Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities
Abstract
Transcriptional regulatory networks (TRNs) have been studied intensely for >25 y. Yet, even for the Escherichia coli TRN—probably the best characterized TRN—several questions remain. Here, we address three questions: ( i ) How complete is our knowledge of the E. coli TRN; ( ii ) how well can we predict gene expression using this TRN; and ( iii ) how robust is our understanding of the TRN? First, we reconstructed a high-confidence TRN (hiTRN) consisting of 147 transcription factors (TFs) regulating 1,538 transcription units (TUs) encoding 1,764 genes. The 3,797 high-confidence regulatory interactions were collected from published, validated chromatin immunoprecipitation (ChIP) data and RegulonDB. For 21 different TF knockouts, up to 63% of the differentially expressed genes in the hiTRN were traced to the knocked-out TF through regulatory cascades. Second, we trained supervised machine learning algorithms to predict the expression of 1,364 TUs given TF activities using 441 samples. The algorithms accurately predicted condition-specific expression for 86% (1,174 of 1,364) of the TUs, while 193 TUs (14%) were predicted better than random TRNs. Third, we identified 10 regulatory modules whose definitions were robust against changes to the TRN or expression compendium. Using surrogate variable analysis, we also identified three unmodeledmore »
- Publication Date:
- Research Org.:
- Univ. of California, San Diego, CA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1378781
- Alternate Identifier(s):
- OSTI ID: 1465783
- Grant/Contract Number:
- SC0008701
- Resource Type:
- Published Article
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 114 Journal Issue: 38; Journal ID: ISSN 0027-8424
- Publisher:
- Proceedings of the National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Fang, Xin, Sastry, Anand, Mih, Nathan, Kim, Donghyuk, Tan, Justin, Yurkovich, James T., Lloyd, Colton J., Gao, Ye, Yang, Laurence, and Palsson, Bernhard O.. Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities. United States: N. p., 2017.
Web. https://doi.org/10.1073/pnas.1702581114.
Fang, Xin, Sastry, Anand, Mih, Nathan, Kim, Donghyuk, Tan, Justin, Yurkovich, James T., Lloyd, Colton J., Gao, Ye, Yang, Laurence, & Palsson, Bernhard O.. Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities. United States. https://doi.org/10.1073/pnas.1702581114
Fang, Xin, Sastry, Anand, Mih, Nathan, Kim, Donghyuk, Tan, Justin, Yurkovich, James T., Lloyd, Colton J., Gao, Ye, Yang, Laurence, and Palsson, Bernhard O.. Tue .
"Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities". United States. https://doi.org/10.1073/pnas.1702581114.
@article{osti_1378781,
title = {Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities},
author = {Fang, Xin and Sastry, Anand and Mih, Nathan and Kim, Donghyuk and Tan, Justin and Yurkovich, James T. and Lloyd, Colton J. and Gao, Ye and Yang, Laurence and Palsson, Bernhard O.},
abstractNote = {Transcriptional regulatory networks (TRNs) have been studied intensely for >25 y. Yet, even for the Escherichia coli TRN—probably the best characterized TRN—several questions remain. Here, we address three questions: ( i ) How complete is our knowledge of the E. coli TRN; ( ii ) how well can we predict gene expression using this TRN; and ( iii ) how robust is our understanding of the TRN? First, we reconstructed a high-confidence TRN (hiTRN) consisting of 147 transcription factors (TFs) regulating 1,538 transcription units (TUs) encoding 1,764 genes. The 3,797 high-confidence regulatory interactions were collected from published, validated chromatin immunoprecipitation (ChIP) data and RegulonDB. For 21 different TF knockouts, up to 63% of the differentially expressed genes in the hiTRN were traced to the knocked-out TF through regulatory cascades. Second, we trained supervised machine learning algorithms to predict the expression of 1,364 TUs given TF activities using 441 samples. The algorithms accurately predicted condition-specific expression for 86% (1,174 of 1,364) of the TUs, while 193 TUs (14%) were predicted better than random TRNs. Third, we identified 10 regulatory modules whose definitions were robust against changes to the TRN or expression compendium. Using surrogate variable analysis, we also identified three unmodeled factors that systematically influenced gene expression. Our computational workflow comprehensively characterizes the predictive capabilities and systems-level functions of an organism’s TRN from disparate data types.},
doi = {10.1073/pnas.1702581114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 38,
volume = 114,
place = {United States},
year = {2017},
month = {9}
}
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https://doi.org/10.1073/pnas.1702581114
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Works referenced in this record:
Few regulatory metabolites coordinate expression of central metabolic genes in Escherichia coli
journal, January 2017
- Kochanowski, Karl; Gerosa, Luca; Brunner, Simon F.
