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Integrated systems biology approach identifies gene targets for endothelial dysfunction Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-11-30 Iguaracy Pinheiro-de-Sousa, Miriam Helena Fonseca-Alaniz, Girolamo Giudice, Iuri Cordeiro Valadão, Silvestre Massimo Modestia, Sarah Viana Mattioli, Ricardo Rosa Junior, Lykourgos-Panagiotis Zalmas, Yun Fang, Evangelia Petsalaki, José Eduardo Krieger
Endothelial dysfunction (ED) is critical in the development and progression of cardiovascular (CV) disorders, yet effective therapeutic targets for ED remain elusive due to limited understanding of its underlying molecular mechanisms. To address this gap, we employed a systems biology approach to identify potential targets for ED. Our study combined multi omics data integration, with siRNA screening
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A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-11-20 Dokyun Na, Do-Hwan Lim, Jae-Sang Hong, Hyang-Mi Lee, Daeahn Cho, Myeong-Sang Yu, Bilal Shaker, Jun Ren, Bomi Lee, Jae Gwang Song, Yuna Oh, Kyungeun Lee, Kwang-Seok Oh, Mi Young Lee, Min-Seok Choi, Han Saem Choi, Yang-Hee Kim, Jennifer M Bui, Kangseok Lee, Hyung Wook Kim, Young Sik Lee, Jörg Gsponer
The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict
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Paralog dispensability shapes homozygous deletion patterns in tumor genomes Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-11-14 Barbara De Kegel, Colm J Ryan
Genomic instability is a hallmark of cancer, resulting in tumor genomes having large numbers of genetic aberrations, including homozygous deletions of protein coding genes. That tumor cells remain viable in the presence of such gene loss suggests high robustness to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness—they
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Phosphatase specificity principles uncovered by MRBLE:Dephos and global substrate identification Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-11-02 Jamin B Hein, Hieu T Nguyen, Dimitriya H Garvanska, Isha Nasa, Thomas Kruse, Yinnian Feng, Blanca Lopez Mendez, Norman Davey, Arminja N Kettenbach, Polly M Fordyce, Jakob Nilsson
Phosphoprotein phosphatases (PPPs) regulate major signaling pathways, but the determinants of phosphatase specificity are poorly understood. This is because methods to investigate this at scale are lacking. Here, we develop a novel in vitro assay, MRBLE:Dephos, that allows multiplexing of dephosphorylation reactions to determine phosphatase preferences. Using MRBLE:Dephos, we establish amino acid preferences
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Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-10-27 David B Bernstein, Batu Akkas, Morgan N Price, Adam P Arkin
The Escherichia coli genome-scale metabolic model (GEM) is an exemplar systems biology model for the simulation of cellular metabolism. Experimental validation of model predictions is essential to pinpoint uncertainty and ensure continued development of accurate models. Here, we quantified the accuracy of four subsequent E. coli GEMs using published mutant fitness data across thousands of genes and
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Canalisation and plasticity on the developmental manifold of Caenorhabditis elegans Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-10-18 David J Jordan, Eric A Miska
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
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Enablers and challenges of spatial omics, a melting pot of technologies Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-10-16 Theodore Alexandrov, Julio Saez-Rodriguez, Sinem K Saka
Spatial omics has emerged as a rapidly growing and fruitful field with hundreds of publications presenting novel methods for obtaining spatially resolved information for any omics data type on spatial scales ranging from subcellular to organismal. From a technology development perspective, spatial omics is a highly interdisciplinary field that integrates imaging and omics, spatial and molecular analyses
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CellNeighborEX: deciphering neighbor-dependent gene expression from spatial transcriptomics data Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-10-10 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
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
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Dimensionality reduction methods for extracting functional networks from large-scale CRISPR screens Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-09-26 Arshia Zernab Hassan, Henry N Ward, Mahfuzur Rahman, Maximilian Billmann, Yoonkyu Lee, Chad L Myers
CRISPR-Cas9 screens facilitate the discovery of gene functional relationships and phenotype-specific dependencies. The Cancer Dependency Map (DepMap) is the largest compendium of whole-genome CRISPR screens aimed at identifying cancer-specific genetic dependencies across human cell lines. A mitochondria-associated bias has been previously reported to mask signals for genes involved in other functions
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Modeling unveils sex differences of signaling networks in mouse embryonic stem cells Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-09-21 Zeba Sultana, Mathurin Dorel, Bertram Klinger, Anja Sieber, Ilona Dunkel, Nils Blüthgen, Edda G Schulz
For a short period during early development of mammalian embryos, both X chromosomes in females are active, before dosage compensation is ensured through X-chromosome inactivation. In female mouse embryonic stem cells (mESCs), which carry two active X chromosomes, increased X-dosage affects cell signaling and impairs differentiation. The underlying mechanisms, however, remain poorly understood. To
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Turning up the heat on essential E. coli genes Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-09-18 Arun Kumar, Peter C Stirling
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.
