Machine learning uncovers independently regulated modules in the Bacillus subtilis transcriptome

Rychel, Kevin; Sastry, Anand V.; Palsson, Bernhard O.

doi:10.1038/s41467-020-20153-9

Machine learning uncovers independently regulated modules in the Bacillus subtilis transcriptome

Journal Article · Fri Dec 11 00:00:00 EST 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-20153-9· OSTI ID:1816212

^[1]; ^[2]; ^[3]

Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Bioengineering; OSTI
Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Bioengineering
Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Bioengineering; Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Pediatrics; Novo Nordisk Foundation Center for Biosustainability, Lyngby (Denmark)

The transcriptional regulatory network (TRN) of Bacillus subtilis coordinates cellular functions of fundamental interest, including metabolism, biofilm formation, and sporulation. Here, we use unsupervised machine learning to modularize the transcriptome and quantitatively describe regulatory activity under diverse conditions, creating an unbiased summary of gene expression. We obtain 83 independently modulated gene sets that explain most of the variance in expression and demonstrate that 76% of them represent the effects of known regulators. The TRN structure and its condition-dependent activity uncover putative or recently discovered roles for at least five regulons, such as a relationship between histidine utilization and quorum sensing. The TRN also facilitates quantification of population-level sporulation states. As this TRN covers the majority of the transcriptome and concisely characterizes the global expression state, it could inform research on nearly every aspect of transcriptional regulation in B. subtilis.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of San Diego, San Diego, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1816212

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (74)

Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency Homann, Nils; Tillonen, Jyrki; Salaspuro, Mikko International Journal of Cancer, Vol. 86, Issue 2 https://doi.org/10.1002/(sici)1097-0215(20000415)86:2<169::aid-ijc4>3.0.co;2-3	journal	April 2000
Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency Homann, Nils; Tillonen, Jyrki; Salaspuro, Mikko International Journal of Cancer, Vol. 86, Issue 2 https://doi.org/10.1002/(SICI)1097-0215(20000415)86:2<169::AID-IJC4>3.0.CO;2-3	journal	April 2000
Insight into the sporulation phosphorelay: Crystal structure of the sensor domain of Bacillus subtilis histidine kinase, KinD : The Crystal Structure of the KinD Sensor Domain Wu, R.; Gu, M.; Wilton, R. Protein Science, Vol. 22, Issue 5 https://doi.org/10.1002/pro.2237	journal	March 2013
Bacillus subtilis sporulation and stationary phase gene expression Phillips, Z. E. V.; Strauch, M. A. Cellular and Molecular Life Sciences (CMLS), Vol. 59, Issue 3 https://doi.org/10.1007/s00018-002-8431-9	journal	March 2002
Independent component analysis: algorithms and applications Hyvärinen, A.; Oja, E. Neural Networks, Vol. 13, Issue 4-5 https://doi.org/10.1016/S0893-6080(00)00026-5	journal	June 2000
Matrix Production and Sporulation in Bacillus subtilis Biofilms Localize to Propagating Wave Fronts Srinivasan, Siddarth; Vladescu, Ioana D.; Koehler, Stephan A. Biophysical Journal, Vol. 114, Issue 6 https://doi.org/10.1016/j.bpj.2018.02.002	journal	March 2018
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 Escorcia-Rodríguez, Juan M.; Tauch, Andreas; Freyre-González, Julio A. Computational and Structural Biotechnology Journal, Vol. 18 https://doi.org/10.1016/j.csbj.2020.05.015	journal	January 2020
Independent component analysis: Mining microarray data for fundamental human gene expression modules Engreitz, Jesse M.; Daigle, Bernie J.; Marshall, Jonathan J. Journal of Biomedical Informatics, Vol. 43, Issue 6 https://doi.org/10.1016/j.jbi.2010.07.001	journal	December 2010
Prokaryotic regulatory systems biology: Common principles governing the functional architectures of Bacillus subtilis and Escherichia coli unveiled by the natural decomposition approach Freyre-González, Julio A.; Treviño-Quintanilla, Luis G.; Valtierra-Gutiérrez, Ilse A. Journal of Biotechnology, Vol. 161, Issue 3 https://doi.org/10.1016/j.jbiotec.2012.03.028	journal	October 2012
The Forespore Line of Gene Expression in Bacillus subtilis Wang, Stephanie T.; Setlow, Barbara; Conlon, Erin M. Journal of Molecular Biology, Vol. 358, Issue 1 https://doi.org/10.1016/j.jmb.2006.01.059	journal	April 2006
Functional requirements of cellular differentiation: lessons from Bacillus subtilis Narula, Jatin; Fujita, Masaya; Igoshin, Oleg A. Current Opinion in Microbiology, Vol. 34 https://doi.org/10.1016/j.mib.2016.07.011	journal	December 2016
Structural and Functional Insights into Bacillus subtilis Sigma Factor Inhibitor, CsfB Martínez-Lumbreras, Santiago; Alfano, Caterina; Evans, Nicola J. Structure, Vol. 26, Issue 4 https://doi.org/10.1016/j.str.2018.02.007	journal	April 2018
Advances and prospects of Bacillus subtilis cellular factories: From rational design to industrial applications Gu, Yang; Xu, Xianhao; Wu, Yaokang Metabolic Engineering, Vol. 50 https://doi.org/10.1016/j.ymben.2018.05.006	journal	November 2018
Proteomic and Functional Analyses Reveal a Unique Lifestyle for Acinetobacter baumannii Biofilms and a Key Role for Histidine Metabolism Cabral, Maria P.; Soares, Nelson C.; Aranda, Jesús Journal of Proteome Research, Vol. 10, Issue 8 https://doi.org/10.1021/pr101299j	journal	June 2011
Interspecies nutrient extraction and toxin delivery between bacteria Stempler, Ofer; Baidya, Amit K.; Bhattacharya, Saurabh Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00344-7	journal	August 2017
