scholarly journals Control-based continuation: a new approach to prototype synthetic gene networks

2021 ◽  
Author(s):  
Irene de Cesare ◽  
Davide Salzano ◽  
Mario di Bernardo ◽  
Ludovic Renson ◽  
Lucia Marucci
Keyword(s):  
Parameter Estimation ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Synthetic Gene ◽  
Toggle Switch ◽  
Additive Process ◽  
Model Free ◽  
Physical Experiments ◽  
Unstable Solutions ◽  
Division Cell

Control-Based Continuation (CBC) is a general and systematic method to carry out the bifurcation analysis of physical experiments. CBC does not rely on a mathematical model and thus overcomes the uncertainty introduced when identifying bifurcation curves indirectly through modelling and parameter estimation. We demonstrate, in silico, CBC applicability to biochemical processes by tracking the equilibrium curve of a toggle switch which includes additive process noise and exhibits bistability. We compare results obtained when CBC uses a model-free and model-based control strategy and show that both can track stable and unstable solutions, revealing bistability. We then demonstrate CBC in conditions more representative of a real experiment using an agent-based simulator describing cells growth and division, cell-to-cell variability, spatial distribution, and diffusion of chemicals. We further show how the identified curves can be used for parameter estimation and discuss how CBC can significantly accelerate the prototyping of synthetic gene regulatory networks.

scholarly journals The Effect of Compositional Context on Synthetic Gene Networks

2016 ◽  
Author(s):  
Enoch Yeung ◽  
Aaron J. Dy ◽  
Kyle B. Martin ◽  
Andrew H. Ng ◽  
Domitilla Del Vecchio ◽  
...  
Keyword(s):  
Gene Networks ◽  
Dynamic Range ◽  
Context Effects ◽  
Synthetic Gene ◽  
Toggle Switch ◽  
Synthetic Gene Networks ◽  
Expression Levels ◽  
Threshold Detection ◽  
Ribosome Binding Sites

SUMMARYIt is well known that synthetic gene expression is highly sensitive to how comprising genetic elements (promoter structure, spacing regions between promoter and coding sequences, ribosome binding sites, etc.) are spatially configured. An important topic that has received far less attention is how the physical layout of entire genes within a synthetic gene network affects their individual expression levels. In this paper we show, both quantitatively and qualitatively, that compositional context can significantly alter expression levels in synthetic gene networks. We also show that these compositional context effects are pervasive both at the transcriptional and translational level. Further, we demonstrate that key characteristics of gene induction, such as ultra-sensitivity and dynamic range, are heavily dependent on compositional context. We postulate that supercoiling can be used to explain these interference effects and validate this hypothesis through modeling and a series of in vitro supercoiling relaxation experiments. On the whole, these results suggest that compositional context introduces feedback in synthetic gene networks. As an illustrative example, we show that a design strategy incorporating compositional context effects can improve threshold detection and memory properties of the toggle switch.

scholarly journals Mammalian synthetic biology: emerging medical applications

2015 ◽  
Vol 12 (106) ◽  
pp. 20141000 ◽  
Author(s):  
Zoltán Kis ◽  
Hugo Sant'Ana Pereira ◽  
Takayuki Homma ◽  
Ryan M. Pedrigi ◽  
Rob Krams
Keyword(s):  
Drug Delivery ◽  
Synthetic Biology ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Logic Gates ◽  
Boolean Logic ◽  
Synthetic Gene ◽  
Medical Applications ◽  
Synthetic Gene Networks ◽  
Gene Circuits

In this review, we discuss new emerging medical applications of the rapidly evolving field of mammalian synthetic biology. We start with simple mammalian synthetic biological components and move towards more complex and therapy-oriented gene circuits. A comprehensive list of ON–OFF switches, categorized into transcriptional, post-transcriptional, translational and post-translational, is presented in the first sections. Subsequently, Boolean logic gates, synthetic mammalian oscillators and toggle switches will be described. Several synthetic gene networks are further reviewed in the medical applications section, including cancer therapy gene circuits, immuno-regulatory networks, among others. The final sections focus on the applicability of synthetic gene networks to drug discovery, drug delivery, receptor-activating gene circuits and mammalian biomanufacturing processes.

scholarly journals Single cell RNA-seq reveals genes vital to in vitro fertilized embryos and parthenotes in pigs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhi-Qiang Du ◽  
Hao Liang ◽  
Xiao-Man Liu ◽  
Yun-Hua Liu ◽  
Chonglong Wang ◽  
...  
Keyword(s):  
Embryo Development ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Rna Binding ◽  
Expression Patterns ◽  
Early Embryo ◽  
Specific Factor ◽  
Early Embryos ◽  
Genome Activation