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Comprehensive quantitative modeling of translation efficiency in a genome-reduced bacterium Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-08-29 Marc Weber, Adrià Sogues, Eva Yus, Raul Burgos, Carolina Gallo, Sira Martínez, Maria Lluch-Senar, Luis Serrano
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
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Mapping temperature-sensitive mutations at a genome scale to engineer growth switches in Escherichia coli Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-08-29 Thorben Schramm, Paul Lubrano, Vanessa Pahl, Amelie Stadelmann, Andreas Verhülsdonk, Hannes Link
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
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SLAM-Drop-seq reveals mRNA kinetic rates throughout the cell cycle Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-08-28 Haiyue Liu, Roberto Arsiè, Daniel Schwabe, Marcel Schilling, Igor Minia, Jonathan Alles, Anastasiya Boltengagen, Christine Kocks, Martin Falcke, Nir Friedman, Markus Landthaler, Nikolaus Rajewsky
RNA abundance is tightly regulated in eukaryotic cells by modulating the kinetic rates of RNA production, processing, and degradation. To date, little is known about time-dependent kinetic rates during dynamic processes. Here, we present SLAM-Drop-seq, a method that combines RNA metabolic labeling and alkylation of modified nucleotides in methanol-fixed cells with droplet-based sequencing to detect
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Robust dimethyl-based multiplex-DIA doubles single-cell proteome depth via a reference channel Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-08-21 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
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
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Predictability of the community-function landscape in wine yeast ecosystems Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-08-07 Javier Ruiz, Miguel de Celis, Juan Diaz-Colunga, Jean CC Vila, Belen Benitez-Dominguez, Javier Vicente, Antonio Santos, Alvaro Sanchez, Ignacio Belda
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
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Consistency across multi-omics layers in a drug-perturbed gut microbial community Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-07-24 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
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
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Genetic effects on molecular network states explain complex traits Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-07-24 Matthias Weith, Jan Großbach, Mathieu Clement-Ziza, Ludovic Gillet, María Rodríguez-López, Samuel Marguerat, Christopher T Workman, Paola Picotti, Jürg Bähler, Ruedi Aebersold, Andreas Beyer
The complexity of many cellular and organismal traits results from the integration of genetic and environmental factors via molecular networks. Network structure and effect propagation are best understood at the level of functional modules, but so far, no concept has been established to include the global network state. Here, we show when and how genetic perturbations lead to molecular changes that
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System-wide optimization of an orthogonal translation system with enhanced biological tolerance Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-07-21 Kyle Mohler, Jack M Moen, Svetlana Rogulina, Jesse Rinehart
Over the past two decades, synthetic biological systems have revolutionized the study of cellular physiology. The ability to site-specifically incorporate biologically relevant non-standard amino acids using orthogonal translation systems (OTSs) has proven particularly useful, providing unparalleled access to cellular mechanisms modulated by post-translational modifications, such as protein phosphorylation
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Real-time genomics for One Health Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-06-16 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
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
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Single-cell biology: what does the future hold? Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-06-15 Maria Polychronidou,Jingyi Hou,M Madan Babu,Prisca Liberali,Ido Amit,Bart Deplancke,Galit Lahav,Shalev Itzkovitz,Matthias Mann,Julio Saez-Rodriguez,Fabian Theis,Roland Eils
In this Editorial, our Chief Editor and members of our Advisory Editorial Board discuss recent breakthroughs, current challenges, and emerging opportunities in single-cell biology and share their vision of "where the field is headed."