A comprehensive evaluation of module detection methods for gene expression data Saelens, Wouter; Cannoodt, Robrecht; Saeys, Yvan Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03424-4	journal	March 2018
The Escherichia coli transcriptome mostly consists of independently regulated modules Sastry, Anand V.; Gao, Ye; Szubin, Richard Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-13483-w	journal	December 2019
Bacillus subtilis utilizes the DNA damage response to manage multicellular development Gozzi, Kevin; Ching, Carly; Paruthiyil, Srinand npj Biofilms and Microbiomes, Vol. 3, Issue 1 https://doi.org/10.1038/s41522-017-0016-3	journal	March 2017
Molecular diagnosis of human cancer type by gene expression profiles and independent component analysis Zhang, Xue Wu; Yap, Yee Leng; Wei, Dong European Journal of Human Genetics, Vol. 13, Issue 12 https://doi.org/10.1038/sj.ejhg.5201495	journal	October 2005
Inferring the transcriptional network of Bacillus subtilis Fadda, Abeer; Fierro, Ana Carolina; Lemmens, Karen Molecular BioSystems, Vol. 5, Issue 12 https://doi.org/10.1039/b907310h	journal	January 2009
Deciding fate in adverse times: Sporulation and competence in Bacillus subtilis Schultz, Daniel; Wolynes, Peter G.; Jacob, Eshel Ben Proceedings of the National Academy of Sciences, Vol. 106, Issue 50 https://doi.org/10.1073/pnas.0912185106	journal	December 2009
Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities Fang, Xin; Sastry, Anand; Mih, Nathan Proceedings of the National Academy of Sciences, Vol. 114, Issue 38 https://doi.org/10.1073/pnas.1702581114	journal	September 2017
Pulcherrimin formation controls growth arrest of the Bacillus subtilis biofilm Arnaouteli, Sofia; Matoz-Fernandez, D. A.; Porter, Michael Proceedings of the National Academy of Sciences, Vol. 116, Issue 27 https://doi.org/10.1073/pnas.1903982116	journal	June 2019
Adaptive evolution reveals a tradeoff between growth rate and oxidative stress during naphthoquinone-based aerobic respiration Anand, Amitesh; Chen, Ke; Yang, Laurence Proceedings of the National Academy of Sciences, Vol. 116, Issue 50 https://doi.org/10.1073/pnas.1909987116	journal	November 2019
Organization and Function of the YsiA Regulon of Bacillus subtilis Involved in Fatty Acid Degradation Matsuoka, Hiroshi; Hirooka, Kazutake; Fujita, Yasutaro Journal of Biological Chemistry, Vol. 282, Issue 8 https://doi.org/10.1074/jbc.M606831200	journal	December 2006
Tryptophan Metabolism in Post-Withdrawal Alcohol-Dependent Patients Gleissenthall, Gabriele v.; Geisler, Simon; Malik, Peter Alcohol and Alcoholism, Vol. 49, Issue 3 https://doi.org/10.1093/alcalc/agu011	journal	March 2014
Assessing reproducibility of matrix factorization methods in independent transcriptomes Cantini, Laura; Kairov, Ulykbek; de Reyniès, Aurélien Bioinformatics, Vol. 35, Issue 21 https://doi.org/10.1093/bioinformatics/btz225	journal	April 2019
OxyR Is a Convergent Target for Mutations Acquired during Adaptation to Oxidative Stress-Prone Metabolic States Anand, Amitesh; Chen, Ke; Catoiu, Edward Molecular Biology and Evolution, Vol. 37, Issue 3 https://doi.org/10.1093/molbev/msz251	journal	October 2019
iModulonDB: a knowledgebase of microbial transcriptional regulation derived from machine learning Rychel, Kevin; Decker, Katherine; Sastry, Anand V. Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa810	journal	October 2020
SubtiWiki in 2018: from genes and proteins to functional network annotation of the model organism Bacillus subtilis Zhu, Bingyao; Stülke, Jörg Nucleic Acids Research, Vol. 46, Issue D1 https://doi.org/10.1093/nar/gkx908	journal	October 2017
E. coli gene regulatory networks are inconsistent with gene expression data Larsen, Simon J.; Röttger, Richard; Schmidt, Harald H. H. W. Nucleic Acids Research, Vol. 47, Issue 1 https://doi.org/10.1093/nar/gky1176	journal	November 2018
