Hyobin Kim, Amit Kumar, Cecilia Lövkvist, António M Palma, Patrick Martin, Junil Kim, Praveen Bhoopathi, Jose Trevino, Paul Fisher, Esha Madan, Rajan Gogna, Kyoung Jae Won
{"title":"CellNeighborEX: deciphering neighbor-dependent gene expression from spatial transcriptomics data.","authors":"Hyobin Kim, Amit Kumar, Cecilia Lövkvist, António M Palma, Patrick Martin, Junil Kim, Praveen Bhoopathi, Jose Trevino, Paul Fisher, Esha Madan, Rajan Gogna, Kyoung Jae Won","doi":"10.15252/msb.202311670","DOIUrl":"10.15252/msb.202311670","url":null,"abstract":"<p><p>Cells have evolved their communication methods to sense their microenvironments and send biological signals. In addition to communication using ligands and receptors, cells use diverse channels including gap junctions to communicate with their immediate neighbors. Current approaches, however, cannot effectively capture the influence of various microenvironments. Here, we propose a novel approach to investigate cell neighbor-dependent gene expression (CellNeighborEX) in spatial transcriptomics (ST) data. To categorize cells based on their microenvironment, CellNeighborEX uses direct cell location or the mixture of transcriptome from multiple cells depending on ST technologies. For each cell type, CellNeighborEX identifies diverse gene sets associated with partnering cell types, providing further insight. We found that cells express different genes depending on their neighboring cell types in various tissues including mouse embryos, brain, and liver cancer. Those genes are associated with critical biological processes such as development or metastases. We further validated that gene expression is induced by neighboring partners via spatial visualization. The neighbor-dependent gene expression suggests new potential genes involved in cell-cell interactions beyond what ligand-receptor co-expression can discover.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11670"},"PeriodicalIF":9.9,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41183096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Canalisation and plasticity on the developmental manifold of Caenorhabditis elegans.","authors":"David J Jordan, Eric A Miska","doi":"10.15252/msb.202311835","DOIUrl":"10.15252/msb.202311835","url":null,"abstract":"<p><p>How do the same mechanisms that faithfully regenerate complex developmental programmes in spite of environmental and genetic perturbations also allow responsiveness to environmental signals, adaptation and genetic evolution? Using the nematode Caenorhabditis elegans as a model, we explore the phenotypic space of growth and development in various genetic and environmental contexts. Our data are growth curves and developmental parameters obtained by automated microscopy. Using these, we show that among the traits that make up the developmental space, correlations within a particular context are predictive of correlations among different contexts. Furthermore, we find that the developmental variability of this animal can be captured on a relatively low-dimensional phenotypic manifold and that on this manifold, genetic and environmental contributions to plasticity can be deconvolved independently. Our perspective offers a new way of understanding the relationship between robustness and flexibility in complex systems, suggesting that projection and concentration of dimension can naturally align these forces as complementary rather than competing.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11835"},"PeriodicalIF":9.9,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marc Weber, Adrià Sogues, Eva Yus, Raul Burgos, Carolina Gallo, Sira Martínez, Maria Lluch-Senar, Luis Serrano
{"title":"Comprehensive quantitative modeling of translation efficiency in a genome-reduced bacterium.","authors":"Marc Weber, Adrià Sogues, Eva Yus, Raul Burgos, Carolina Gallo, Sira Martínez, Maria Lluch-Senar, Luis Serrano","doi":"10.15252/msb.202211301","DOIUrl":"10.15252/msb.202211301","url":null,"abstract":"<p><p>Translation efficiency has been mainly studied by ribosome profiling, which only provides an incomplete picture of translation kinetics. Here, we integrated the absolute quantifications of tRNAs, mRNAs, RNA half-lives, proteins, and protein half-lives with ribosome densities and derived the initiation and elongation rates for 475 genes (67% of all genes), 73 with high precision, in the bacterium Mycoplasma pneumoniae (Mpn). We found that, although the initiation rate varied over 160-fold among genes, most of the known factors had little impact on translation efficiency. Local codon elongation rates could not be fully explained by the adaptation to tRNA abundances, which varied over 100-fold among tRNA isoacceptors. We provide a comprehensive quantitative view of translation efficiency, which suggests the existence of unidentified mechanisms of translational regulation in Mpn.