An experimentally supported model of the Bacillus subtilis global transcriptional regulatory network

Organisms from all domains of life use gene regulation networks to control cell growth, identity, function, and responses to environmental challenges. Although accurate global regulatory models would provide critical evolutionary and functional insights, they remain incomplete, even for the best studied organisms. Efforts to build comprehensive networks are confounded by challenges including network scale, degree of connectivity, complexity of organism–environment interactions, and difficulty of estimating the activity of regulatory factors. Taking advantage of the large number of known regulatory interactions in Bacillus subtilis and two transcriptomics datasets (including one with 38 separate experiments collected specifically for this study), we use a new combination of network component analysis and model selection to simultaneously estimate transcription factor activities and learn a substantially expanded transcriptional regulatory network for this bacterium. In total, we predict 2,258 novel regulatory interactions and recall 74% of the previously known interactions. We obtained experimental support for 391 (out of 635 evaluated) novel regulatory edges (62% accuracy), thus significantly increasing our understanding of various cell processes, such as spore formation.

• Publication year

  2015

• Venue

  Molecular Systems Biology

• Publication date

  2015-11-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.15252/msb.20156236PMID 26577401PMCID 4670728
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A Validated Regulatory Network for Th17 Cell Specification.

  2025cited by this paper
• An Integrated Approach to Reconstructing Genome-Scale Transcriptional Regulatory Networks

  2015cited by this paper
• Temporal and evolutionary dynamics of two-component signaling pathways.

  2015cited by this paper
• An experimentally supported model of the Bacillus subtilis global transcriptional regulatory network

  2015cited by this paper
• Genome-wide mapping of TnrA-binding sites provides new insights into the TnrA regulon in Bacillus subtilis

  2015cited by this paper
• Microbial Forensics: Predicting Phenotypic Characteristics and Environmental Conditions from Large-Scale Gene Expression Profiles

  2015cited by this paper
• CodY Regulates Expression of the Bacillus subtilis Extracellular Proteases Vpr and Mpr

  2015cited by this paper
• Genome-wide identification of Bacillus subtilis Zur-binding sites associated with a Zur box expands its known regulatory network

  2015cited by this paper
• Genome-Wide Analysis of Phosphorylated PhoP Binding to Chromosomal DNA Reveals Several Novel Features of the PhoPR-Mediated Phosphate Limitation Response in Bacillus subtilis

  2015cited by this paper
• cMonkey2: Automated, systematic, integrated detection of co-regulated gene modules for any organism

  2015cited by this paper
• A Closed-Form Solution for Transcription Factor Activity Estimation Using Network Component Analysis

  2014influential reference
• Algorithms for Computational Biology

  2014cited by this paper
• Biofilm formation by Bacillus subtilis: new insights into regulatory strategies and assembly mechanisms

  2014cited by this paper
• Developmentally-Regulated Excision of the SPβ Prophage Reconstitutes a Gene Required for Spore Envelope Maturation in Bacillus subtilis

  2014influential reference
• A system-level model for the microbial regulatory genome

  2014cited by this paper
• Hierarchical expression of genes controlled by the Bacillus subtilis global regulatory protein CodY

  2014cited by this paper
• An integrative, multi-scale, genome-wide model reveals the phenotypic landscape of Escherichia coli

  2014cited by this paper
• A high-resolution network model for global gene regulation in Mycobacterium tuberculosis

  2014cited by this paper
• Spore formation in Bacillus subtilis.

  2014cited by this paper
• Bacterial sigma factors: a historical, structural, and genomic perspective.