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Updated benchmarking of variant effect predictors using deep mutational scanning Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-06-13 Benjamin J Livesey, Joseph A Marsh
The assessment of variant effect predictor (VEP) performance is fraught with biases introduced by benchmarking against clinical observations. In this study, building on our previous work, we use independently generated measurements of protein function from deep mutational scanning (DMS) experiments for 26 human proteins to benchmark 55 different VEPs, while introducing minimal data circularity. Many
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A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-06-01 Amandine Moretton, Savvas Kourtis, Antoni Gañez Zapater, Chiara Calabrò, Maria Lorena Espinar Calvo, Frédéric Fontaine, Evangelia Darai, Etna Abad Cortel, Samuel Block, Laura Pascual-Reguant, Natalia Pardo-Lorente, Ritobrata Ghose, Matthew G Vander Heiden, Ana Janic, André C Müller, Joanna I Loizou, Sara Sdelci
While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description
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Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-05-26 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
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
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Large-scale phosphomimetic screening identifies phospho-modulated motif-based protein interactions Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-05-23 Johanna Kliche, Dimitriya Hristoforova Garvanska, Leandro Simonetti, Dilip Badgujar, Doreen Dobritzsch, Jakob Nilsson, Norman E Davey, Ylva Ivarsson
Phosphorylation is a ubiquitous post-translation modification that regulates protein function by promoting, inhibiting or modulating protein–protein interactions. Hundreds of thousands of phosphosites have been identified but the vast majority have not been functionally characterised and it remains a challenge to decipher phosphorylation events modulating interactions. We generated a phosphomimetic proteomic
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Multiplying insights from perturbation experiments: predicting new perturbation combinations. Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-05-11 Joshua Welch
Experimentally exploring the effect of all perturbation combinations is not feasible. In their recent study, Theis and colleagues (Lotfollahi et al, 2023) present an approach that uses deep generative models to predict the effects of new perturbations from high-throughput single perturbation experiments.
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Mapping single-cell responses to population-level dynamics during antibiotic treatment Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-05-10 Kyeri Kim, Teng Wang, Helena R Ma, Emrah Şimşek, Boyan Li, Virgile Andreani, Lingchong You
Treatment of sensitive bacteria with beta-lactam antibiotics often leads to two salient population-level features: a transient increase in total population biomass before a subsequent decline, and a linear correlation between growth and killing rates. However, it remains unclear how these population-level responses emerge from collective single-cell responses. During beta-lactam treatment, it is well-recognized
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Transcription factor expression is the main determinant of variability in gene co-activity Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-05-09 Lucas van Duin, Robert Krautz, Sarah Rennie, Robin Andersson
Many genes are co-expressed and form genomic domains of coordinated gene activity. However, the regulatory determinants of domain co-activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the co-regulatory processes underlying domain co-activity and systematically quantify their effect sizes. We employ transcriptional decomposition to extract from RNA
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Predicting cellular responses to complex perturbations in high-throughput screens Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-05-08 Mohammad Lotfollahi, Anna Klimovskaia Susmelj, Carlo De Donno, Leon Hetzel, Yuge Ji, Ignacio L Ibarra, Sanjay R Srivatsan, Mohsen Naghipourfar, Riza M Daza, Beth Martin, Jay Shendure, Jose L McFaline-Figueroa, Pierre Boyeau, F Alexander Wolf, Nafissa Yakubova, Stephan Günnemann, Cole Trapnell, David Lopez-Paz, Fabian J Theis
Recent advances in multiplexed single-cell transcriptomics experiments facilitate the high-throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible. Therefore, computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder
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GRaNIE and GRaNPA: inference and evaluation of enhancer-mediated gene regulatory networks Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-04-19 Aryan Kamal, Christian Arnold, Annique Claringbould, Rim Moussa, Nila H Servaas, Maksim Kholmatov, Neha Daga, Daria Nogina, Sophia Mueller-Dott, Armando Reyes-Palomares, Giovanni Palla, Olga Sigalova, Daria Bunina, Caroline Pabst, Judith B Zaugg