Adaptation of Bacillus subtilis to growth at low temperature: a combined transcriptomic and proteomic appraisal Budde, I. Microbiology, Vol. 152, Issue 3 https://doi.org/10.1099/mic.0.28530-0	journal	March 2006
Evidence that entry into sporulation in Bacillus subtilis is governed by a gradual increase in the level and activity of the master regulator Spo0A Fujita, M. Genes & Development, Vol. 19, Issue 18 https://doi.org/10.1101/gad.1335705	journal	September 2005
Python for Scientific Computing Oliphant, Travis E. Computing in Science & Engineering, Vol. 9, Issue 3 https://doi.org/10.1109/MCSE.2007.58	journal	January 2007
Regulation of flagellar motility during biofilm formation Guttenplan, Sarah B.; Kearns, Daniel B. FEMS Microbiology Reviews, Vol. 37, Issue 6 https://doi.org/10.1111/1574-6976.12018	journal	November 2013
Spore formation in B acillus subtilis: Bacillus subtilis sporulation Tan, Irene S.; Ramamurthi, Kumaran S. Environmental Microbiology Reports, Vol. 6, Issue 3 https://doi.org/10.1111/1758-2229.12130	journal	December 2013
Regulation of the Bacillus subtilis trp operon by an RNA-binding protein Gollnick, Paul Molecular Microbiology, Vol. 11, Issue 6 https://doi.org/10.1111/j.1365-2958.1994.tb00377.x	journal	March 1994
Biofilm formation by B acillus subtilis : new insights into regulatory strategies and assembly mechanisms: Regulation and assembly of Bacillus subtilis biofilms Cairns, Lynne S.; Hobley, Laura; Stanley-Wall, Nicola R. Molecular Microbiology, Vol. 93, Issue 4 https://doi.org/10.1111/mmi.12697	journal	July 2014
Cannibalism by Sporulating Bacteria Gonzalez-Pastor, J. E. Science, Vol. 301, Issue 5632 https://doi.org/10.1126/science.1086462	journal	July 2003
Condition-Dependent Transcriptome Reveals High-Level Regulatory Architecture in Bacillus subtilis Nicolas, P.; Mader, U.; Dervyn, E. Science, Vol. 335, Issue 6072 https://doi.org/10.1126/science.1206848	journal	March 2012
Genetic Control of Amadori Product Degradation in Bacillus subtilis via Regulation of frlBONMD Expression by FrlR Deppe, Veronika Maria; Klatte, Stephanie; Bongaerts, Johannes Applied and Environmental Microbiology, Vol. 77, Issue 9 https://doi.org/10.1128/AEM.02515-10	journal	May 2011
Catabolite Repression of the Bacillus subtilis FadR Regulon, Which Is Involved in Fatty Acid Catabolism Tojo, Shigeo; Satomura, Takenori; Matsuoka, Hiroshi Journal of Bacteriology, Vol. 193, Issue 10 https://doi.org/10.1128/JB.00016-11	journal	May 2011
Genomic Reconstruction of the Transcriptional Regulatory Network in Bacillus subtilis Leyn, S. A.; Kazanov, M. D.; Sernova, N. V. Journal of Bacteriology, Vol. 195, Issue 11 https://doi.org/10.1128/JB.00140-13	journal	March 2013
The ResD Response Regulator, through Functional Interaction with NsrR and Fur, Plays Three Distinct Roles in Bacillus subtilis Transcriptional Control Henares, B.; Kommineni, S.; Chumsakul, O. Journal of Bacteriology, Vol. 196, Issue 2 https://doi.org/10.1128/JB.01166-13	journal	November 2013
Expression of the σ ^F -Directed csfB Locus Prevents Premature Appearance of σ ^G Activity during Sporulation of Bacillus subtilis Chary, Vasant K.; Xenopoulos, Panagiotis; Piggot, Patrick J. Journal of Bacteriology, Vol. 189, Issue 23 https://doi.org/10.1128/JB.01265-07	journal	December 2007
Regulation of the SOS response in Bacillus subtilis: evidence for a LexA repressor homolog Wojciechowski, M. F.; Peterson, K. R.; Love, P. E. Journal of Bacteriology, Vol. 173, Issue 20 https://doi.org/10.1128/JB.173.20.6489-6498.1991	journal	October 1991
Global Gene Expression Profiles of Bacillus subtilis Grown under Anaerobic Conditions Ye, Rick W.; Tao, Wang; Bedzyk, Laura Journal of Bacteriology, Vol. 182, Issue 16 https://doi.org/10.1128/JB.182.16.4458-4465.2000	journal	August 2000