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11301"},"PeriodicalIF":9.9,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Turning up the heat on essential E. coli genes.","authors":"Arun Kumar, Peter C Stirling","doi":"10.15252/msb.202311933","DOIUrl":"10.15252/msb.202311933","url":null,"abstract":"<p><p>Temperature-sensitive (TS) alleles create tunable thermoswitches to deplete essential cellular activities and are used to dissect gene function. In their recent study, Link and colleagues (Schramm et al 2023) use a CRISPR-based approach to systematically create TS alleles across essential genes in E. coli.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11933"},"PeriodicalIF":9.9,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10286012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thorben Schramm, Paul Lubrano, Vanessa Pahl, Amelie Stadelmann, Andreas Verhülsdonk, Hannes Link
{"title":"Mapping temperature-sensitive mutations at a genome scale to engineer growth switches in Escherichia coli.","authors":"Thorben Schramm, Paul Lubrano, Vanessa Pahl, Amelie Stadelmann, Andreas Verhülsdonk, Hannes Link","doi":"10.15252/msb.202311596","DOIUrl":"10.15252/msb.202311596","url":null,"abstract":"<p><p>Temperature-sensitive (TS) mutants are a unique tool to perturb and engineer cellular systems. Here, we constructed a CRISPR library with 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. 1,269 of these mutants showed temperature-sensitive growth in a time-resolved competition assay. We reconstructed 94 TS mutants and measured their metabolism under growth arrest at 42°C using metabolomics. Metabolome changes were strong and mutant-specific, showing that metabolism of nongrowing E. coli is perturbation-dependent. For example, 24 TS mutants of metabolic enzymes overproduced the direct substrate metabolite due to a bottleneck in their associated pathway. A strain with TS homoserine kinase (ThrB<sup>F267D</sup> ) produced homoserine for 24 h, and production was tunable by temperature. Finally, we used a TS subunit of DNA polymerase III (DnaX<sup>L289Q</sup> ) to decouple growth from arginine overproduction in engineered E. coli. These results provide a strategy to identify TS mutants en masse and demonstrate their large potential to produce bacterial metabolites with nongrowing cells.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11596"},"PeriodicalIF":9.9,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10112762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marvin Thielert, Ericka Cm Itang, Constantin Ammar, Florian A Rosenberger, Isabell Bludau, Lisa Schweizer, Thierry M Nordmann, Patricia Skowronek, Maria Wahle, Wen-Feng Zeng, Xie-Xuan Zhou, Andreas-David Brunner, Sabrina Richter, Mitchell P Levesque, Fabian J Theis, Martin Steger, Matthias Mann
{"title":"Robust dimethyl-based multiplex-DIA doubles single-cell proteome depth via a reference channel.","authors":"Marvin Thielert, Ericka Cm Itang, Constantin Ammar, Florian A Rosenberger, Isabell Bludau, Lisa Schweizer, Thierry M Nordmann, Patricia Skowronek, Maria Wahle, Wen-Feng Zeng, Xie-Xuan Zhou, Andreas-David Brunner, Sabrina Richter, Mitchell P Levesque, Fabian J Theis, Martin Steger, Matthias Mann","doi":"10.15252/msb.202211503","DOIUrl":"10.15252/msb.202211503","url":null,"abstract":"<p><p>Single-cell proteomics aims to characterize biological function and heterogeneity at the level of proteins in an unbiased manner. It is currently limited in proteomic depth, throughput, and robustness, which we address here by a streamlined multiplexed workflow using data-independent acquisition (mDIA). We demonstrate automated and complete dimethyl labeling of bulk or single-cell samples, without losing proteomic depth. Lys-N digestion enables five-plex quantification at MS1 and MS2 level. Because the multiplexed channels are quantitatively isolated from each other, mDIA accommodates a reference channel that does not interfere with the target channels. Our algorithm RefQuant takes advantage of this and confidently quantifies twice as many proteins per single cell compared to our previous work (Brunner et al, PMID 35226415), while our workflow currently allows routine analysis of 80 single cells per day. Finally, we combined mDIA with spatial proteomics to increase the throughput of Deep Visual Proteomics seven-fold for microdissection and four-fold for MS analysis. Applying this to primary cutaneous melanoma, we discovered proteomic signatures of cells within distinct tumor microenvironments, showcasing its potential for precision oncology.