AbstractSuccessful early embryo development requires the correct reprogramming and configuration of gene networks by the timely and faithful execution of zygotic genome activation (ZGA). However, the regulatory principle of molecular elements and circuits fundamental to embryo development remains largely obscure. Here, we profiled the transcriptomes of single zygotes and blastomeres, obtained from in vitro fertilized (IVF) or parthenogenetically activated (PA) porcine early embryos (1- to 8-cell), focusing on the gene expression dynamics and regulatory networks associated with maternal-to-zygote transition (MZT) (mainly maternal RNA clearance and ZGA). We found that minor and major ZGAs occur at 1-cell and 4-cell stages for both IVF and PA embryos, respectively. Maternal RNAs gradually decay from 1- to 8-cell embryos. Top abundantly expressed genes (CDV3, PCNA, CDR1, YWHAE, DNMT1, IGF2BP3, ARMC1, BTG4, UHRF2 and gametocyte-specific factor 1-like) in both IVF and PA early embryos identified are of vital roles for embryo development. Differentially expressed genes within IVF groups are different from that within PA groups, indicating bi-parental and maternal-only embryos have specific sets of mRNAs distinctly decayed and activated. Pathways enriched from DEGs showed that RNA associated pathways (RNA binding, processing, transport and degradation) could be important. Moreover, mitochondrial RNAs are found to be actively transcribed, showing dynamic expression patterns, and for DNA/H3K4 methylation and transcription factors as well. Taken together, our findings provide an important resource to investigate further the epigenetic and genome regulation of MZT events in early embryos of pigs.

Synthetic gene networks in mammalian cells

2010 ◽  
Vol 21 (5) ◽  
pp. 690-696 ◽  
Author(s):  
Wilfried Weber ◽  
Martin Fussenegger
Keyword(s):  
Mammalian Cells ◽  
Gene Networks ◽  
Synthetic Gene ◽  
Synthetic Gene Networks

Therapeutic synthetic gene networks

2012 ◽  
Vol 23 (5) ◽  
pp. 703-711 ◽  
Author(s):  
Maria Karlsson ◽  
Wilfried Weber
Keyword(s):  
Gene Networks ◽  
Synthetic Gene ◽  
Synthetic Gene Networks

A study of structural properties of gene network graphs for mathematical modeling of integrated mosaic gene networks

2017 ◽  
Vol 15 (02) ◽  
pp. 1650045 ◽  
Author(s):  
Olga V. Petrovskaya ◽  
Evgeny D. Petrovskiy ◽  
Inna N. Lavrik ◽  
Vladimir A. Ivanisenko
Keyword(s):  
Mathematical Modeling ◽  
Gene Regulatory Networks ◽  
Gene Networks ◽  
Gene Network ◽  
Regulatory Networks ◽  
Network Modeling ◽  
Computer Experiments ◽  
Linear Control ◽  
Expression Of Genes ◽  
Gene Regulatory

Gene network modeling is one of the widely used approaches in systems biology. It allows for the study of complex genetic systems function, including so-called mosaic gene networks, which consist of functionally interacting subnetworks. We conducted a study of a mosaic gene networks modeling method based on integration of models of gene subnetworks by linear control functionals. An automatic modeling of 10,000 synthetic mosaic gene regulatory networks was carried out using computer experiments on gene knockdowns/knockouts. Structural analysis of graphs of generated mosaic gene regulatory networks has revealed that the most important factor for building accurate integrated mathematical models, among those analyzed in the study, is data on expression of genes corresponding to the vertices with high properties of centrality.

scholarly journals On Robust State Estimation of Gene Networks

2010 ◽  
Vol 2 ◽  
pp. 117959721000200 ◽  
Author(s):  
Chia-Hua Chuang ◽  
Chun-Liang Lin
Keyword(s):  
Parameter Estimation ◽  
Kalman Filter ◽  
Quantitative Analysis ◽  
State Estimation ◽  
Gene Networks ◽  
Gene Network ◽  
Biological Systems ◽  
Uncertain Process ◽  
Network Systems ◽  
Internal States

Gene networks in biological systems are not only nonlinear but also stochastic due to noise corruption. How to accurately estimate the internal states of the noisy gene networks is an attractive issue to researchers. However, the internal states of biological systems are mostly inaccessible by direct measurement. This paper intends to develop a robust extended Kalman filter for state and parameter estimation of a class of gene network systems with uncertain process noises. Quantitative analysis of the estimation performance is conducted and some representative examples are provided for demonstration.

scholarly journals From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130542 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Michael M. Shen
Keyword(s):  
Stem Cells ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Network Models ◽  
Cell Types ◽  
Mammalian Development ◽  
A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

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