The TOL system encoded by plasmid pWW0 of Pseudomonas putida mt-2 is able to sense a large number of both exogenous and endogenous signals as inputs for the genetic and metabolic circuit that determines the biodegradation of m-xylene. However, whether the enormous combinatorial space of inputs is translated into an equally variable response landscape or is processed into very few outcomes remains unclear. To address this question, we set out to define the number of states that can be obtained by a network of a given set of genes under the control of a specified regulatory circuit that is exposed to all possible combinations of inputs. To this end, the TOL network and its regulatory wiring were formalized as a synchronous logic Boolean circuit that had 10 signals (i.e. pathway substrates, temperature, sugars, amino acids, metabolic regimes and global regulators) as possible inputs. The analysis of the attractors of the circuit using a satisfiability (SAT) algorithm revealed that only eight transcriptional states are reached in response to the 1024 possible combinations of stimuli. The experimental validation resulted in a refinement of the model through the addition of a previously unknown interaction that controls the meta catabolic pathway. The full induction of the two xyl operons occurred with only 1.6% of the input combinations, which suggests that the architecture of the network allows the expression of the xyl genes only under a very narrow range of conditions. These data not only explain much of the unusual layout of the TOL circuit but also strengthen the view of the regulatory circuits of environmental bacteria as digital decision-making devices. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-05-06T13:37:11Z 2016-01-22T07:08:46Z

<font face="Arial, Verdana" size="2">Cell density, refers to exponential phase (if low), or stationary phase (if high) [1].</font>

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m-xylene is metabolized to 3MBz in the model TOL Regulatory Network [1]. 

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<font face="Arial, Verdana" size="2">Histone-like protein HU</font>

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<font face="Arial, Verdana" size="2">Casamino acids, mix of amino acids and small peptides [1]. </font>

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<font face="Arial, Verdana" size="2">?70, housekeeping RNAP subunit sigma factor</font>

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<font face="Arial, Verdana" size="2">m-xylene, aromatic compounds substrate of the TOL pathway</font><div><font face="Arial, Verdana" size="2">PubChem ID: </font><span style="background-color: rgb(255, 255, 255); color: rgb(85, 85, 85); font-family: Arial, Verdana, sans-serif; font-size: 14px; line-height: 19.384401321411133px;">7929</span></div><div><span style="background-color: rgb(255, 255, 255); color: rgb(85, 85, 85); font-family: Arial, Verdana, sans-serif; font-size: 14px; line-height: 19.384401321411133px;"><br/></span></div>

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<font face="Arial, Verdana" size="2">Glucose, a six-carbon sugar</font><div><font face="Arial, Verdana" size="2">PubChem ID: </font><span style="background-color: rgb(255, 255, 255); color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 12px; line-height: 16.798599243164063px; white-space: nowrap;">79025</span></div>

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<font face="Arial, Verdana" size="2">Cold shock represented by low temperatures [1].</font>

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<font face="Arial, Verdana" size="2">?54, nitrogen-related RNAP subunit sigma factor</font>

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<font face="Arial, Verdana" size="2">Heat shock represented by high temperatures of or stress triggered by a denaturing compound [1].</font>

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<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Exodeoxyribonuclease III [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Pseudomonas putida KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1042227" ref="ordinalpos=3&ncbi_uid=1042227&link_uid=1042227" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">crc</span></a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">1042227</span></font></div>

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<font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">RNA polymerase factor sigma-32 [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1042633" ref="ordinalpos=11&ncbi_uid=1042633&link_uid=1042633" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">rpoH</span></a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">1042633</span></font></div>

