Learning perturbation-inducible cell states from observability analysis of transcriptome dynamics

Hasnain, Aqib; Balakrishnan, Shara; Joshy, Dennis M.; Smith, Jen; Haase, Steven B.; Yeung, Enoch

doi:10.1038/s41467-023-37897-9

Learning perturbation-inducible cell states from observability analysis of transcriptome dynamics

Journal Article · Wed May 31 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-37897-9· OSTI ID:1975887

; Balakrishnan, Shara; Joshy, Dennis M.; Smith, Jen; ; Yeung, Enoch

Abstract

A major challenge in biotechnology and biomanufacturing is the identification of a set of biomarkers for perturbations and metabolites of interest. Here, we develop a data-driven, transcriptome-wide approach to rank perturbation-inducible genes from time-series RNA sequencing data for the discovery of analyte-responsive promoters. This provides a set of biomarkers that act as a proxy for the transcriptional state referred to as cell state. We construct low-dimensional models of gene expression dynamics and rank genes by their ability to capture the perturbation-specific cell state using a novel observability analysis. Using this ranking, we extract 15 analyte-responsive promoters for the organophosphate malathion in the underutilized host organism Pseudomonas fluorescens SBW25. We develop synthetic genetic reporters from each analyte-responsive promoter and characterize their response to malathion. Furthermore, we enhance malathion reporting through the aggregation of the response of individual reporters with a synthetic consortium approach, and we exemplify the library’s ability to be useful outside the lab by detecting malathion in the environment. The engineered host cell, a living malathion sensor, can be optimized for use in environmental diagnostics while the developed machine learning tool can be applied to discover perturbation-inducible gene expression systems in the compendium of host organisms.

View Journal Article

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: Air Force Research Laboratory; Army Research Office; Army Research Office Young Investigators Program Award; Defense Advanced Research Projects Agency; USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1975887

Alternate ID(s):: OSTI ID: 2424213

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

References (60)