- Molecular Systems Biology, Vol. 13, Issue 1
Determining the Control Circuitry of Redox Metabolism at the Genome-Scale
journal, April 2014
- Federowicz, Stephen; Kim, Donghyuk; Ebrahim, Ali
- PLoS Genetics, Vol. 10, Issue 4
Decoding genome-wide GadEWX-transcriptional regulatory networks reveals multifaceted cellular responses to acid stress in Escherichia coli
journal, August 2015
- Seo, Sang Woo; Kim, Donghyuk; O’Brien, Edward J.
- Nature Communications, Vol. 6, Issue 1
The DNA-binding network of Mycobacterium tuberculosi s
journal, January 2015
- Minch, Kyle J.; Rustad, Tige R.; Peterson, Eliza J. R.
- Nature Communications, Vol. 6, Issue 1
An experimentally supported model of the Bacillus subtilis global transcriptional regulatory network
journal, November 2015
- Arrieta‐Ortiz, Mario L.; Hafemeister, Christoph; Bate, Ashley Rose
- Molecular Systems Biology, Vol. 11, Issue 11
Subsystem Identification Through Dimensionality Reduction of Large-Scale Gene Expression Data
journal, July 2003
- Kim, P. M.
- Genome Research, Vol. 13, Issue 7
DAVID: Database for Annotation, Visualization, and Integrated Discovery
journal, January 2003
- Dennis, Glynn; Sherman, Brad T.; Hosack, Douglas A.
- Genome Biology, Vol. 4, Issue 9, Article No. R60
Gene Expression Prediction by Soft Integration and the Elastic Net—Best Performance of the DREAM3 Gene Expression Challenge
journal, February 2010
- Gustafsson, Mika; Hörnquist, Michael
- PLoS ONE, Vol. 5, Issue 2
Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling
journal, July 2003
- Gardner, T. S.
- Science, Vol. 301, Issue 5629
The PurR regulon in Escherichia coli K-12 MG1655
journal, May 2011
- Cho, Byung-Kwan; Federowicz, Stephen A.; Embree, Mallory
- Nucleic Acids Research, Vol. 39, Issue 15
A system‐level model for the microbial regulatory genome
journal, July 2014
- Brooks, Aaron N.; Reiss, David J.; Allard, Antoine
- Molecular Systems Biology, Vol. 10, Issue 7
Gene Expression Profiling and the Use of Genome-Scale In Silico Models of Escherichia coli for Analysis: Providing Context for Content
journal, April 2009
- Lewis, N. E.; Cho, B. -K.; Knight, E. M.
- Journal of Bacteriology, Vol. 191, Issue 11
Genome-scale Analysis of Escherichia coli FNR Reveals Complex Features of Transcription Factor Binding
journal, June 2013
- Myers, Kevin S.; Yan, Huihuang; Ong, Irene M.
- PLoS Genetics, Vol. 9, Issue 6
Metagenes and molecular pattern discovery using matrix factorization
journal, March 2004
- Brunet, J. -P.; Tamayo, P.; Golub, T. R.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 12
Finding community structure in very large networks
journal, December 2004
- Clauset, Aaron; Newman, M. E. J.; Moore, Cristopher
- Physical Review E, Vol. 70, Issue 6
Integrating high-throughput and computational data elucidates bacterial networks
journal, May 2004
- Covert, Markus W.; Knight, Eric M.; Reed, Jennifer L.
- Nature, Vol. 429, Issue 6987
Detecting and Removing Inconsistencies between Experimental Data and Signaling Network Topologies Using Integer Linear Programming on Interaction Graphs
journal, September 2013
- Melas, Ioannis N.; Samaga, Regina; Alexopoulos, Leonidas G.
- PLoS Computational Biology, Vol. 9, Issue 9
The Mycobacterium tuberculosis regulatory network and hypoxia
journal, July 2013
- Galagan, James E.; Minch, Kyle; Peterson, Matthew
- Nature, Vol. 499, Issue 7457
Systems biology definition of the core proteome of metabolism and expression is consistent with high-throughput data
journal, August 2015
- Yang, Laurence; Tan, Justin; O’Brien, Edward J.