  2014cited by this paper
• Robust data-driven incorporation of prior knowledge into the inference of dynamic regulatory networks

  2013influential reference
• SubtiWiki–a database for the model organism Bacillus subtilis that links pathway, interaction and expression information

  2013influential reference
• Mapping Yeast Transcriptional Networks

  2013cited by this paper
• Reconstructing transcriptional regulatory networks by probabilistic network component analysis

  2013influential reference
• Network component analysis provides quantitative insights on an Arabidopsis transcription factor-gene regulatory network

  2013cited by this paper
• Sticking together: building a biofilm the Bacillus subtilis way

  2013cited by this paper
• Genome-wide identification of Bacillus subtilis CodY-binding sites at single-nucleotide resolution

  2013influential reference
• Transcriptional regulation is insufficient to explain substrate-induced flux changes in Bacillus subtilis

  2013cited by this paper
• Heterogeneity in protein expression induces metabolic variability in a modeled Escherichia coli population

  2013cited by this paper
• The WalRK (YycFG) and σI RsgI regulators cooperate to control CwlO and LytE expression in exponentially growing and stressed Bacillus subtilis cells

  2013cited by this paper
• Lessons from the modular organization of the transcriptional regulatory network of Bacillus subtilis

  2013cited by this paper
• Genome-wide Mapping

  2013cited by this paper
• Chance and Necessity in Bacillus subtilis Development

  2013cited by this paper
• Genomic Reconstruction of the Transcriptional Regulatory Network in Bacillus subtilis

  2013cited by this paper
• Genome-scale models of metabolism and gene expression extend and refine growth phenotype prediction

  2013cited by this paper
• SlrA/SinR/SlrR inhibits motility gene expression upstream of a hypersensitive and hysteretic switch at the level of σD in Bacillus subtilis

  2012cited by this paper
• Genome-wide identification of genes directly regulated by the pleiotropic transcription factor Spx in Bacillus subtilis

  2012cited by this paper
• Global Network Reorganization During Dynamic Adaptations of Bacillus subtilis Metabolism

  2012influential reference
• The Bacillus subtilis endospore: assembly and functions of the multilayered coat

  2012influential reference
• High- and low-affinity cre boxes for CcpA binding in Bacillus subtilis revealed by genome-wide analysis

  2012cited by this paper
• RegulonDB v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more

  2012cited by this paper
• Condition-Dependent Transcriptome Reveals High-Level Regulatory Architecture in Bacillus subtilis

  2012influential reference
• A validated regulatory network for Th17 cell specification.

  2012cited by this paper
• Wisdom of crowds for robust gene network inference

  2012influential reference
• Global probabilistic annotation of metabolic networks enables enzyme discovery

  2012cited by this paper
• Reconstructing genome-wide regulatory network of E. coli using transcriptome data and predicted transcription factor activities

  2011influential reference
• parmigene - a parallel R package for mutual information estimation and gene network reconstruction

  2011cited by this paper
• DREAM4: Combining Genetic and Dynamic Information to Identify Biological Networks and Dynamical Models

  2010influential reference
• Revealing strengths and weaknesses of methods for gene network inference

  2010cited by this paper
• Genome-wide binding profiles of the Bacillus subtilis transition state regulator AbrB and its homolog Abh reveals their interactive role in transcriptional regulation

  2010cited by this paper
• Morphology and physico-chemical properties of Bacillus spores surrounded or not with an exosporium: consequences on their ability to adhere to stainless steel.

  2010cited by this paper
• which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multi-species integrative biclustering

  2010cited by this paper
• DREAM3: Network Inference Using Dynamic Context Likelihood of Relatedness and the Inferelator

  2010cited by this paper
• A distance-weighted interaction map reveals a previously uncharacterized layer of the Bacillus subtilis spore coat.

  2010cited by this paper
• ExprEssence - Revealing the essence of differential experimental data in the context of an interaction/regulation net-work

  2010cited by this paper
• Trimming of mammalian transcriptional networks using network component analysis

  2010cited by this paper
• Cytoscape 2.8: new features for data integration and network visualization

  2010cited by this paper
• Hierarchical evolution of the bacterial sporulation network.

  2010cited by this paper
• Inferring Regulatory Networks from Expression Data Using Tree-Based Methods

  2010influential reference
• Stable isotope labeling by amino acids in cell culture (SILAC) applied to quantitative proteomics of Bacillus subtilis.

  2010cited by this paper
• Inferring the transcriptional network of Bacillus subtilis.