On the theory of optimal sensor placement Chmielewski, Donald J.; Palmer, Tasha; Manousiouthakis, Vasilios AIChE Journal, Vol. 48, Issue 5 https://doi.org/10.1002/aic.690480510	journal	May 2002
Genetic toxicity of malathion: A review Flessel, Peter; Quintana, P. J. E.; Hooper, Kim Environmental and Molecular Mutagenesis, Vol. 22, Issue 1 https://doi.org/10.1002/em.2850220104	journal	January 1993
Application of Bacterial Whole-Cell Biosensors in Health Song, Yizhi; Rampley, Cordelia P. N.; Chen, Xiaoyu Handbook of Cell Biosensors https://doi.org/10.1007/978-3-030-23217-7_136	book	October 2021
The toxicological properties of impurities in malathion Aldridge, W. N.; Miles, J. W.; Mount, D. L. Archives of Toxicology, Vol. 42, Issue 2 https://doi.org/10.1007/BF00316489	journal	January 1978
Toxicity of malathion to mammals, aquatic organisms and tissue culture cells Dési, I.; Dura, G.; Gönczi, L. Archives of Environmental Contamination and Toxicology, Vol. 3, Issue 4 https://doi.org/10.1007/BF02220812	journal	December 1975
On Robust Computation of Koopman Operator and Prediction in Random Dynamical Systems Sinha, Subhrajit; Huang, Bowen; Vaidya, Umesh Journal of Nonlinear Science, Vol. 30, Issue 5 https://doi.org/10.1007/s00332-019-09597-6	journal	November 2019
Spectral Properties of Dynamical Systems, Model Reduction and Decompositions Mezić, Igor Nonlinear Dynamics, Vol. 41, Issue 1-3 https://doi.org/10.1007/s11071-005-2824-x	journal	August 2005
Analysis and optimization of certain qualities of controllability and observability for linear dynamical systems Müller, P. C.; Weber, H. I. Automatica, Vol. 8, Issue 3 https://doi.org/10.1016/0005-1098(72)90044-1	journal	May 1972
Whole cell biosensors Bousse, Luc Sensors and Actuators B: Chemical, Vol. 34, Issue 1-3 https://doi.org/10.1016/S0925-4005(96)01906-5	journal	August 1996
A genetically engineered whole-cell pigment-based bacterial biosensing system for quantification of N-butyryl homoserine lactone quorum sensing signal Yong, Yang-Chun; Zhong, Jian-Jiang Biosensors and Bioelectronics, Vol. 25, Issue 1 https://doi.org/10.1016/j.bios.2009.06.010	journal	September 2009
A modular cell-based biosensor using engineered genetic logic circuits to detect and integrate multiple environmental signals Wang, Baojun; Barahona, Mauricio; Buck, Martin Biosensors and Bioelectronics, Vol. 40, Issue 1 https://doi.org/10.1016/j.bios.2012.08.011	journal	February 2013
Microbial whole-cell biosensors: Current applications, challenges, and future perspectives Moraskie, Michael; Roshid, Md Harun Or; O'Connor, Gregory Biosensors and Bioelectronics, Vol. 191 https://doi.org/10.1016/j.bios.2021.113359	journal	November 2021
Genetic parts to program bacteria Voigt, Christopher A. Current Opinion in Biotechnology, Vol. 17, Issue 5 https://doi.org/10.1016/j.copbio.2006.09.001	journal	October 2006
Environmentally Controlled Invasion of Cancer Cells by Engineered Bacteria Anderson, J. Christopher; Clarke, Elizabeth J.; Arkin, Adam P. Journal of Molecular Biology, Vol. 355, Issue 4 https://doi.org/10.1016/j.jmb.2005.10.076	journal	January 2006
Extracting spatial–temporal coherent patterns in large-scale neural recordings using dynamic mode decomposition Brunton, Bingni W.; Johnson, Lise A.; Ojemann, Jeffrey G. Journal of Neuroscience Methods, Vol. 258 https://doi.org/10.1016/j.jneumeth.2015.10.010	journal	January 2016
Identification and control of gene networks in living organisms via supervised and unsupervised learning Driscoll, Michael E.; Gardner, Timothy S. Journal of Process Control, Vol. 16, Issue 3 https://doi.org/10.1016/j.jprocont.2005.06.010	journal	March 2006
Independent component analysis of E. coli's transcriptome reveals the cellular processes that respond to heterologous gene expression Tan, Justin; Sastry, Anand V.; Fremming, Karoline S. Metabolic Engineering, Vol. 61 https://doi.org/10.1016/j.ymben.2020.07.002	journal	September 2020
Spectral analysis of nonlinear flows Rowley, Clarence W.; MeziĆ, Igor; Bagheri, Shervin Journal of Fluid Mechanics, Vol. 641 https://doi.org/10.1017/S0022112009992059	journal	November 2009
Dynamic mode decomposition of numerical and experimental data Schmid, Peter J. Journal of Fluid Mechanics, Vol. 656 https://doi.org/10.1017/S0022112010001217	journal	July 2010
Redox-Based Synthetic Biology Enables Electrochemical Detection of the Herbicides Dicamba and Roundup via Rewired Escherichia coli VanArsdale, Eric; Tsao, Chen-yu; Liu, Yi ACS Sensors, Vol. 4, Issue 5 https://doi.org/10.1021/acssensors.9b00085	journal	April 2019
Development of Colorimetric-Based Whole-Cell Biosensor for Organophosphorus Compounds by Engineering Transcription Regulator DmpR Chong, Huiqing; Ching, Chi Bun ACS Synthetic Biology, Vol. 5, Issue 11 https://doi.org/10.1021/acssynbio.6b00061	journal	July 2016