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 34
Nonsmooth nonnegative matrix factorization (nsNMF)
journal, March 2006
- Pascual-Montano, A.; Carazo, J. M.; Kochi, K.
- IEEE Transactions on Pattern Analysis and Machine Intelligence, Vol. 28, Issue 3
limma powers differential expression analyses for RNA-sequencing and microarray studies
journal, January 2015
- Ritchie, Matthew E.; Phipson, Belinda; Wu, Di
- Nucleic Acids Research, Vol. 43, Issue 7
Functional organisation of Escherichia coli transcriptional regulatory network
journal, August 2008
- Martínez-Antonio, Agustino; Janga, Sarath Chandra; Thieffry, Denis
- Journal of Molecular Biology, Vol. 381, Issue 1
Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network
journal, November 2014
- Rustad, Tige R.; Minch, Kyle J.; Ma, Shuyi
- Genome Biology, Vol. 15, Issue 11
Stability-driven nonnegative matrix factorization to interpret spatial gene expression and build local gene networks
journal, April 2016
- Wu, Siqi; Joseph, Antony; Hammonds, Ann S.
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 16
Wisdom of crowds for robust gene network inference
journal, July 2012
- Marbach, Daniel; Costello, James C.; Küffner, Robert
- Nature Methods, Vol. 9, Issue 8
The Bacterial Response Regulator ArcA Uses a Diverse Binding Site Architecture to Regulate Carbon Oxidation Globally
journal, October 2013
- Park, Dan M.; Akhtar, Md. Sohail; Ansari, Aseem Z.
- PLoS Genetics, Vol. 9, Issue 10
Flexible structure alignment by chaining aligned fragment pairs allowing twists
journal, September 2003
- Ye, Y.; Godzik, A.
- Bioinformatics, Vol. 19, Issue Suppl 2
Estimating mutual information
journal, June 2004
- Kraskov, Alexander; Stögbauer, Harald; Grassberger, Peter
- Physical Review E, Vol. 69, Issue 6
Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli
journal, September 2014
- Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem
- Nature Communications, Vol. 5, Issue 1
Genome-scale reconstruction of the sigma factor network in Escherichia coli: topology and functional states
journal, January 2014
- Cho, Byung-Kwan; Kim, Donghyuk; Knight, Eric M.
- BMC Biology, Vol. 12, Issue 1
Shared control of gene expression in bacteria by transcription factors and global physiology of the cell
journal, January 2013
- Berthoumieux, Sara; de Jong, Hidde; Baptist, Guillaume
- Molecular Systems Biology, Vol. 9, Issue 1
Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis
journal, January 2007
- Leek, Jeffrey T.; Storey, John D.
- PLoS Genetics, Vol. 3, Issue 9
Evidence classification of high-throughput protocols and confidence integration in RegulonDB
journal, January 2013
- Weiss, Verena; Medina-Rivera, Alejandra; Huerta, Araceli M.
- Database, Vol. 2013
An integrative, multi‐scale, genome‐wide model reveals the phenotypic landscape of E scherichia coli
journal, July 2014
- Carrera, Javier; Estrela, Raissa; Luo, Jing
- Molecular Systems Biology, Vol. 10, Issue 7
Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis
journal, September 2010
- Chandrasekaran, Sriram; Price, Nathan D.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 41
The architecture of ArgR-DNA complexes at the genome-scale in Escherichia coli
journal, March 2015
- Cho, Suhyung; Cho, Yoo-Bok; Kang, Taek Jin
- Nucleic Acids Research, Vol. 43, Issue 6
Multi-omics integration accurately predicts cellular state in unexplored conditions for Escherichia coli
journal, October 2016
- Kim, Minseung; Rai, Navneet; Zorraquino, Violeta
- Nature Communications, Vol. 7, Issue 1
Genome-scale reconstruction of the Lrp regulatory network in Escherichia coli
journal, December 2008
- Cho, B. -K.; Barrett, C. L.; Knight, E. M.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 49
Prokaryotic genome regulation: A revolutionary paradigm
journal, January 2012
- Ishihama, Akira
- Proceedings of the Japan Academy, Series B, Vol. 88, Issue 9
Deciphering the transcriptional regulatory logic of amino acid metabolism
journal, November 2011
- Cho, Byung-Kwan; Federowicz, Stephen; Park, Young-Seoub
- Nature Chemical Biology, Vol. 8, Issue 1
Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655
journal, August 2015
- Seo, Sang Woo; Kim, Donghyuk; Szubin, Richard
- Cell Reports, Vol. 12, Issue 8
COLOMBOS v3.0: leveraging gene expression compendia for cross-species analyses: Table 1.
