An integrated approach to reconstructing genome-scale transcriptional regulatory networks

Imam, Saheed; Noguera, Daniel R.; Donohue, Timothy J.; Leslie, Christina

doi:10.1371/journal.pcbi.1004103

Title: An integrated approach to reconstructing genome-scale transcriptional regulatory networks

Abstract

Transcriptional regulatory networks (TRNs) program cells to dynamically alter their gene expression in response to changing internal or environmental conditions. In this study, we develop a novel workflow for generating large-scale TRN models that integrates comparative genomics data, global gene expression analyses, and intrinsic properties of transcription factors (TFs). An assessment of this workflow using benchmark datasets for the well-studied γ-proteobacterium Escherichia coli showed that it outperforms expression-based inference approaches, having a significantly larger area under the precision-recall curve. Further analysis indicated that this integrated workflow captures different aspects of the E. coli TRN than expression-based approaches, potentially making them highly complementary. We leveraged this new workflow and observations to build a large-scale TRN model for the α-Proteobacterium Rhodobacter sphaeroides that comprises 120 gene clusters, 1211 genes (including 93 TFs), 1858 predicted protein-DNA interactions and 76 DNA binding motifs. We found that ~67% of the predicted gene clusters in this TRN are enriched for functions ranging from photosynthesis or central carbon metabolism to environmental stress responses. We also found that members of many of the predicted gene clusters were consistent with prior knowledge in R. sphaeroides and/or other bacteria. Experimental validation of predictions from this R. sphaeroides TRN model showedmore »« less

Authors:

Imam, Saheed ^[1]; Noguera, Daniel R. ^[1]; Donohue, Timothy J. ^[1]; Leslie, Christina ^[2]

Univ. of Wisconsin, Madison, WI (United States)
Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

Publication Date:: 2015-02-27

Research Org.:: Univ. of Wisconsin, Madison, WI (United States); Great Lakes Bioenergy Research Center (GLBRC), Madison, WI (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR). Scientific Discovery through Advanced Computing (SciDAC)

OSTI Identifier:: 1204400

Grant/Contract Number:: FC02-07ER64494; FG02-04ER25627

Resource Type:: Accepted Manuscript

Journal Name:: PLoS Computational Biology (Online)

Additional Journal Information:: Journal Name: PLoS Computational Biology (Online); Journal Volume: 11; Journal Issue: 2; Journal ID: ISSN 1553-7358

Publisher:: Public Library of Science

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Imam, Saheed, Noguera, Daniel R., Donohue, Timothy J., and Leslie, Christina. An integrated approach to reconstructing genome-scale transcriptional regulatory networks.  United States: N. p., 2015. 
Web.  doi:10.1371/journal.pcbi.1004103.

Copy to clipboard


                    Imam, Saheed, Noguera, Daniel R., Donohue, Timothy J., & Leslie, Christina. An integrated approach to reconstructing genome-scale transcriptional regulatory networks.  United States.  https://doi.org/10.1371/journal.pcbi.1004103

Copy to clipboard


                    Imam, Saheed, Noguera, Daniel R., Donohue, Timothy J., and Leslie, Christina. Fri .  
"An integrated approach to reconstructing genome-scale transcriptional regulatory networks".  United States.  https://doi.org/10.1371/journal.pcbi.1004103.  https://www.osti.gov/servlets/purl/1204400.

Copy to clipboard


                    
@article{osti_1204400,

  title        = {An integrated approach to reconstructing genome-scale transcriptional regulatory networks},

  author       = {Imam, Saheed and Noguera, Daniel R. and Donohue, Timothy J. and Leslie, Christina},

  abstractNote = {Transcriptional regulatory networks (TRNs) program cells to dynamically alter their gene expression in response to changing internal or environmental conditions. In this study, we develop a novel workflow for generating large-scale TRN models that integrates comparative genomics data, global gene expression analyses, and intrinsic properties of transcription factors (TFs). An assessment of this workflow using benchmark datasets for the well-studied γ-proteobacterium Escherichia coli showed that it outperforms expression-based inference approaches, having a significantly larger area under the precision-recall curve. Further analysis indicated that this integrated workflow captures different aspects of the E. coli TRN than expression-based approaches, potentially making them highly complementary. We leveraged this new workflow and observations to build a large-scale TRN model for the α-Proteobacterium Rhodobacter sphaeroides that comprises 120 gene clusters, 1211 genes (including 93 TFs), 1858 predicted protein-DNA interactions and 76 DNA binding motifs. We found that ~67% of the predicted gene clusters in this TRN are enriched for functions ranging from photosynthesis or central carbon metabolism to environmental stress responses. We also found that members of many of the predicted gene clusters were consistent with prior knowledge in R. sphaeroides and/or other bacteria. Experimental validation of predictions from this R. sphaeroides TRN model showed that high precision and recall was also obtained for TFs involved in photosynthesis (PpsR), carbon metabolism (RSP_0489) and iron homeostasis (RSP_3341). In addition, this integrative approach enabled generation of TRNs with increased information content relative to R. sphaeroides TRN models built via other approaches. We also show how this approach can be used to simultaneously produce TRN models for each related organism used in the comparative genomics analysis. Our results highlight the advantages of integrating comparative genomics of closely related organisms with gene expression data to assemble large-scale TRN models with high-quality predictions.},