Regulation of the Acetoin Catabolic Pathway Is Controlled by Sigma L in Bacillus subtilis Ould Ali, Naima; Bignon, Joelle; Rapoport, Georges Journal of Bacteriology, Vol. 183, Issue 8 https://doi.org/10.1128/JB.183.8.2497-2504.2001	journal	April 2001
The E1β and E2 Subunits of the Bacillus subtilis Pyruvate Dehydrogenase Complex Are Involved in Regulation of Sporulation Gao, Haichun; Jiang, Xin; Pogliano, Kit Journal of Bacteriology, Vol. 184, Issue 10 https://doi.org/10.1128/JB.184.10.2780-2788.2002	journal	May 2002
Genetic Composition of the Bacillus subtilis SOS System Au, Nora; Kuester-Schoeck, Elke; Mandava, Veena Journal of Bacteriology, Vol. 187, Issue 22 https://doi.org/10.1128/JB.187.22.7655-7666.2005	journal	November 2005
TRACE METAL REQUIREMENTS FOR SPORULATION OF BACILLUS MEGATERIUM Kolodziej, Bruno J.; Slepecky, Ralph A. Journal of Bacteriology, Vol. 88, Issue 4 https://doi.org/10.1128/JB.88.4.821-830.1964	journal	October 1964
Regulation of the Histidine Utilization (Hut) System in Bacteria Bender, R. A. Microbiology and Molecular Biology Reviews, Vol. 76, Issue 3 https://doi.org/10.1128/MMBR.00014-12	journal	August 2012
Bacillus subtilis Systems Biology: Applications of -Omics Techniques to the Study of Endospore Formation Bate, Ashley R.; Bonneau, Richard; Eichenberger, Patrick Microbiology Spectrum, Vol. 2, Issue 2 https://doi.org/10.1128/microbiolspec.TBS-0019-2013	journal	March 2014
Lessons from the modular organization of the transcriptional regulatory network of Bacillus subtilis Freyre-González, Julio A.; Manjarrez-Casas, Alejandra M.; Merino, Enrique BMC Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1186/1752-0509-7-127	journal	November 2013
The MarR-like protein PchR (YvmB) regulates expression of genes involved in pulcherriminic acid biosynthesis and in the initiation of sporulation in Bacillus subtilis Randazzo, Paola; Aubert-Frambourg, Anne; Guillot, Alain BMC Microbiology, Vol. 16, Issue 1 https://doi.org/10.1186/s12866-016-0807-3	journal	August 2016
The Program of Gene Transcription for a Single Differentiating Cell Type during Sporulation in Bacillus subtilis Eichenberger, Patrick; Fujita, Masaya; Jensen, Shane T. PLoS Biology, Vol. 2, Issue 10 https://doi.org/10.1371/journal.pbio.0020328	journal	September 2004
A Negative Feedback Loop That Limits the Ectopic Activation of a Cell Type–Specific Sporulation Sigma Factor of Bacillus subtilis Serrano, Mónica; Real, Gonçalo; Santos, Joana PLoS Genetics, Vol. 7, Issue 9 https://doi.org/10.1371/journal.pgen.1002220	journal	September 2011
Coherent Functional Modules Improve Transcription Factor Target Identification, Cooperativity Prediction, and Disease Association Karczewski, Konrad J.; Snyder, Michael; Altman, Russ B. PLoS Genetics, Vol. 10, Issue 2 https://doi.org/10.1371/journal.pgen.1004122	journal	February 2014
Transcription and translation of the sigG gene is tuned for proper execution of the switch from early to late gene expression in the developing Bacillus subtilis spore Mearls, Elizabeth B.; Jackter, Jacquelin; Colquhoun, Jennifer M. PLOS Genetics, Vol. 14, Issue 4 https://doi.org/10.1371/journal.pgen.1007350	journal	April 2018
Extracellular DNA Release by Undomesticated Bacillus subtilis Is Regulated by Early Competence Zafra, Olga; Lamprecht-Grandío, María; de Figueras, Carolina González PLoS ONE, Vol. 7, Issue 11 https://doi.org/10.1371/journal.pone.0048716	journal	November 2012
Exopolymer Diversity and the Role of Levan in Bacillus subtilis Biofilms Dogsa, Iztok; Brloznik, Mojca; Stopar, David PLoS ONE, Vol. 8, Issue 4 https://doi.org/10.1371/journal.pone.0062044	journal	April 2013
Noise in a phosphorelay drives stochastic entry into sporulation in Bacillus subtilis Russell, Jonathan R.; Cabeen, Matthew T.; Wiggins, Paul A. The EMBO Journal, Vol. 36, Issue 19 https://doi.org/10.15252/embj.201796988	journal	August 2017
