Editing Gene regulatory network (section)

=== Stochastic gene networks ===

Experimental results<ref>{{cite journal | vauthors = Elowitz MB, Levine AJ, Siggia ED, Swain PS | title = Stochastic gene expression in a single cell | journal = Science | volume = 297 | issue = 5584 | pages = 1183–1186 | date = August 2002 | pmid = 12183631 | doi = 10.1126/science.1070919 | s2cid = 10845628 | bibcode = 2002Sci...297.1183E | url = https://authors.library.caltech.edu/records/wsymf-b6c81/files/ElowitzSOM.pdf?download=1 }}</ref>
<ref>{{cite journal | vauthors = Blake WJ, KAErn M, Cantor CR, Collins JJ | title = Noise in eukaryotic gene expression | journal = Nature | volume = 422 | issue = 6932 | pages = 633–637 | date = April 2003 | pmid = 12687005 | doi = 10.1038/nature01546 | s2cid = 4347106 | bibcode = 2003Natur.422..633B }}</ref> have demonstrated that gene expression is a stochastic process. Thus, many authors are now using the stochastic formalism, after the work by Arkin et al.<ref>{{cite journal | vauthors = Arkin A, Ross J, McAdams HH | title = Stochastic kinetic analysis of developmental pathway bifurcation in phage lambda-infected Escherichia coli cells | journal = Genetics | volume = 149 | issue = 4 | pages = 1633–1648 | date = August 1998 | pmid = 9691025 | pmc = 1460268 | doi = 10.1093/genetics/149.4.1633 }}</ref> Works on single gene expression<ref>{{cite journal | vauthors = Raser JM, O'Shea EK | title = Noise in gene expression: origins, consequences, and control | journal = Science | volume = 309 | issue = 5743 | pages = 2010–2013 | date = September 2005 | pmid = 16179466 | pmc = 1360161 | doi = 10.1126/science.1105891 | bibcode = 2005Sci...309.2010R }}</ref> and small synthetic genetic networks,<ref>{{cite journal | vauthors = Elowitz MB, Leibler S | title = A synthetic oscillatory network of transcriptional regulators | journal = Nature | volume = 403 | issue = 6767 | pages = 335–338 | date = January 2000 | pmid = 10659856 | doi = 10.1038/35002125 | s2cid = 41632754 | bibcode = 2000Natur.403..335E }}</ref><ref>{{cite journal | vauthors = Gardner TS, Cantor CR, Collins JJ | title = Construction of a genetic toggle switch in Escherichia coli | journal = Nature | volume = 403 | issue = 6767 | pages = 339–342 | date = January 2000 | pmid = 10659857 | doi = 10.1038/35002131 | s2cid = 345059 | bibcode = 2000Natur.403..339G }}</ref> such as the genetic toggle switch of Tim Gardner and [[James Collins (bioengineer)|Jim Collins]], provided additional experimental data on the phenotypic variability and the stochastic nature of gene expression. The first versions of stochastic models of gene expression involved only instantaneous reactions and were driven by the [[Gillespie algorithm]].<ref>{{cite journal |author=Gillespie DT |title=A general method for numerically simulating the stochastic time evolution of coupled chemical reactions |journal=J. Comput. Phys. |volume=22 |pages=403–34 |year=1976 |doi=10.1016/0021-9991(76)90041-3 |issue=4|bibcode=1976JCoPh..22..403G }}</ref>

Since some processes, such as gene transcription, involve many reactions and could not be correctly modeled as an instantaneous reaction in a single step, it was proposed to model these reactions as single step multiple delayed reactions in order to account for the time it takes for the entire process to be complete.<ref>{{cite journal | vauthors = Roussel MR, Zhu R | title = Validation of an algorithm for delay stochastic simulation of transcription and translation in prokaryotic gene expression | journal = Physical Biology | volume = 3 | issue = 4 | pages = 274–284 | date = December 2006 | pmid = 17200603 | doi = 10.1088/1478-3975/3/4/005 | bibcode = 2006PhBio...3..274R | s2cid = 21456299 }}</ref>

From here, a set of reactions were proposed<ref>{{cite journal | vauthors = Ribeiro A, Zhu R, Kauffman SA | title = A general modeling strategy for gene regulatory networks with stochastic dynamics | journal = Journal of Computational Biology | volume = 13 | issue = 9 | pages = 1630–1639 | date = November 2006 | pmid = 17147485 | doi = 10.1089/cmb.2006.13.1630 | s2cid = 6629364 }}</ref> that allow generating GRNs. These are then simulated using a modified version of the Gillespie algorithm, that can simulate multiple time delayed reactions (chemical reactions where each of the products is provided a time delay that determines when will it be released in the system as a "finished product").