  2009cited by this paper
• MicrobesOnline: an integrated portal for comparative and functional genomics

  2009cited by this paper
• MEME Suite: tools for motif discovery and searching

  2009cited by this paper
• From a consortium sequence to a unified sequence: the Bacillus subtilis 168 reference genome a decade later

  2009influential reference
• DISTILLER: a data integration framework to reveal condition dependency of complex regulons in Escherichia coli

  2009cited by this paper
• The coat morphogenetic protein SpoVID is necessary for spore encasement in Bacillus subtilis

  2009cited by this paper
• LysM, a widely distributed protein motif for binding to (peptido)glycans

  2008cited by this paper
• Reconstruction and analysis of the genetic and metabolic regulatory networks of the central metabolism of Bacillus subtilis

  2008cited by this paper
• Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles

  2007influential reference
• Genome-scale Reconstruction of Metabolic Network in Bacillus subtilis Based on High-throughput Phenotyping and Gene Essentiality Data*

  2007cited by this paper
• Control of key metabolic intersections in Bacillus subtilis

  2007influential reference
• Network motifs: theory and experimental approaches

  2007cited by this paper
• DBTBS: a database of transcriptional regulation in Bacillus subtilis containing upstream intergenic conservation information

  2007cited by this paper
• The Inferelator: an algorithm for learning parsimonious regulatory networks from systems-biology data sets de novo

  2006cited by this paper
• Probabilistic inference of transcription factor concentrations and gene-specific regulatory activities

  2006influential reference
• The forespore line of gene expression in Bacillus subtilis.

  2006cited by this paper
• Associate Editor: Golan Yona Downloaded from

  2006influential reference
• Theoretical Biology and Medical Modelling Open Access Predicting Transcription Factor Activities from Combined Analysis of Microarray and Chip Data: a Partial Least Squares Approach

  2005influential reference
• ARACNE: An Algorithm for the Reconstruction of Gene Regulatory Networks in a Mammalian Cellular Context

  2004cited by this paper
• Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments

  2004influential reference
• Dynamic Patterns of Subcellular Protein Localization during Spore Coat Morphogenesis in Bacillus subtilis

  2004cited by this paper
• The Program of Gene Transcription for a Single Differentiating Cell Type during Sporulation in Bacillus subtilis

  2004influential reference
• A master regulator for biofilm formation by Bacillus subtilis

  2004cited by this paper
• Transcriptome-based determination of multiple transcription regulator activities in Escherichia coli by using network component analysis.

  2004influential reference
• Controlling competence in Bacillus subtilis: shared use of regulators.

  2003cited by this paper
• The Spo0A regulon of Bacillus subtilis

  2003cited by this paper
• Structure and function of the feed-forward loop network motif

  2003cited by this paper
• Network component analysis: Reconstruction of regulatory signals in biological systems

  2003influential reference
• Antibiotics that inhibit cell wall biosynthesis induce expression of the Bacillus subtilisσW and σM regulons

  2002cited by this paper
• Antibiotics that inhibit cell wall biosynthesis induce expression of the Bacillus subtilis sigma(W) and sigma(M) regulons.

  2002cited by this paper
• A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes

  2001cited by this paper
• Genome‐wide analysis of the general stress response in Bacillus subtilis

  2001cited by this paper
• Synthesis and characterization of the spore proteins of Bacillus subtilis YdhD, YkuD, and YkvP, which carry a motif conserved among cell wall binding proteins.

  2000cited by this paper
• The transcriptional profile of early to middle sporulation in Bacillus subtilis.

  2000cited by this paper
• A vital stain for studying membrane dynamics in bacteria: a novel mechanism controlling septation during Bacillus subtilis sporulation

  1999cited by this paper
• Bacillus subtilis yckG andyckF Encode Two Key Enzymes of the Ribulose Monophosphate Pathway Used by Methylotrophs, and yckH Is Required for Their Expression

  1999cited by this paper
• The competence transcription factor of Bacillus subtilis recognizes short A/T-rich sequences arranged in a unique, flexible pattern along the DNA helix.