An experimentally supported model of the Bacillus subtilis global transcriptional regulatory network Arrieta‐Ortiz, Mario L.; Hafemeister, Christoph; Bate, Ashley Rose Molecular Systems Biology, Vol. 11, Issue 11 https://doi.org/10.15252/msb.20156236	journal	November 2015
A review of independent component analysis application to microarray gene expression data Kong, Wei; Vanderburg, Charles R.; Gunshin, Hiromi BioTechniques, Vol. 45, Issue 5 https://doi.org/10.2144/000112950	journal	November 2008
Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes Magnúsdóttir, Stefanía; Ravcheev, Dmitry; de Crécy-Lagard, Valérie Frontiers in Genetics, Vol. 6 https://doi.org/10.3389/fgene.2015.00148	journal	April 2015
Molecular Interaction and Cellular Location of RecA and CheW Proteins in Salmonella enterica during SOS Response and Their Implication in Swarming Irazoki, Oihane; Aranda, Jesús; Zimmermann, Timo Frontiers in Microbiology, Vol. 7 https://doi.org/10.3389/fmicb.2016.01560	journal	October 2016
Secretome of Intestinal Bacilli: A Natural Guard against Pathologies Ilinskaya, Olga N.; Ulyanova, Vera V.; Yarullina, Dina R. Frontiers in Microbiology, Vol. 8 https://doi.org/10.3389/fmicb.2017.01666	journal	September 2017
Histidine Metabolism and IGPD Play a Key Role in Cefquinome Inhibiting Biofilm Formation of Staphylococcus xylosus Zhou, Yong-hui; Xu, Chang-geng; Yang, Yan-bei Frontiers in Microbiology, Vol. 9 https://doi.org/10.3389/fmicb.2018.00665	journal	April 2018
Activation of the PhoPR-Mediated Response to Phosphate Limitation Is Regulated by Wall Teichoic Acid Metabolism in Bacillus subtilis Devine, Kevin M. Frontiers in Microbiology, Vol. 9 https://doi.org/10.3389/fmicb.2018.02678	journal	November 2018
Azithromycin Inhibits Biofilm Formation by Staphylococcus xylosus and Affects Histidine Biosynthesis Pathway Ding, Wenya; Zhou, Yonghui; Qu, Qianwei Frontiers in Pharmacology, Vol. 9 https://doi.org/10.3389/fphar.2018.00740	journal	July 2018
Independent Component Analysis for Unraveling the Complexity of Cancer Omics Datasets Sompairac, Nicolas; Nazarov, Petr V.; Czerwinska, Urszula International Journal of Molecular Sciences, Vol. 20, Issue 18 https://doi.org/10.3390/ijms20184414	journal	September 2019
A comprehensive evaluation of module detection methods for gene expression data Saelens, Wouter; Cannoodt, Robrecht; Saeys, Yvan Zenodo https://doi.org/10.5281/zenodo.1157937	dataset	January 2018
A Comprehensive Evaluation Of Module Detection Methods For Gene Expression Data Saelens, Wouter; Cannoodt, Robrecht; Saeys, Yvan Zenodo https://doi.org/10.5281/zenodo.1157938	dataset	January 2018
The MarR-like protein PchR (YvmB) regulates expression of genes involved in pulcherriminic acid biosynthesis and in the initiation of sporulation in Bacillus subtilis Randazzo, Paola; Aubert-Frambourg, Anne; Guillot, Alain Figshare https://doi.org/10.6084/m9.figshare.c.3620231	collection	January 2016

Similar Records

The Escherichia coli transcriptome mostly consists of independently regulated modules

Journal Article · Tue Dec 03 19:00:00 EST 2019 · Nature Communications · OSTI ID:1624220

Reconstruction of the regulatory network for Bacillus subtilis and reconciliation with gene expression data

Journal Article · Thu Mar 17 20:00:00 EDT 2016 · Frontiers in Microbiology · OSTI ID:1337227

Extensive cellular multi-tasking within Bacillus subtilis biofilms

Journal Article · Mon Jul 31 20:00:00 EDT 2023 · mSystems · OSTI ID:2204039

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Machine learning uncovers independently regulated modules in the Bacillus subtilis transcriptome

Citation Formats

References (74)

Similar Records

Related Subjects