journal, November 2015
- Moretto, Marco; Sonego, Paolo; Dierckxsens, Nicolas
- Nucleic Acids Research, Vol. 44, Issue D1
Local and global regulation of transcription initiation in bacteria
journal, August 2016
- Browning, Douglas F.; Busby, Stephen J. W.
- Nature Reviews Microbiology, Vol. 14, Issue 10
Model-based redesign of global transcription regulation
journal, February 2009
- Carrera, Javier; Rodrigo, Guillermo; Jaramillo, Alfonso
- Nucleic Acids Research, Vol. 37, Issue 5
Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles
journal, January 2007
- Faith, Jeremiah J.; Hayete, Boris; Thaden, Joshua T.
- PLoS Biology, Vol. 5, Issue 1
Functional determinants of transcription factors in Escherichia coli: protein families and binding sites
journal, February 2003
- Madan Babu, M.; Teichmann, Sarah A.
- Trends in Genetics, Vol. 19, Issue 2
Works referencing / citing this record:
Sources, propagation and consequences of stochasticity in cellular growth
journal, October 2018
- Thomas, Philipp; Terradot, Guillaume; Danos, Vincent
- Nature Communications, Vol. 9, Issue 1
Systematic identification of metabolites controlling gene expression in E. coli
journal, October 2019
- Lempp, Martin; Farke, Niklas; Kuntz, Michelle
- Nature Communications, Vol. 10, Issue 1
The Escherichia coli transcriptome mostly consists of independently regulated modules
journal, December 2019
- Sastry, Anand V.; Gao, Ye; Szubin, Richard
- Nature Communications, Vol. 10, Issue 1
Microbial life cycles link global modularity in regulation to mosaic evolution
journal, July 2019
- van Gestel, Jordi; Ackermann, Martin; Wagner, Andreas
- Nature Ecology & Evolution, Vol. 3, Issue 8
Estimation of Transcription Factor Activity in Knockdown Studies
journal, July 2019
- Trescher, Saskia; Leser, Ulf
- Scientific Reports, Vol. 9, Issue 1
Stochastic modelling reveals mechanisms of metabolic heterogeneity
journal, March 2019
- Tonn, Mona K.; Thomas, Philipp; Barahona, Mauricio
- Communications Biology, Vol. 2, Issue 1
Genetic Neural Networks: an artificial neural network architecture for capturing gene expression relationships
journal, November 2018
- Eetemadi, Ameen; Tagkopoulos, Ilias
- Bioinformatics, Vol. 35, Issue 13
Systematic discovery of uncharacterized transcription factors in Escherichia coli K-12 MG1655
journal, August 2018
- Gao, Ye; Yurkovich, James T.; Seo, Sang Woo
- Nucleic Acids Research
Predictive models of eukaryotic transcriptional regulation reveals changes in transcription factor roles and promoter usage between metabolic conditions
journal, April 2019
- Holland, Petter; Bergenholm, David; Börlin, Christoph S.
- Nucleic Acids Research, Vol. 47, Issue 10
Escherichia coli Lrp Regulates One-Third of the Genome via Direct, Cooperative, and Indirect Routes
journal, November 2018
- Kroner, Grace M.; Wolfe, Michael B.; Freddolino, Peter L.
- Journal of Bacteriology, Vol. 201, Issue 3
Reconstruction of a Global Transcriptional Regulatory Network for Control of Lipid Metabolism in Yeast by Using Chromatin Immunoprecipitation with Lambda Exonuclease Digestion
journal, July 2018
- Bergenholm, David; Liu, Guodong; Holland, Petter
- mSystems, Vol. 3, Issue 4
ShinyOmics: collaborative exploration of omics-data
journal, January 2020
- Surujon, Defne; van Opijnen, Tim
- BMC Bioinformatics, Vol. 21, Issue 1
Construction and Analysis of Gene Co-Expression Networks in Escherichia coli
journal, March 2018
- Liu, Wei; Li, Li; Long, Xuhe
- Cells, Vol. 7, Issue 3