  1998cited by this paper
• The competence transcription factor of Bacillus subtilis

  1998cited by this paper
• The complete genome sequence of the Gram-positive bacterium Bacillus subtilis

  1997influential reference
• Discrimination Among the B. Cereus Group, in Comparison to B. Subtilis, by Structural Carbohydrate P

  1995cited by this paper

• A tetrameric SpoVA2 membrane complex is required for DPA transport into Bacillus anthracis spores

  2026cites this paper
• Transcriptome-Guided Analysis and Application of the Mechanisms Influencing PamyE Promoter Activity.

  2025cites this paper
• Resistance and germination of spores of Bacillus species lacking members of a spore integral inner membrane protein family and locations of these proteins in spores

  2025cites this paper
• Uncovering Functional Gene Regulatory Networks in Bulk and Single-Cell Data through Robust Transcription Factor Activity Estimation and Model-Guided Experimental Validation

  2025cites this paper
• Predicting gene regulatory network interactions with high certainty using the Linear Profile Likelihood - LiPLike

  2025cites this paper
• Transcriptome data are insufficient to control false discoveries in regulatory network inference

  2024cites this paper
• PMF-GRN: a variational inference approach to single-cell gene regulatory network inference using probabilistic matrix factorization

  2024cites this paper
• Regulator DegU can remarkably influence alkaline protease AprE biosynthesis in Bacillus licheniformis 2709.

  2024cites this paper
• MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore

  2024influential citation
• Augusta: From RNA‐Seq to gene regulatory networks and Boolean models

  2024cites this paper
• Spore germination: Two ion channels are better than one

  2024cites this paper
• SpoVAF and FigP assemble into oligomeric ion channels that enhance spore germination

  2024cites this paper
• Structure-primed embedding on the transcription factor manifold enables transparent model architectures for gene regulatory network and latent activity inference

  2024cites this paper
• Real-time nanoscale investigation of spore coat assembly in Bacillus subtilis

  2024cites this paper
• Robust Multi-view Co-expression Network Inference

  2024cites this paper
• EnsInfer: a simple ensemble approach to network inference outperforms any single method

  2023cites this paper
• Regulation of late-acting operons by three transcription factors and a CRISPR-Cas component during Myxococcus xanthus development

  2023cites this paper
• Sustainable utilization of feather waste to produce alkaline serine protease by genetically engineered Bacillus amyloliquefaciens

  2023cites this paper
• Optimizing data integration improves gene regulatory network inference in Arabidopsis thaliana

  2023cites this paper
• Simultaneous estimation of gene regulatory network structure and RNA kinetics from single cell gene expression

  2023cites this paper
• Sporulation conditions influence the surface and adhesion properties of Bacillus subtilis spores

  2023cites this paper
• Bacillus subtilis NrnB is expressed during sporulation and acts as a unique 3′-5′ exonuclease

  2023cites this paper
• Identification and engineering of the aprE regulatory region and relevant regulatory proteins in Bacillus licheniformis 2709.

  2023cites this paper
• Identification of CgeA as a glycoprotein that anchors polysaccharides to the spore surface in Bacillus subtilis

  2023cites this paper
• Enhance the biocontrol efficiency of Bacillus velezensis Bs916 for white spot syndrome virus in crayfish by overproduction of cyclic lipopeptide locillomycin

  2023cites this paper
• A Variational Inference Approach to Single-Cell Gene Regulatory Network Inference using Probabilistic Matrix Factorization

  2023cites this paper
• New Thoughts on an Old Topic: Secrets of Bacterial Spore Resistance Slowly Being Revealed

  2023cites this paper
• An atlas of gene regulatory networks for memory CD4+ T cells in youth and old age

  2023cites this paper
• Expression of the 2Duf protein in wild-type Bacillus subtilis spores stabilizes inner membrane proteins and increases spore resistance to wet heat and hydrogen peroxide.

  2023cites this paper
• etiBsu1209: A comprehensive multiscale metabolic model for Bacillus subtilis

  2023cites this paper
• Structure primed embedding on the transcription factor manifold enables transparent model architectures for gene regulatory network and latent activity inference

  2023cites this paper
• Prediction and validation of novel SigB regulon members in Bacillus subtilis and regulon structure comparison to Bacillales members

  2023cites this paper
• Revisiting regulatory coherence: accounting for temporal bias in plant gene co-expression analyses.