Reconstructing dynamic regulatory maps Ernst, Jason; Vainas, Oded; Harbison, Christopher T. Molecular Systems Biology, Vol. 3, Issue 1 https://doi.org/10.1038/msb4100115	journal	January 2007
Tandem fluorescent protein timers for in vivo analysis of protein dynamics Khmelinskii, Anton; Keller, Philipp J.; Bartosik, Anna Nature Biotechnology, Vol. 30, Issue 7 https://doi.org/10.1038/nbt.2281	journal	June 2012
Near-optimal probabilistic RNA-seq quantification Bray, Nicolas L.; Pimentel, Harold; Melsted, Páll Nature Biotechnology, Vol. 34, Issue 5 https://doi.org/10.1038/nbt.3519	journal	April 2016
Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks di Bernardo, Diego; Thompson, Michael J.; Gardner, Timothy S. Nature Biotechnology, Vol. 23, Issue 3 https://doi.org/10.1038/nbt1075	journal	March 2005
Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli Bennett, Bryson D.; Kimball, Elizabeth H.; Gao, Melissa Nature Chemical Biology, Vol. 5, Issue 8 https://doi.org/10.1038/nchembio.186	journal	June 2009
A comprehensive library of fluorescent transcriptional reporters for Escherichia coli Zaslaver, Alon; Bren, Anat; Ronen, Michal Nature Methods, Vol. 3, Issue 8, p. 623-628 https://doi.org/10.1038/nmeth895	journal	August 2006
The mode-of-action by network identification (MNI) algorithm: a network biology approach for molecular target identification Xing, Heming; Gardner, Timothy S. Nature Protocols, Vol. 1, Issue 6 https://doi.org/10.1038/nprot.2006.300	journal	December 2006
A progesterone biosensor derived from microbial screening Grazon, Chloé; Baer, R. C.; Kuzmanović, Uroš Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-14942-5	journal	March 2020
Gene regulatory network inference from sparsely sampled noisy data Aalto, Atte; Viitasaari, Lauri; Ilmonen, Pauliina Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-17217-1	journal	July 2020
dynGENIE3: dynamical GENIE3 for the inference of gene networks from time series expression data Huynh-Thu, Vân Anh; Geurts, Pierre Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-21715-0	journal	February 2018
Observability of complex systems Liu, Yang-Yu; Slotine, Jean-Jacques; Barabási, Albert-László Proceedings of the National Academy of Sciences, Vol. 110, Issue 7 https://doi.org/10.1073/pnas.1215508110	journal	January 2013
Singular value decomposition for genome-wide expression data processing and modeling Alter, O.; Brown, P. O.; Botstein, D. Proceedings of the National Academy of Sciences, Vol. 97, Issue 18, p. 10101-10106 https://doi.org/10.1073/pnas.97.18.10101	journal	August 2000
edgeR: a Bioconductor package for differential expression analysis of digital gene expression data Robinson, M. D.; McCarthy, D. J.; Smyth, G. K. Bioinformatics, Vol. 26, Issue 1 https://doi.org/10.1093/bioinformatics/btp616	journal	November 2009
Trimmomatic: a flexible trimmer for Illumina sequence data Bolger, Anthony M.; Lohse, Marc; Usadel, Bjoern Bioinformatics, Vol. 30, Issue 15 https://doi.org/10.1093/bioinformatics/btu170	journal	April 2014
A novel analysis of gene array data: yeast cell cycle Sirovich, Lawrence Biology Methods and Protocols, Vol. 5, Issue 1 https://doi.org/10.1093/biomethods/bpaa018	journal	January 2020
A data-driven method for quantifying the impact of a genetic circuit on its host Hasnain, Aqib; Becker, Diveena; Siba, Atsede 2019 IEEE Biomedical Circuits and Systems Conference (BioCAS) https://doi.org/10.1109/BIOCAS.2019.8919140	conference	October 2019
Optimal reporter placement in sparsely measured genetic networks using the Koopman operator Hasnain, Aqib; Boddupalli, Nibodh; Yeung, Enoch 2019 IEEE 58th Conference on Decision and Control (CDC) https://doi.org/10.1109/CDC40024.2019.9029917	conference	December 2019
Programming living sensors for environment, health and biomanufacturing Wan, Xinyi; Saltepe, Behide; Yu, Luyang Microbial Biotechnology, Vol. 14, Issue 6 https://doi.org/10.1111/1751-7915.13820	journal	May 2021
Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling Gardner, T. S. Science, Vol. 301, Issue 5629 https://doi.org/10.1126/science.1081900	journal	July 2003
Noise in Gene Expression: Origins, Consequences, and Control Raser, J. M. Science, Vol. 309, Issue 5743 https://doi.org/10.1126/science.1105891	journal	September 2005
Programmable probiotics for detection of cancer in urine Danino, Tal; Prindle, Arthur; Kwong, Gabriel A. Science Translational Medicine, Vol. 7, Issue 289 https://doi.org/10.1126/scitranslmed.aaa3519	journal	May 2015