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<font face="Georgia">There are two IHF genes in <em>Pseudomonas putida</em> [1]. </font><div style="font-style: normal;"><font face="Georgia"><br/></font><div><font face="Georgia"><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Integration host factor</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> subunit alpha [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas putida</span>KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1045640" ref="ordinalpos=2&ncbi_uid=1045640&link_uid=1045640" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">ihfA</a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">1045640</span></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div></div><div style="font-style: normal;"><font face="Georgia"><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Integration host factor</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> subunit beta [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas putida</span>KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font></div><div style="font-style: normal;"><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/1043345" ref="ordinalpos=3&ncbi_uid=1043345&link_uid=1043345" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">ihfB</a></font></div><div style="font-style: normal;"><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">1043345</span></font></div>

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<font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">PTS transporter subunit IIA-like nitrogen-regulatory protein </span><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">PtsN</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">[</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1044865" ref="ordinalpos=1&ncbi_uid=1044865&link_uid=1044865" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">ptsN</span></a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">1044865</span></font></div>

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<font face="Arial, Verdana" size="2">Catabolic operon [1]. </font>

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<font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Transcriptional activator of xyl-meta pathway operon [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P07859" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P07859</a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/9121240" ref="ordinalpos=1&ncbi_uid=9121240&link_uid=9121240" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">xylS</span></a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">9121240</span></font></div>

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<font size="2" face="Georgia">Hyper-expressed form of XylS</font><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Transcriptional activator of xyl-meta pathway operon [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P07859" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P07859</a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/9121240" ref="ordinalpos=1&ncbi_uid=9121240&link_uid=9121240" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">xylS</span></a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">9121240</span></font></div></div>

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<div><font face="Georgia"><span style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Transcriptional regulator </span><span class="highlight" style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">XylR </span><span style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">[</span><em style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida</em><span style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font></div><div><font face="Georgia"><span style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P06519" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P06519</a></font></div><div><font face="Georgia"><span style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4226942" ref="ordinalpos=1&ncbi_uid=4226942&link_uid=4226942" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">xylR</span></a></font></div><div><font face="Georgia"><span style="font-size: 10pt; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">4226942</span></font></div><div style="font-family: Arial, Verdana;"><span style="font-size: 10pt; font-family: arial, helvetica, clean, sans-serif; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><br/></span></div>

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<font face="Arial, Verdana" size="2">Represents a catabolic operon. m-Xylene enters the TCA cycle through the activity of multiple enzymes, here represented as <em>meta</em> [1]. </font>

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<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Glycine betaine transporter periplasmic subunit [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida W619</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/6111248" ref="ordinalpos=2&ncbi_uid=6111248&link_uid=6111248" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">proX</span></a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">6111248</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;"><br/></span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">Referred to unknown protein labeled X. [1]</span></font></div>

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<font face="Arial, Verdana" size="2">Catabolic operon [1]. </font>

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<font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">RNA polymerase sigma factor</span><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">RpoS</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div style="line-height: normal;"><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1044853" ref="ordinalpos=2&ncbi_uid=1044853&link_uid=1044853" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">rpoS</span></a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">1044853</span></font></div>

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<font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Transcriptional regulator </span><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">TurA</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">[</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida NBRC 14164</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/16139004" ref="ordinalpos=1&ncbi_uid=16139004&link_uid=16139004" style="font-size: 10pt; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">turA</span></a></font></div><div><font face="Georgia"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12px; line-height: 16.19982147216797px;">16139004</span></font></div>

2015-12-19T22:12:44Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">LytTR family two component transcriptional regulator [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Pseudomonas</span> putida KT2440</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">]</span></font><div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px;">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1043711" ref="ordinalpos=2&ncbi_uid=1043711&link_uid=1043711" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">pprA</span></a><span style="line-height: 17.999801635742188px;"><br/></span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">1043711</span></font></div></div></div>

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Crc is activated by CAA and inactivated by CellDens. CellDens is dominant over the activity of CAA [1].

Crc and PtsN are low when Cell Density is high [1-3]

CAA activates Crc [1,4]. 

S_11 1 S_1 1

Heat activates RpoH [1].