  2023cites this paper
• Atlas-Guided Discovery of Transcription Factors for T Cell Programming

  2023cites this paper
• Multi-View Independent Component Analysis with Shared and Individual Sources

  2022cites this paper
• Probabilistic Matrix Factorization for Gene Regulatory Network Inference

  2022cites this paper
• Extensive cellular multi-tasking within Bacillus subtilis biofilms

  2022cites this paper
• Comparative biological network analysis for differentially expressed proteins as a function of bacilysin biosynthesis in Bacillus subtilis.

  2022cites this paper
• Role of novel polysaccharide layers in assembly of the exosporium, the outermost protein layer of the Bacillus anthracis spore

  2022cites this paper
• Transcriptomic Analysis Reveals the Role of tmRNA on Biofilm Formation in Bacillus subtilis

  2022cites this paper
• A Sporulation-Specific sRNA Bvs196 Contributing to the Developing Spore in Bacillus velezensis

  2022cites this paper
• Systems-level identification of key transcription factors in immune cell specification

  2022cites this paper
• The impact of PrsA over-expression on the Bacillus subtilis transcriptome during fed-batch fermentation of alpha-amylase production

  2022cites this paper
• Using genome-wide expression compendia to study microorganisms

  2022cites this paper
• Mathematical models to study the biology of pathogens and the infectious diseases they cause

  2022cites this paper
• Seed banks alter the molecular evolutionary dynamics of Bacillus subtilis

  2022cites this paper
• Network-based approaches for modeling disease regulation and progression

  2022cites this paper
• NetREX-CF integrates incomplete transcription factor data with gene expression to reconstruct gene regulatory networks

  2022cites this paper
• Time-Resolved Proteomics of Germinating Spores of Bacillus cereus

  2022cites this paper
• Single-cell gene regulatory network inference at scale: The Inferelator 3.0

  2021influential citation
• PEAK Predicts Gene Regulatory Network Linkages during Sea Urchin Development with High Sensitivity from Gene Expression Data Alone

  2021cites this paper
• Bacillus pumilus Group Comparative Genomics: Toward Pangenome Features, Diversity, and Marine Environmental Adaptation

  2021cites this paper
• Prediction of Whole-Cell Transcriptional Response with Machine Learning

  2021cites this paper
• Quantitative prediction of conditional vulnerabilities in regulatory and metabolic networks using PRIME

  2021cites this paper
• Quantitative prediction of conditional vulnerabilities in regulatory and metabolic networks of Mycobacterium tuberculosis

  2021cites this paper
• ClpC-Mediated Sporulation Regulation at Engulfment Stage in Bacillus anthracis

  2021cites this paper
• Single cell gene regulatory networks in plants: Opportunities for enhancing climate change stress resilience

  2021cites this paper
• Different Resource Allocation in a Bacillus subtilis Population Displaying Bimodal Motility

  2021cites this paper
• Gene regulatory network inference in long-lived C. elegans reveals modular properties that are predictive of novel aging genes

  2021cites this paper
• High-performance single-cell gene regulatory network inference at scale: the Inferelator 3.0

  2021cites this paper
• Developmental gene regulatory network connections predicted by machine learning from gene expression data alone

  2021cites this paper
• Quantitative prediction of conditional vulnerabilities in regulatory and metabolic networks using PRIME

  2021cites this paper
• Taiji-reprogram: a framework to uncover cell-type specific regulators and predict cellular reprogramming cocktails

  2021cites this paper
• Resistance properties and the role of the inner membrane and coat of Bacillus subtilis spores with extreme wet heat resistance

  2021cites this paper
• A new role for SR1 from Bacillus subtilis: regulation of sporulation by inhibition of kinA translation

  2021cites this paper
• A Bayesian inference transcription factor activity model for the analysis of single-cell transcriptomes

