus (sea urchin) during the embryonic midgut development. A dynamic regulatory mechanism for endo16 expression controlled by three binding sites, UI, R and Otx is identified and demonstrated to be consistent with experimental findings. Furthermore, we show that during transition from specification to differentiation in wild type endo16 expression profile, SLM reveals three binary activities are not sufficient to explain the transcriptional regulation of endo16 expression and additional activities of binding sites are required. Further analyses suggest detailed mechanism of R switch activity where indirect dependency occurs in between UI activity and R switch during specification to differentiation stage. CONCLUSIONS/SIGNIFICANCE: The sequential logic formalism allows for a simplification of regulation network dynamics going from a continuous to a discrete representation of gene activation in time. In effect our SLM is non-parametric and model-independent, yet providing rich biological insight. The demonstration of the efficacy of this approach in endo16 is a promising step for further application of the proposed method.

Project description:In this work, we describe a logic device in which an act of computation is associated with finding a path connecting input and output ports. The device is based on an active ring circuit comprising electric and magnetic parts. The electric part includes an amplifier, a phase shifter, and an attenuator. The magnetic part is a multi-port magnetic matrix comprising delay lines and frequency filters. Signals propagating on different paths may accumulate different phase shifts. Auto-oscillations occur in the circuit when the magnetic and electric parts match each other to meet the resonance amplitude and phase conditions. The system naturally searches for a resonance path that depends on the position of the electric phase shifter and amplification level. The path is detected by the set of power sensors. The proposed logic device can be used for solving a variety of computational problems. We present the results of numerical modeling illustrating prime factorization and finding the shortest path connected selected points on the mesh. We also present experimental data on the proof-of-the-concept experiment for the two-path device. The magnetic part consists of two waveguides made of single-crystal yttrium iron garnet Y3Fe2(FeO4)3 (YIG) films. Different phase shifts per delay line are achieved by adjusting the magnitude and direction of the bias magnetic field. The auto-oscillation signal changes the propagation path in the magnetic matrix depending on the position of the outer electric phase shifter. The power difference between the active and passive paths exceeds 40 dBm at room temperature. The described logic devices are robust, deterministic, and operate at room temperature. The number of possible paths increases factorial with the size of the mesh. It may be possible to encode information in paths and retrieve it using the external phase shifters and attenuators. Potentially, combinatorial logic devices may compete with quantum computers in functional throughput. Physical limits and constraints are also discussed.

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Designing sequential transcription logic: a simple genetic circuit for conditional memory.

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Designing sequential transcription logic: a simple genetic circuit for conditional memory.

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