Heat shock induces the expression/activity of RpoH [1,2]

S_24 1

IHF is activated by CellDens [1].

IHF and RpoS are high when Cell Density is high [1-3]

S_1 1

PtsN is activated by Glu and inhibited by CellDens [1].

Crc and PtsN are low when Cell Density is high [1,3]

PtsN is regulated by glucose [1,4]

S_18 1 S_1 1

\r\n \r\n \r\n <div class="page" title="Page 6">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">The regulation of the Upper metabolic operon is controlled by: ((<span style="font-style: oblique;">m</span>-xyl ^ (XylR ^ (IHF ^ (RpoN)))) ^¬ (Crc V (PtsN  V (TurA V (PprA))))) [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>

Crc is a negative regulator of Upper [1]. 

TurA is a negative regulator of Upper [1]. 

PprA is a negative regulator of Upper [1]. 

PtsN is a negative regulator of Upper [1]. 

IHF activates the Upper metabolic operon [1]. 

m-xyl activates the Upper metabolic operon [1]. 

XylR activates the Upper metabolic operon [1]. 

RpoN activates the Upper metabolic operon [1]. 

S_13 1 S_5 1 S_14 1 S_23 1 S_22 1 S_7 1 S_2 1 S_20 1

RpoD activates XylS [1]. 

S_12 1

\r\n \r\n \r\n <div class="page" title="Page 6">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Helvetica" size="2">m-xyl, RpoN, HU, and XylR are all required to activate XylSh. Crc and PtsN each deactivate XylSh and are dominant over the activators [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>

Crc deactivates XylSh [1]. 

PtsN deactivates XylSh [1]. 

HU activates XylSh [1]. 

m-xyl activates XylSh [1]. 

XylR activates XylSh [1]. 

RpoN activates XylSh [1]. 

S_13 1 S_6 1 S_14 1 S_23 1 S_2 1 S_7 1

XylR is activated by RpoD, while IHF, Crc, and ProX deactivate XylR and are dominant over XylR [1]. 

Crc inhibits XylR, XylS, and the catabolic operons (upper and meta) [1-2]

RpoD activates XylR [1].

ProX inhibits XylR [1]. 

S_12 1 S_16 1 S_2 1

<font face="Georgia" size="2">The regulation of Meta is described as: ((((((m-xyl ^ Upper) V 3MBz) ^ XylS) V XylSh) ^ (RpoD V (RpoS V (RpoH)))) ^¬ Crc) [1]. </font>

<span style="font-style: normal;">CAA controls the activity of </span><em>meta</em> through Crc. Crc deactivates the <em>meta</em> operon [1,4]. 

<span style="font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; font-size: 12px; line-height: 18px; background-color: rgb(255, 255, 255);">The </span><em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 12px; vertical-align: baseline; background-color: rgb(255, 255, 255); font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px;">meta</em><span style="font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; font-size: 12px; line-height: 18px; background-color: rgb(255, 255, 255);"> operon is expressed from the </span><em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 12px; vertical-align: baseline; background-color: rgb(255, 255, 255); font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px;">Pm</em><span style="font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; font-size: 12px; line-height: 18px; background-color: rgb(255, 255, 255);"> promoter and is activated by XylS in response to 3MBz [1-3]</span>

<em>m</em>-Xyl <span style="font-style: normal;">is an activator of </span><em>meta</em><span style="font-style: normal;"> and can activate <em>meta</em> under certain conditions [1]. </span>

<span style="font-style: normal;">Upper is an activator of Meta and can activate </span><em>meta</em> under certain conditions [1]. 

RpoH is an activator of <em>meta</em> and can activate <em>meta</em> under certain conditions [1]. 

RpoD<span style="font-style: normal;"> is an activator of <em>meta</em> and can activate <em>meta</em> under certain conditions [1]. </span>

XylSh is an activator of <em>meta</em> and can activate <em>meta</em> under certain conditions [1]. 