  2021cites this paper
• Identification of an RNA sponge that controls the RoxS riboregulator of central metabolism in Bacillus subtilis

  2021cites this paper
• Inferring gene regulatory network from single-cell transcriptomic data by integrating multiple prior networks

  2021cites this paper
• Levels and Characteristics of mRNAs in Spores of Firmicute Species

  2021influential citation
• Kinetic Modeling and Meta-Analysis of the Bacillus subtilis SigB Regulon during Spore Germination and Outgrowth

  2021cites this paper
• Spo0A can efficiently enhance the expression of the alkaline protease gene aprE in Bacillus licheniformis by specifically binding to its regulatory region.

  2020cites this paper
• Reconstruction of Gene Regulatory Networks by integrating biological model and a recommendation system

  2020cites this paper
• Evolution in the Debian GNU/Linux software network: analogies and differences with gene regulatory networks

  2020cites this paper
• A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV

  2020influential citation
• Evolutionary Analysis of the Bacillus subtilis Genome Reveals New Genes Involved in Sporulation

  2020cites this paper
• Identifiability and experimental design in perturbation studies

  2020cites this paper
• OutPredict: multiple datasets can improve prediction of expression and inference of causality

  2020cites this paper
• The spore coat is essential for Bacillus subtilis spore resistance to pulsed light, and pulsed light treatment eliminates some spore coat proteins.

  2020cites this paper
• Machine learning uncovers independently regulated modules in the Bacillus subtilis transcriptome

  2020cites this paper
• Abasy Atlas v2.2: The most comprehensive and up-to-date inventory of meta-curated, historical, bacterial regulatory networks, their completeness and system-level characterization

  2020cites this paper
• Impact of high salinity and the compatible solute glycine betaine on gene expression of Bacillus subtilis.

  2020cites this paper
• Network reconstruction for trans acting genetic loci using multi-omics data and prior information

  2020cites this paper
• Inferring TF activities and activity regulators from gene expression data with constraints from TF perturbation data

  2020cites this paper
• Plugging Small RNAs into the Network

  2020cites this paper
• Channels modestly impact compartment‐specific ATP levels during Bacillus subtilis sporulation and a rise in the mother cell ATP level is not necessary for Pro‐σK cleavage

  2020cites this paper
• Reconciliation of Regulatory Data: The Regulatory Networks of Escherichia coli and Bacillus subtilis

  2020cites this paper
• Phenotypical characterization of spontaneous morphological variants of Bacillus sp. strains

  2020cites this paper
• An Optimised Proteomics Workflow for the Detection of Small Proteins.

  2020cites this paper
• Physiology of guanosine-based second messenger signaling in Bacillus subtilis

  2020cites this paper
• Disrupting the ArcA regulatory network increases tetracycline susceptibility of TetR Escherichia coli

  2020cites this paper
• A review of methods for the reconstruction and analysis of integrated genome-scale models of metabolism and regulation.

  2020cites this paper
• Predictive regulatory and metabolic network models for systems analysis of Clostridioides difficile

  2020cites this paper
• Bacterial Spore mRNA – What’s Up With That?

  2020cites this paper
• Transcriptome based functional identification and application of regulator AbrB on alkaline protease synthesis in Bacillus licheniformis 2709.

  2020cites this paper
• Bacillus subtilis YngB is a UTP-glucose-1-phosphate uridylyltransferase contributing to wall teichoic acid modification and glycolipid formation during anaerobic growth

  2020cites this paper
• Bacillus subtilis YngB contributes to wall teichoic acid glucosylation and glycolipid formation during anaerobic growth

  2020cites this paper
• uncovers the

  2020cites this paper
• Motifs in Big Networks: Methods and Applications

  2019cites this paper
• Expansion of the Spore Surface Polysaccharide Layer in Bacillus subtilis by Deletion of Genes Encoding Glycosyltransferases and Glucose Modification Enzymes

  2019cites this paper
• A B-cell acute lymphoblastic leukemia regulatory network defines novel therapeutic targets in IGH-CRLF 2 patients

  2019cites this paper