  doi          = {10.1371/journal.pcbi.1004103},

  journal      = {PLoS Computational Biology (Online)},

  number       = 2,

  volume       = 11,

  place        = {United States},

  year         = {2015},

  month        = {2}

}

Copy to clipboard

Journal Article:

Free Publicly Available Full Text

Accepted Manuscript (DOE)

Publisher's Version of Record

https://doi.org/10.1371/journal.pcbi.1004103

Other availability

Search WorldCat to find libraries that may hold this journal

Citation Metrics:

Cited by: 21 works

Citation information provided by
Web of Science

Save / Share:

Export Metadata

Save to My Library

Works referenced in this record:

Control of Proteobacterial Central Carbon Metabolism by the HexR Transcriptional Regulator: A CASE STUDY IN
journal, August 2011

Leyn, Semen A.; Li, Xiaoqing; Zheng, Qingxiang
Journal of Biological Chemistry, Vol. 286, Issue 41
DOI: 10.1074/jbc.M111.267963

Regulation of bacterial photosynthesis genes by the small noncoding RNA PcrZ
journal, September 2012

Mank, N. N.; Berghoff, B. A.; Hermanns, Y. N.
Proceedings of the National Academy of Sciences, Vol. 109, Issue 40
DOI: 10.1073/pnas.1207067109

Dialogue on Reverse-Engineering Assessment and Methods: The DREAM of High-Throughput Pathway Inference
journal, October 2007

Stolovitzky, G.; Monroe, D.; Califano, A.
Annals of the New York Academy of Sciences, Vol. 1115, Issue 1
DOI: 10.1196/annals.1407.021

Module networks revisited: computational assessment and prioritization of model predictions
journal, January 2009

Joshi, A.; De Smet, R.; Marchal, K.
Bioinformatics, Vol. 25, Issue 4
DOI: 10.1093/bioinformatics/btn658

A Tight Link between Orthologs and Bidirectional Best Hits in Bacterial and Archaeal Genomes
journal, November 2012

Wolf, Yuri I.; Koonin, Eugene V.
Genome Biology and Evolution, Vol. 4, Issue 12
DOI: 10.1093/gbe/evs100

Aerobic and anaerobic regulation in Rhodobacter sphaeroides 2.4.1: the role of the fnrL gene.
journal, November 1995

Zeilstra-Ryalls, J. H.; Kaplan, S.
Journal of Bacteriology, Vol. 177, Issue 22
DOI: 10.1128/jb.177.22.6422-6431.1995

MEME: discovering and analyzing DNA and protein sequence motifs
journal, July 2006

Bailey, T. L.; Williams, N.; Misleh, C.
Nucleic Acids Research, Vol. 34, Issue Web Server
DOI: 10.1093/nar/gkl198

Control of Photosystem Formation inRhodobacter sphaeroides
journal, June 1998

Zeilstra-Ryalls, Jill; Gomelsky, Mark; Eraso, Jesus M.
Journal of Bacteriology, Vol. 180, Issue 11
DOI: 10.1128/JB.180.11.2801-2809.1998

Convergence of the Transcriptional Responses to Heat Shock and Singlet Oxygen Stresses
journal, September 2012

Dufour, Yann S.; Imam, Saheed; Koo, Byoung-Mo
PLoS Genetics, Vol. 8, Issue 9
DOI: 10.1371/journal.pgen.1002929

Studies of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding specificity
journal, May 2013

Rajagopalan, Senapathy; Teter, Sarah J.; Zwart, Petrus H.
Nature Structural & Molecular Biology, Vol. 20, Issue 6
DOI: 10.1038/nsmb.2568

Postgenomic Adventures with Rhodobacter sphaeroides
journal, October 2007

Mackenzie, Chris; Eraso, Jesus M.; Choudhary, Madhusudan
Annual Review of Microbiology, Vol. 61, Issue 1, p. 283-307
DOI: 10.1146/annurev.micro.61.080706.093402

Oxygen-insensitive synthesis of the photosynthetic membranes of Rhodobacter sphaeroides: a mutant histidine kinase.
journal, May 1995

Eraso, J. M.; Kaplan, S.
Journal of Bacteriology, Vol. 177, Issue 10
DOI: 10.1128/jb.177.10.2695-2706.1995