Enhancers play a vital role in gene regulation and are critical in mediating the impact of noncoding genetic variants associated with complex traits. Enhancer activity is a cell-type-specific process regulated by transcription factors (TFs), epigenetic mechanisms and genetic variants. Despite the strong mechanistic link between TFs and enhancers, we currently lack a framework for jointly analysing
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Multisite assessment of reproducibility in high-content cell migration imaging data Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-04-17 Jianjiang Hu, Xavier Serra-Picamal, Gert-Jan Bakker, Marleen Van Troys, Sabina Winograd-Katz, Nil Ege, Xiaowei Gong, Yuliia Didan, Inna Grosheva, Omer Polansky, Karima Bakkali, Evelien Van Hamme, Merijn van Erp, Manon Vullings, Felix Weiss, Jarama Clucas, Anna M Dowbaj, Erik Sahai, Christophe Ampe, Benjamin Geiger, Peter Friedl, Matteo Bottai, Staffan Strömblad
High-content image-based cell phenotyping provides fundamental insights into a broad variety of life science disciplines. Striving for accurate conclusions and meaningful impact demands high reproducibility standards, with particular relevance for high-quality open-access data sharing and meta-analysis. However, the sources and degree of biological and technical variability, and thus the reproducibility
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A self-propagating, barcoded transposon system for the dynamic rewiring of genomic networks Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-27 Max A English, Miguel A Alcantar, James J Collins
In bacteria, natural transposon mobilization can drive adaptive genomic rearrangements. Here, we build on this capability and develop an inducible, self-propagating transposon platform for continuous genome-wide mutagenesis and the dynamic rewiring of gene networks in bacteria. We first use the platform to study the impact of transposon functionalization on the evolution of parallel Escherichia coli
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Systems-level transcriptional regulation of Caenorhabditis elegans metabolism Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-21 Shivani Nanda, Marc-Antoine Jacques, Wen Wang, Chad L Myers, L Safak Yilmaz, Albertha JM Walhout
Metabolism is controlled to ensure organismal development and homeostasis. Several mechanisms regulate metabolism, including allosteric control and transcriptional regulation of metabolic enzymes and transporters. So far, metabolism regulation has mostly been described for individual genes and pathways, and the extent of transcriptional regulation of the entire metabolic network remains largely unknown
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Stress-sensitive dynamics of miRNAs and Elba1 in Drosophila embryogenesis Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-20 Lovisa Örkenby, Signe Skog, Helen Ekman, Alessandro Gozzo, Unn Kugelberg, Rashmi Ramesh, Srivathsa Magadi, Gianluca Zambanini, Anna Nordin, Claudio Cantú, Daniel Nätt, Anita Öst
Early-life stress can result in life-long effects that impact adult health and disease risk, but little is known about how such programming is established and maintained. Here, we show that such epigenetic memories can be initiated in the Drosophila embryo before the major wave of zygotic transcription, and higher-order chromatin structures are established. An early short heat shock results in elevated
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Automated assembly of molecular mechanisms at scale from text mining and curated databases Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-20 John A Bachman, Benjamin M Gyori, Peter K Sorger
The analysis of omic data depends on machine-readable information about protein interactions, modifications, and activities as found in protein interaction networks, databases of post-translational modifications, and curated models of gene and protein function. These resources typically depend heavily on human curation. Natural language processing systems that read the primary literature have the potential
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Turnover and replication analysis by isotope labeling (TRAIL) reveals the influence of tissue context on protein and organelle lifetimes Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-17 John Hasper, Kevin Welle, Jennifer Hryhorenko, Sina Ghaemmaghami, Abigail Buchwalter
The lifespans of proteins range from minutes to years within mammalian tissues. Protein lifespan is relevant to organismal aging, as long-lived proteins accrue damage over time. It is unclear how protein lifetime is shaped by tissue context, where both cell turnover and proteolytic degradation contribute to protein turnover. We develop turnover and replication analysis by 15N isotope labeling (TRAIL)
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A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-17 Catera L Wilder, Diane Lefaudeux, Raisa Mathenge, Kensei Kishimoto, Alma Zuniga Munoz, Minh A Nguyen, Aaron S Meyer, Quen J Cheng, Alexander Hoffmann