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 9","pages":"e11503"},"PeriodicalIF":8.5,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10236507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sander Wuyts, Renato Alves, Maria Zimmermann-Kogadeeva, Suguru Nishijima, Sonja Blasche, Marja Driessen, Philipp E Geyer, Rajna Hercog, Ece Kartal, Lisa Maier, Johannes B Müller, Sarela Garcia Santamarina, Thomas Sebastian B Schmidt, Daniel C Sevin, Anja Telzerow, Peter V Treit, Tobias Wenzel, Athanasios Typas, Kiran R Patil, Matthias Mann, Michael Kuhn, Peer Bork
{"title":"Consistency across multi-omics layers in a drug-perturbed gut microbial community.","authors":"Sander Wuyts, Renato Alves, Maria Zimmermann-Kogadeeva, Suguru Nishijima, Sonja Blasche, Marja Driessen, Philipp E Geyer, Rajna Hercog, Ece Kartal, Lisa Maier, Johannes B Müller, Sarela Garcia Santamarina, Thomas Sebastian B Schmidt, Daniel C Sevin, Anja Telzerow, Peter V Treit, Tobias Wenzel, Athanasios Typas, Kiran R Patil, Matthias Mann, Michael Kuhn, Peer Bork","doi":"10.15252/msb.202311525","DOIUrl":"10.15252/msb.202311525","url":null,"abstract":"<p><p>Multi-omics analyses are used in microbiome studies to understand molecular changes in microbial communities exposed to different conditions. However, it is not always clear how much each omics data type contributes to our understanding and whether they are concordant with each other. Here, we map the molecular response of a synthetic community of 32 human gut bacteria to three non-antibiotic drugs by using five omics layers (16S rRNA gene profiling, metagenomics, metatranscriptomics, metaproteomics and metabolomics). We find that all the omics methods with species resolution are highly consistent in estimating relative species abundances. Furthermore, different omics methods complement each other for capturing functional changes. For example, while nearly all the omics data types captured that the antipsychotic drug chlorpromazine selectively inhibits Bacteroidota representatives in the community, the metatranscriptome and metaproteome suggested that the drug induces stress responses related to protein quality control. Metabolomics revealed a decrease in oligosaccharide uptake, likely caused by Bacteroidota depletion. Our study highlights how multi-omics datasets can be utilized to reveal complex molecular responses to external perturbations in microbial communities.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 9","pages":"e11525"},"PeriodicalIF":9.9,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10240795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Javier Ruiz, Miguel de Celis, Juan Diaz-Colunga, Jean Cc Vila, Belen Benitez-Dominguez, Javier Vicente, Antonio Santos, Alvaro Sanchez, Ignacio Belda
{"title":"Predictability of the community-function landscape in wine yeast ecosystems.","authors":"Javier Ruiz, Miguel de Celis, Juan Diaz-Colunga, Jean Cc Vila, Belen Benitez-Dominguez, Javier Vicente, Antonio Santos, Alvaro Sanchez, Ignacio Belda","doi":"10.15252/msb.202311613","DOIUrl":"10.15252/msb.202311613","url":null,"abstract":"<p><p>Predictively linking taxonomic composition and quantitative ecosystem functions is a major aspiration in microbial ecology, which must be resolved if we wish to engineer microbial consortia. Here, we have addressed this open question for an ecological function of major biotechnological relevance: alcoholic fermentation in wine yeast communities. By exhaustively phenotyping an extensive collection of naturally occurring wine yeast strains, we find that most ecologically and industrially relevant traits exhibit phylogenetic signal, allowing functional traits in wine yeast communities to be predicted from taxonomy. Furthermore, we demonstrate that the quantitative contributions of individual wine yeast strains to the function of complex communities followed simple quantitative rules. These regularities can be integrated to quantitatively predict the function of newly assembled consortia. Besides addressing theoretical questions in functional ecology, our results and methodologies can provide a blueprint for rationally managing microbial processes of biotechnological relevance.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 9","pages":"e11613"},"PeriodicalIF":8.5,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10291995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lara Urban, Albert Perlas, Olga Francino, Joan Martí-Carreras, Brenda A Muga, Jenniffer W Mwangi, Laura Boykin Okalebo, Jo-Ann L Stanton, Amanda Black, Nick Waipara, Claudia Fontsere, David Eccles, Harika Urel, Tim Reska, Hernán E Morales, Marc Palmada-Flores, Tomas Marques-Bonet, Mrinalini Watsa, Zane Libke, Gideon Erkenswick, Cock van Oosterhout