For example, basic transcription of a gene can be represented by the following single-step reaction (RNAP is the RNA polymerase, RBS is the RNA ribosome binding site, and Pro<sub>&nbsp;''i''</sub> is the promoter region of gene ''i''):

: <math> \text{RNAP} + \text{Pro}_i \overset{k_{i,bas}}

\longrightarrow \text{Pro}_i(\tau _i^1 ) + \text{RBS}_i(\tau_i^1)+ \text{RNAP}(\tau _i^2) </math>

Furthermore, there seems to be a trade-off between the noise in gene expression, the speed with which genes can switch, and the metabolic cost associated their functioning. More specifically, for any given level of metabolic cost, there is an optimal trade-off between noise and processing speed and increasing the metabolic cost leads to better speed-noise trade-offs.<ref name="a30">{{cite journal | vauthors = Zabet NR, Chu DF | title = Computational limits to binary genes | journal = Journal of the Royal Society, Interface | volume = 7 | issue = 47 | pages = 945–954 | date = June 2010 | pmid = 20007173 | pmc = 2871807 | doi = 10.1098/rsif.2009.0474 }}</ref><ref name="a31">{{cite journal | vauthors = Chu DF, Zabet NR, Hone AN | title = Optimal parameter settings for information processing in gene regulatory networks | journal = Bio Systems | volume = 104 | issue = 2–3 | pages = 99–108 | date = May–Jun 2011 | pmid = 21256918 | doi = 10.1016/j.biosystems.2011.01.006 | bibcode = 2011BiSys.104...99C | url = https://kar.kent.ac.uk/30778/1/optimalParameterSettings_Chu.pdf }}</ref><ref name="a32">{{cite journal | vauthors = Zabet NR | title = Negative feedback and physical limits of genes | journal = Journal of Theoretical Biology | volume = 284 | issue = 1 | pages = 82–91 | date = September 2011 | pmid = 21723295 | doi = 10.1016/j.jtbi.2011.06.021 | arxiv = 1408.1869 | s2cid = 14274912 | bibcode = 2011JThBi.284...82Z }}</ref>

A recent work proposed a simulator (SGNSim, ''Stochastic Gene Networks Simulator''),<ref>{{cite journal | vauthors = Ribeiro AS, Lloyd-Price J | title = SGN Sim, a stochastic genetic networks simulator | journal = Bioinformatics | volume = 23 | issue = 6 | pages = 777–779 | date = March 2007 | pmid = 17267430 | doi = 10.1093/bioinformatics/btm004 | doi-access = free }}</ref> that can model GRNs where transcription and translation are modeled as multiple time delayed events and its dynamics is driven by a stochastic simulation algorithm (SSA) able to deal with multiple time delayed events.
The time delays can be drawn from several distributions and the reaction rates from complex
functions or from physical parameters. SGNSim can generate ensembles of GRNs within a set of user-defined parameters, such as topology. It can also be used to model specific GRNs and systems of chemical reactions. Genetic perturbations such as gene deletions, gene over-expression, insertions, frame shift mutations can also be modeled as well.

The GRN is created from a graph with the desired topology, imposing in-degree and out-degree distributions. Gene promoter activities are affected by other genes expression products that act as inputs, in the form of monomers or combined into multimers and set as direct or indirect. Next, each direct input is assigned to an operator site and different transcription factors can be allowed, or not, to compete for the same operator site, while indirect inputs are given a target. Finally, a function is assigned to each gene, defining the gene's response to a combination of transcription factors (promoter state). The transfer functions (that is, how genes respond to a combination of inputs) can be assigned to each combination of promoter states as desired.

In other recent work, multiscale models of gene regulatory networks have been developed that focus on synthetic biology applications. Simulations have been used that model all biomolecular interactions in transcription, translation, regulation, and induction of gene regulatory networks, guiding the design of synthetic systems.<ref>{{cite journal | vauthors = Kaznessis YN | title = Models for synthetic biology | journal = BMC Systems Biology | volume = 1 | pages = 47 | date = November 2007 | pmid = 17986347 | pmc = 2194732 | doi = 10.1186/1752-0509-1-47 | doi-access = free }}</ref>