Type I interferons (IFN) induce powerful antiviral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts, type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the
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A methylation clock model of mild SARS-CoV-2 infection provides insight into immune dysregulation Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-15 Weiguang Mao, Clare M Miller, Venugopalan D Nair, Yongchao Ge, Mary Anne S Amper, Antonio Cappuccio, Mary-Catherine George, Carl W Goforth, Kristy Guevara, Nada Marjanovic, German Nudelman, Hanna Pincas, Irene Ramos, Rachel S G Sealfon, Alessandra Soares-Schanoski, Sindhu Vangeti, Mital Vasoya, Dawn L Weir, Elena Zaslavsky, , Seunghee Kim-Schulze, Sacha Gnjatic, Miriam Merad, Andrew G Letizia, Olga
DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly
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Cracking the code of cellular protein–protein interactions: Alphafold and whole-cell crosslinking to the rescue Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-10 Toni Träger, Panagiotis L Kastritis
Integration of experimental and computational methods is crucial to better understanding protein–protein interactions (PPIs), ideally in their cellular context. In their recent work, Rappsilber and colleagues (O'Reilly et al, 2023) identified bacterial PPIs using an array of approaches. They combined whole-cell crosslinking, co-fractionation mass spectrometry, and open-source data mining with artificial
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Phosphorylation-linked complex profiling identifies assemblies required for Hippo signal integration Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-10 Federico Uliana, Rodolfo Ciuffa, Ranjan Mishra, Andrea Fossati, Fabian Frommelt, Sabrina Keller, Martin Mehnert, Eivind Salmorin Birkeland, Frank van Drogen, Nevena Srejic, Matthias Peter, Nicolas Tapon, Ruedi Aebersold, Matthias Gstaiger
While several computational methods have been developed to predict the functional relevance of phosphorylation sites, experimental analysis of the interdependency between protein phosphorylation and Protein–Protein Interactions (PPIs) remains challenging. Here, we describe an experimental strategy to establish interdependencies between protein phosphorylation and complex formation. This strategy is
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Higher-order modular regulation of the human proteome Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-09 Georg Kustatscher, Martina Hödl, Edward Rullmann, Piotr Grabowski, Emmanuel Fiagbedzi, Anja Groth, Juri Rappsilber
Operons are transcriptional modules that allow bacteria to adapt to environmental changes by coordinately expressing the relevant set of genes. In humans, biological pathways and their regulation are more complex. If and how human cells coordinate the expression of entire biological processes is unclear. Here, we capture 31 higher-order co-regulation modules, which we term progulons, by help of supervised
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Resuscitation dynamics reveal persister partitioning after antibiotic treatment Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-03 Xin Fang, Kyle R Allison
Bacteria can survive antibiotics by forming dormant, drug-tolerant persisters. Persisters can resuscitate from dormancy after treatment and prolong infections. Resuscitation is thought to occur stochastically, but its transient, single-cell nature makes it difficult to investigate. We tracked the resuscitation of individual persisters by microscopy after ampicillin treatment and, by characterizing
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A circuit for secretion-coupled cellular autonomy in multicellular eukaryotic cells Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-03-01 Lingxia Qiao, Saptarshi Sinha, Amer Ali Abd El-Hafeez, I-Chung Lo, Krishna K Midde, Tony Ngo, Nicolas Aznar, Inmaculada Lopez-Sanchez, Vijay Gupta, Marilyn G Farquhar, Padmini Rangamani, Pradipta Ghosh
Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell's ability to “secrete-and-sense” growth factors (GFs): a poorly understood phenomenon. Using an integrated computational and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled
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Vibrio natriegens genome-scale modeling reveals insights into halophilic adaptations and resource allocation Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-02-27 Lucas Coppens, Tanya Tschirhart, Dagmar H Leary, Sophie M Colston, Jaimee R Compton, William Judson Hervey, Karl L Dana, Gary J Vora, Sergio Bordel, Rodrigo Ledesma-Amaro
Vibrio natriegens is a Gram-negative bacterium with an exceptional growth rate that has the potential to become a standard biotechnological host for laboratory and industrial bioproduction. Despite this burgeoning interest, the current lack of organism-specific qualitative and quantitative computational tools has hampered the community's ability to rationally engineer this bacterium. In this study