A Gibbs Sampling Method to Detect Overrepresented Motifs in the Upstream Regions of Coexpressed Genes
journal, April 2002

Thijs, Gert; Marchal, Kathleen; Lescot, Magali
Journal of Computational Biology, Vol. 9, Issue 2
DOI: 10.1089/10665270252935566

Molecular genetic analysis suggesting interactions between AppA and PpsR in regulation of photosynthesis gene expression in Rhodobacter sphaeroides 2.4.1.
journal, January 1997

Gomelsky, M.; Kaplan, S.
Journal of Bacteriology, Vol. 179, Issue 1
DOI: 10.1128/jb.179.1.128-134.1997

DISTILLER: a data integration framework to reveal condition dependency of complex regulons in Escherichia coli
journal, January 2009

Lemmens, Karen; De Bie, Tijl; Dhollander, Thomas
Genome Biology, Vol. 10, Issue 3
DOI: 10.1186/gb-2009-10-3-r27

AppA, a Redox Regulator of Photosystem Formation in Rhodobacter sphaeroides 2.4.1, Is a Flavoprotein : IDENTIFICATION OF A NOVEL FAD BINDING DOMAIN
journal, December 1998

Gomelsky, Mark; Kaplan, Samuel
Journal of Biological Chemistry, Vol. 273, Issue 52
DOI: 10.1074/jbc.273.52.35319

Pathways Involved in Reductant Distribution during Photobiological H ₂ Production by Rhodobacter sphaeroides
journal, August 2011

Kontur, Wayne S.; Ziegelhoffer, Eva C.; Spero, Melanie A.
Applied and Environmental Microbiology, Vol. 77, Issue 20
DOI: 10.1128/AEM.05273-11

Gene Ontology: tool for the unification of biology
journal, May 2000

Ashburner, Michael; Ball, Catherine A.; Blake, Judith A.
Nature Genetics, Vol. 25, Issue 1
DOI: 10.1038/75556

Mining genome databases to identify and understand new gene regulatory systems
journal, April 2002

Stormo, G.
Current Opinion in Microbiology, Vol. 5, Issue 2
DOI: 10.1016/S1369-5274(02)00309-0

Role of the fnrL Gene in Photosystem Gene Expression and Photosynthetic Growth of Rhodobacter sphaeroides 2.4.1
journal, March 1998

Zeilstra-Ryalls, Jill H.; Kaplan, Samuel
Journal of Bacteriology, Vol. 180, Issue 6
DOI: 10.1128/JB.180.6.1496-1503.1998

The Pfam protein families database
journal, January 2004

Bateman, Alex; Coin, Lachlan; Durbin, Richard
Nucleic Acids Research, Vol. 32, Issue S1, p. D138-D141
DOI: 10.1093/nar/gkh121

Ferric uptake regulation protein acts as a repressor, employing iron(II) as a cofactor to bind the operator of an iron transport operon in Escherichia coli
journal, August 1987

Bagg, Anne; Neilands, J. B.
Biochemistry, Vol. 26, Issue 17
DOI: 10.1021/bi00391a039

Cyclic AMP in prokaryotes.
journal, January 1992

Botsford, J. L.; Harman, J. G.
Microbiological Reviews, Vol. 56, Issue 1
DOI: 10.1128/MMBR.56.1.100-122.1992

RegPredict: an integrated system for regulon inference in prokaryotes by comparative genomics approach
journal, June 2010

Novichkov, P. S.; Rodionov, D. A.; Stavrovskaya, E. D.
Nucleic Acids Research, Vol. 38, Issue Web Server
DOI: 10.1093/nar/gkq531

The oxygen-responsive transcriptional regulator FNR of Escherichia coli : the search for signals and reactions
journal, July 1997

Unden, Gottfried; Schirawski, Jan
Molecular Microbiology, Vol. 25, Issue 02
DOI: 10.1046/j.1365-2958.1997.4731841.x

AppA Is a Blue Light Photoreceptor that Antirepresses Photosynthesis Gene Expression in Rhodobacter sphaeroides
journal, September 2002

Masuda, Shinji; Bauer, Carl E.
Cell, Vol. 110, Issue 5
DOI: 10.1016/S0092-8674(02)00876-0

Validating module network learning algorithms using simulated data
journal, May 2007

Michoel, Tom; Maere, Steven; Bonnet, Eric
BMC Bioinformatics, Vol. 8, Issue S2
DOI: 10.1186/1471-2105-8-S2-S5

iRsp1095: A genome-scale reconstruction of the Rhodobacter sphaeroides metabolic network
journal, January 2011

Imam, Saheed; Yilmaz, Safak; Sohmen, Ugur
BMC Systems Biology, Vol. 5, Issue 1
DOI: 10.1186/1752-0509-5-116