RpoS is an activator of <em>meta</em> and can activate <em>meta</em> under certain conditions [1]. 

S_10 1 S_4 1 S_12 1 S_19 1 S_2 1 S_13 1 S_8 1 S_4 1 S_12 1 S_19 1 S_9 1 S_2 1 S_3 1 S_4 1 S_12 1 S_19 1 S_9 1 S_2 1

ProX is activated by Glu and deactivated by CellDens [1]. 

CellDens deactivates ProX [1].

Glu activates ProX [1].

S_18 1 S_1 1

<font face="Georgia" size="2">The logical regulation of Meta2 is defined as ((((((m-xyl ^ Upper) v 3MBz) ^ XylS) ^ XylSh) ^ (RpoD  v (RpoS ^ (RpoH)))) ^¬ (Crc v ProX)) [1].  </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 9.000000pt; font-family: 'Helvetica'">In </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">Pseu-\r\ndomonas</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">, the CR that is triggered by amino acids is\r\nexerted through the inhibition of the translation of the target\r\ngenes by the RNA-binding protein Crc (Aranda-Olmedo\r\n</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">et al</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">., 2005; Moreno </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">et al</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">., 2009). This protein targets the\r\nmRNA of the two local regulators of the TOL system (XylR\r\nand XylS) and the catabolic operons (Moreno </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">et al</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">., 2010). </span></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 9.000000pt; font-family: 'Helvetica'">The </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">upper </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">operon encodes the\r\nenzymes that are required for the conversion of </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">m</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">-xylene\r\ninto 3-methylbenzoate (3MBz), whereas </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">meta </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">encodes\r\nthe enzymes that catalyse the metabolization of 3MBz\r\ninto pyruvate and acetaldehyde. The </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">upper </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">operon is\r\nexpressed from the </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">Pu </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">promoter, which is activated by the\r\ntranscriptional factor (TF) named XylR in response to the\r\npresence of </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">m</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">-xylene. The </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">meta </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">operon, however, is\r\nexpressed from the </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">Pm </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">promoter and is activated by XylS\r\nin response to 3MBz (Franklin </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">et al</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">., 1981; Inouye </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'; font-style: oblique">et al</span><span style="font-size: 9.000000pt; font-family: 'Helvetica'">.,\r\n1983). In addition, XylR also triggers the expression of\r\nXylS, which leads to its overproduction. A distinct property\r\nof the TOL network is that such overexpression of XylS due </span><span style="font-size: 9pt; font-family: Helvetica;">to XylR can trigger the expression of </span><span style="font-size: 9pt; font-family: Helvetica; font-style: oblique;">Pm </span><span style="font-size: 9pt; font-family: Helvetica;">even in the\r\nabsence of its cognate inducer 3MBz (Mermod </span><span style="font-size: 9pt; font-family: Helvetica; font-style: oblique;">et al</span><span style="font-size: 9pt; font-family: Helvetica;">.,\r\n1987).</span></p>\r\n \r\n \r\n \r\n <p><span style="font-family: Helvetica; font-size: 9pt;"> </span><span style="font-size: 9.000000pt; font-family: 'Helvetica'"> </span></p>\r\n </div>\r\n </div>\r\n </div>

S_3 1 S_4 1 S_12 1 S_19 1 S_9 1 S_2 1 S_16 1 S_10 1 S_4 1 S_12 1 S_19 1 S_2 1 S_16 1 S_13 1 S_4 1 S_12 1 S_19 1 S_9 1 S_8 1 S_2 1 S_16 1

RpoS is activated by CellDens [1].

IHF and RpoS are high when Cell Density is high [1-3]

S_1 1

Cold induces the activity of TurA [1].

Cold shock induces the expression/activity of TurA and PprA [1,2]

S_21 1

Cold activates PprA [1].

Cold shock induces the expression/activity of TurA and PprA [1,2]

S_21 1