Genetically encoded regulatory circuits control biological function. A major focus of systems biology is to understand these circuits by establishing the relationship between specific structures and functions. Of special interest are multifunctional circuits that are capable of performing distinct behaviors without changing their topology. A particularly simple example of such a system is the AC-DC circuit. Found in multiple regulatory processes, this circuit consists of three genes connected in a combination of a toggle switch and a repressilator. Using dynamical system theory we analyze the available dynamical regimes to show that the AC-DC can exhibit both oscillations and bistability. We found that both dynamical regimes can coexist robustly in the same region of parameter space, generating novel emergent behaviors not available to the individual subnetwork components. We demonstrate that the AC-DC circuit provides a mechanism to rapidly switch between oscillations and steady expression and, in the presence of noise, the multi-functionality of the circuit offers the possibility to control the coherence of oscillations. Additionally, we provide evidence that the availability of a bistable oscillatory regime allows the AC-DC circuit to behave as an excitable system capable of stochastic pulses and spatial signal propagation. Taken together these results reveal how a system as simple as the AC-DC circuit can produce multiple complex dynamical behaviors in the same parameter region and is well suited for the construction of multifunctional synthetic genetic circuits. Likewise, the analysis reveals the potential of this circuit to facilitate the evolution of distinct patterning mechanisms.
Transcriptional regulation by transcription factors and post-transcriptional regulation by microRNAs constitute two major modes of regulation of gene expression. While gene expression motifs incorporating solely transcriptional regulation are well investigated, the dynamics of motifs with dual strategies of regulation, i.e., both transcriptional and post-transcriptional regulation, have not been studied as extensively. In this paper, we probe the dynamics of a four-gene motif with dual strategies of regulation of gene expression. Some of the functional characteristics are compared with those o…
An information-theoretic perspective on feed-forward loop abundances in transcriptional networks
Universal Biology Institute, The University of Tokyo（东京大学通用生物学研究所）；Indian Institute of Engineering Science and Technology, Shibpur（印度工程科学和技术学院，希布普尔分校）；Bose Institute（玻色研究所）
The study of transcription remains one of the centerpieces of modern biology with implications in settings from development to metabolism to evolution to disease. Precision measurements using a host of different techniques including fluorescence and sequencing readouts have raised the bar for what it means to quantitatively understand transcriptional regulation. In particular our understanding of the simplest genetic circuit is sufficiently refined both experimentally and theoretically that it has become possible to carefully discriminate between different conceptual pictures of how this regul…
Background: Networks in different domains are characterized by similar global characteristics while differing in local structures. To further extend this concept, we investigated network regularities on a fine scale in order to examine the functional impact of recurring motifs in signed oriented biological networks. In this work we generalize to signaling net works some considerations made on feedback and feed forward loops and extend them by adding a close scrutiny of Linear Triplets, which have not yet been investigate in detail. Results: We studied the role of triplets, either open or close…
The intrinsic stochasticity of gene expression is usually mitigated in higher eukaryotes by post-transcriptional regulation channels that stabilise the output layer, most notably protein levels. The discovery of small non-coding RNAs (miRNAs) in specific motifs of the genetic regulatory network has led to identifying noise buffering as the possible key function they exert in regulation. Recent in vitro} and in silico studies have corroborated this hypothesis. It is however also known that miRNA-mediated noise reduction is hampered by transcriptional bursting in simple topologies. Here, using s…
MERLIN-SUITE: Probabilistic modular GRN inference from multi-omics data integrating regulatory priors and transcription factor activity
Wisconsin Institute for Discovery, University of Wisconsin-Madison（威斯康星发现研究所，威斯康星大学麦迪逊分校）；Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison（威斯康星大学麦迪逊分校生物统计与医学信息学系）
Gene regulatory networks (GRNs) control cellular function and decision making during tissue development and homeostasis. Mathematical tools based on dynamical systems theory are often used to model these networks, but the size and complexity of these models mean that their behaviour is not always intuitive and the underlying mechanisms can be difficult to decipher. For this reason, methods that simplify and aid exploration of complex networks are necessary. To this end we develop a broadly applicable form of the Zwanzig-Mori projection. By first converting a thermodynamic state ensemble model …
Synthetic genetic circuits are implemented in living cells for their operation. During gene expression, proteins are produced from the respective genes, by formation of complexes through the process of transcription and translation. In transcription the circuit uses RNAP, etc. as resource from the host cell and in translation, ribosome, tRNA and other cellular resources are supplied to the operating circuit. As the cell contains these resources in limited number, the circuit can suffer from unprecedented resource competition which might destroy the circuit functionality, or introduce some emer…