Genetic Characterization of Pseudomonas fluorescens SBW25 rsp Gene Expression in the Phytosphere and In Vitro Jackson, R. W.; Preston, G. M.; Rainey, P. B. Journal of Bacteriology, Vol. 187, Issue 24 https://doi.org/10.1128/JB.187.24.8477-8488.2005	journal	November 2005
Sublethal Exposure to Commercial Formulations of the Herbicides Dicamba, 2,4-Dichlorophenoxyacetic Acid, and Glyphosate Cause Changes in Antibiotic Susceptibility in Escherichia coli and Salmonella enterica serovar Typhimurium Kurenbach, Brigitta; Marjoshi, Delphine; Amábile-Cuevas, Carlos F. mBio, Vol. 6, Issue 2 https://doi.org/10.1128/mBio.00009-15	journal	March 2015
Approximation of Large-Scale Dynamical Systems Antoulas, Athanasios C. Advances in Design and Control https://doi.org/10.1137/1.9780898718713	book	January 2005
FunPat: function-based pattern analysis on RNA-seq time series data Sanavia, Tiziana; Finotello, Francesca; Di Camillo, Barbara BMC Genomics, Vol. 16, Issue S6 https://doi.org/10.1186/1471-2164-16-S6-S2	journal	June 2015
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Love, Michael I.; Huber, Wolfgang; Anders, Simon Genome Biology, Vol. 15, Issue 12 https://doi.org/10.1186/s13059-014-0550-8	journal	December 2014
Ancient DNA and the rewriting of human history: be sparing with Occam’s razor Haber, Marc; Mezzavilla, Massimo; Xue, Yali Genome Biology, Vol. 17, Issue 1 https://doi.org/10.1186/s13059-015-0866-z	journal	January 2016
How many biological replicates are needed in an RNA-seq experiment and which differential expression tool should you use? Schurch, Nicholas J.; Schofield, Pietá; Gierliński, Marek RNA, Vol. 22, Issue 6 https://doi.org/10.1261/rna.053959.115	journal	March 2016
GFF Utilities: GffRead and GffCompare Pertea, Geo; Pertea, Mihaela F1000Research, Vol. 9 https://doi.org/10.12688/f1000research.23297.2	journal	September 2020
Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles Faith, Jeremiah J.; Hayete, Boris; Thaden, Joshua T. PLoS Biology, Vol. 5, Issue 1 https://doi.org/10.1371/journal.pbio.0050008	journal	January 2007
Clustering gene expression time series data using an infinite Gaussian process mixture model McDowell, Ian C.; Manandhar, Dinesh; Vockley, Christopher M. PLOS Computational Biology, Vol. 14, Issue 1 https://doi.org/10.1371/journal.pcbi.1005896	journal	January 2018
Dynamic distribution decomposition for single-cell snapshot time series identifies subpopulations and trajectories during iPSC reprogramming Taylor-King, Jake P.; Riseth, Asbjørn N.; Macnair, Will PLOS Computational Biology, Vol. 16, Issue 1 https://doi.org/10.1371/journal.pcbi.1007491	journal	January 2020
A One Pot, One Step, Precision Cloning Method with High Throughput Capability Engler, Carola; Kandzia, Romy; Marillonnet, Sylvestre PLoS ONE, Vol. 3, Issue 11, Article No. e3647 https://doi.org/10.1371/journal.pone.0003647	journal	November 2008
RNA-Seq differential expression analysis: An extended review and a software tool Costa-Silva, Juliana; Domingues, Douglas; Lopes, Fabricio Martins PLOS ONE, Vol. 12, Issue 12 https://doi.org/10.1371/journal.pone.0190152	journal	December 2017
Learning Deep Neural Network Representations for Koopman Operators of Nonlinear Dynamical Systems Yeung, Enoch; Kundu, Soumya; Hodas, Nathan 2019 American Control Conference (ACC) https://doi.org/10.23919/ACC.2019.8815339	conference	July 2019
Prediction of fitness in bacteria with causal jump dynamic mode decomposition Balakrishnan, Shara; Hasnain, Aqib; Boddupalli, Nibodh 2020 American Control Conference (ACC) https://doi.org/10.23919/ACC45564.2020.9147230	conference	July 2020
Temporal Dynamic Methods for Bulk RNA-Seq Time Series Data Oh, Vera-Khlara S.; Li, Robert W. Genes, Vol. 12, Issue 3 https://doi.org/10.3390/genes12030352	journal	February 2021
Identification of the EdcR Estrogen-Dependent Repressor in Caenibius tardaugens NBRC 16725: Construction of a Cellular Estradiol Biosensor Ibero, Juan; Galán, Beatriz; García, José L. Genes, Vol. 12, Issue 12 https://doi.org/10.3390/genes12121846	journal	November 2021
Pesticides in Drinking Water—A Review Syafrudin, Muhammad; Kristanti, Risky Ayu; Yuniarto, Adhi International Journal of Environmental Research and Public Health, Vol. 18, Issue 2 https://doi.org/10.3390/ijerph18020468	journal	January 2021

Similar Records

Metabolic Interactions between Brachypodium and Pseudomonas fluorescens under Controlled Iron-Limited Conditions

Journal Article · Mon Jan 04 19:00:00 EST 2021 · mSystems · OSTI ID:1755462

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Dynamical systems
Science & Technology
Synthetic biology
Systems analysis
Time series

Learning perturbation-inducible cell states from observability analysis of transcriptome dynamics

Citation Formats

References (60)

Similar Records

Related Subjects