Electron Partitioning During Light- and Nutrient-Powered Hydrogen Production by Rhodobacter sphaeroides
journal, January 2010

Yilmaz, Luftu Safak; Kontur, Wayne S.; Sanders, Alison P.
BioEnergy Research, Vol. 3, Issue 1
DOI: 10.1007/s12155-009-9072-8

Co-regulation of lipoamide dehydrogenase and 2-oxoglutarate dehydrogenase synthesis in Escherichia coli : characterisation of an ArcA binding site in the lpd promoter
journal, December 1998

Cunningham, Louise; Georgellis, Dimitris; Green, Jeffrey
FEMS Microbiology Letters, Vol. 169, Issue 2
DOI: 10.1111/j.1574-6968.1998.tb13347.x

A comparison of normalization methods for high density oligonucleotide array data based on variance and bias
journal, January 2003

Bolstad, B. M.; Irizarry, R. A.; Astrand, M.
Bioinformatics, Vol. 19, Issue 2
DOI: 10.1093/bioinformatics/19.2.185

Reconstruction of microbial transcriptional regulatory networks
journal, February 2004

Herrgård, Markus J.; Covert, Markus W.; Palsson, Bernhard Ø
Current Opinion in Biotechnology, Vol. 15, Issue 1
DOI: 10.1016/j.copbio.2003.11.002

IscR, an Fe-S cluster-containing transcription factor, represses expression of Escherichia coli genes encoding Fe-S cluster assembly proteins
journal, December 2001

Schwartz, C. J.; Giel, J. L.; Patschkowski, T.
Proceedings of the National Academy of Sciences, Vol. 98, Issue 26
DOI: 10.1073/pnas.251550898

Making connections between novel transcription factors and their DNA motifs
journal, January 2005

Tan, K.
Genome Research, Vol. 15, Issue 2
DOI: 10.1101/gr.3069205

OrthoMCL: Identification of Ortholog Groups for Eukaryotic Genomes
journal, September 2003

Li, L.
Genome Research, Vol. 13, Issue 9
DOI: 10.1101/gr.1224503

In Vitro and In Vivo Analysis of the Role of PrrA in Rhodobacter sphaeroides 2.4.1 hemA Gene Expression
journal, April 2006

Ranson-Olson, B.; Jones, D. F.; Donohue, T. J.
Journal of Bacteriology, Vol. 188, Issue 9
DOI: 10.1128/JB.188.9.3208-3218.2006

The Use of Chromatin Immunoprecipitation to Define PpsR Binding Activity in Rhodobacter sphaeroides 2.4.1
journal, August 2008

Bruscella, P.; Eraso, J. M.; Roh, J. H.
Journal of Bacteriology, Vol. 190, Issue 20
DOI: 10.1128/JB.00719-08

Reconstruction of the Core and Extended Regulons of Global Transcription Factors
journal, July 2010

Dufour, Yann S.; Kiley, Patricia J.; Donohue, Timothy J.
PLoS Genetics, Vol. 6, Issue 7
DOI: 10.1371/journal.pgen.1001027

Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data
journal, May 2003

Segal, Eran; Shapira, Michael; Regev, Aviv
Nature Genetics, Vol. 34, Issue 2
DOI: 10.1038/ng1165

Protein-protein interactions between CbbR and RegA (PrrA), transcriptional regulators of the cbb operons of Rhodobacter sphaeroides
journal, February 2009

Dangel, Andrew W.; Tabita, F. Robert
Molecular Microbiology, Vol. 71, Issue 3
DOI: 10.1111/j.1365-2958.2008.06558.x

Identifying the conserved network of cis-regulatory sites of a eukaryotic genome
journal, November 2005

Wang, T.; Stormo, G. D.
Proceedings of the National Academy of Sciences, Vol. 102, Issue 48
DOI: 10.1073/pnas.0505147102

Towards a Rigorous Assessment of Systems Biology Models: The DREAM3 Challenges
journal, February 2010

Prill, Robert J.; Marbach, Daniel; Saez-Rodriguez, Julio
PLoS ONE, Vol. 5, Issue 2
DOI: 10.1371/journal.pone.0009202

The catabolite repressor/activator (Cra) protein of enteric bacteria.
journal, June 1996

Saier, M. H.; Ramseier, T. M.
Journal of Bacteriology, Vol. 178, Issue 12
DOI: 10.1128/jb.178.12.3411-3417.1996

The arginine regulon of Escherichia coli: whole-system transcriptome analysis discovers new genes and provides an integrated view of arginine regulation
journal, November 2006

Caldara, M.; Charlier, D.; Cunin, R.
Microbiology, Vol. 152, Issue 11
DOI: 10.1099/mic.0.29088-0