{"title":"Real-time genomics for One Health.","authors":"Lara Urban, Albert Perlas, Olga Francino, Joan Martí-Carreras, Brenda A Muga, Jenniffer W Mwangi, Laura Boykin Okalebo, Jo-Ann L Stanton, Amanda Black, Nick Waipara, Claudia Fontsere, David Eccles, Harika Urel, Tim Reska, Hernán E Morales, Marc Palmada-Flores, Tomas Marques-Bonet, Mrinalini Watsa, Zane Libke, Gideon Erkenswick, Cock van Oosterhout","doi":"10.15252/msb.202311686","DOIUrl":"10.15252/msb.202311686","url":null,"abstract":"<p><p>The ongoing degradation of natural systems and other environmental changes has put our society at a crossroad with respect to our future relationship with our planet. While the concept of One Health describes how human health is inextricably linked with environmental health, many of these complex interdependencies are still not well-understood. Here, we describe how the advent of real-time genomic analyses can benefit One Health and how it can enable timely, in-depth ecosystem health assessments. We introduce nanopore sequencing as the only disruptive technology that currently allows for real-time genomic analyses and that is already being used worldwide to improve the accessibility and versatility of genomic sequencing. We showcase real-time genomic studies on zoonotic disease, food security, environmental microbiome, emerging pathogens, and their antimicrobial resistances, and on environmental health itself - from genomic resource creation for wildlife conservation to the monitoring of biodiversity, invasive species, and wildlife trafficking. We stress why equitable access to real-time genomics in the context of One Health will be paramount and discuss related practical, legal, and ethical limitations.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11686"},"PeriodicalIF":8.5,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9963827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eyal Simonovsky, Moran Sharon, Maya Ziv, Omry Mauer, Idan Hekselman, Juman Jubran, Ekaterina Vinogradov, Chanan M Argov, Omer Basha, Lior Kerber, Yuval Yogev, Ayellet V Segrè, Hae Kyung Im, Ohad Birk, Lior Rokach, Esti Yeger-Lotem
{"title":"Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation.","authors":"Eyal Simonovsky, Moran Sharon, Maya Ziv, Omry Mauer, Idan Hekselman, Juman Jubran, Ekaterina Vinogradov, Chanan M Argov, Omer Basha, Lior Kerber, Yuval Yogev, Ayellet V Segrè, Hae Kyung Im, Ohad Birk, Lior Rokach, Esti Yeger-Lotem","doi":"10.15252/msb.202211407","DOIUrl":"10.15252/msb.202211407","url":null,"abstract":"<p><p>How do aberrations in widely expressed genes lead to tissue-selective hereditary diseases? Previous attempts to answer this question were limited to testing a few candidate mechanisms. To answer this question at a larger scale, we developed \"Tissue Risk Assessment of Causality by Expression\" (TRACE), a machine learning approach to predict genes that underlie tissue-selective diseases and selectivity-related features. TRACE utilized 4,744 biologically interpretable tissue-specific gene features that were inferred from heterogeneous omics datasets. Application of TRACE to 1,031 disease genes uncovered known and novel selectivity-related features, the most common of which was previously overlooked. Next, we created a catalog of tissue-associated risks for 18,927 protein-coding genes (https://netbio.bgu.ac.il/trace/). As proof-of-concept, we prioritized candidate disease genes identified in 48 rare-disease patients. TRACE ranked the verified disease gene among the patient's candidate genes significantly better than gene prioritization methods that rank by gene constraint or tissue expression. Thus, tissue selectivity combined with machine learning enhances genetic and clinical understanding of hereditary diseases.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11407"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10318151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}