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Protein complexes in cells by AI-assisted structural proteomics Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-02-23 Francis J O'Reilly, Andrea Graziadei, Christian Forbrig, Rica Bremenkamp, Kristine Charles, Swantje Lenz, Christoph Elfmann, Lutz Fischer, Jörg Stülke, Juri Rappsilber
Accurately modeling the structures of proteins and their complexes using artificial intelligence is revolutionizing molecular biology. Experimental data enable a candidate-based approach to systematically model novel protein assemblies. Here, we use a combination of in-cell crosslinking mass spectrometry and co-fractionation mass spectrometry (CoFrac-MS) to identify protein–protein interactions in
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Unravelling metabolic cross-feeding in a yeast–bacteria community using 13C-based proteomics Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-02-13 Natalia Gabrielli, Christoniki Maga-Nteve, Eleni Kafkia, Mandy Rettel, Jakob Loeffler, Stephan Kamrad, Athanasios Typas, Kiran Raosaheb Patil
Cross-feeding is fundamental to the diversity and function of microbial communities. However, identification of cross-fed metabolites is often challenging due to the universality of metabolic and biosynthetic intermediates. Here, we use 13C isotope tracing in peptides to elucidate cross-fed metabolites in co-cultures of Saccharomyces cerevisiae and Lactococcus lactis. The community was grown on lactose
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Cell sorters see things more clearly now Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-02-13 Daniel Schraivogel, Lars M Steinmetz
Microscopy and fluorescence-activated cell sorting (FACS) are two of the most important tools for single-cell phenotyping in basic and biomedical research. Microscopy provides high-resolution snapshots of cell morphology and the inner workings of cells, while FACS isolates thousands of cells per second using simple parameters, such as the intensity of fluorescent protein labels. Recent technologies
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Host inflammatory dynamics reveal placental immune modulation by Group B Streptococcus during pregnancy Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-02-06 Felicia Kuperwaser, Gal Avital, Michelle J Vaz, Kristen N Noble, Allison N Dammann, Tara M Randis, David M Aronoff, Adam J Ratner, Itai Yanai
Group B Streptococcus (GBS) is a pathobiont that can ascend to the placenta and cause adverse pregnancy outcomes, in part through production of the toxin β-hemolysin/cytolysin (β-h/c). Innate immune cells have been implicated in the response to GBS infection, but the impact of β-h/c on their response is poorly defined. We show that GBS modulates innate immune cell states by subversion of host inflammation
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Evolution of genome fragility enables microbial division of labor Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-02-02 Enrico Sandro Colizzi, Bram van Dijk, Roeland M H Merks, Daniel E Rozen, Renske M A Vroomans
Division of labor can evolve when social groups benefit from the functional specialization of its members. Recently, a novel means of coordinating the division of labor was found in the antibiotic-producing bacterium Streptomyces coelicolor, where specialized cells are generated through large-scale genomic re-organization. We investigate how the evolution of a genome architecture enables such mutation-driven
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Efficient plasmid transfer via natural competence in a microbial co-culture Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-01-30 Yu-Yu Cheng, Zhichao Zhou, James M Papadopoulos, Jason D Zuke, Tanya G Falbel, Karthik Anantharaman, Briana M Burton, Ophelia S Venturelli
The molecular and ecological factors shaping horizontal gene transfer (HGT) via natural transformation in microbial communities are largely unknown, which is critical for understanding the emergence of antibiotic-resistant pathogens. We investigate key factors shaping HGT in a microbial co-culture by quantifying extracellular DNA release, species growth, and HGT efficiency over time. In the co-culture
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One-shot 13C15N-metabolic flux analysis for simultaneous quantification of carbon and nitrogen flux Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-01-27 Khushboo Borah Slater, Martin Beyß, Ye Xu, Jim Barber, Catia Costa, Jane Newcombe, Axel Theorell, Melanie J Bailey, Dany J V Beste, Johnjoe McFadden, Katharina Nöh
Metabolic flux is the final output of cellular regulation and has been extensively studied for carbon but much less is known about nitrogen, which is another important building block for living organisms. For the tuberculosis pathogen, this is particularly important in informing the development of effective drugs targeting the pathogen's metabolism. Here we performed 13C15N dual isotopic labeling of
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Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-01-26 Fabian Fröhlich, Luca Gerosa, Jeremy Muhlich, Peter K Sorger
BRAF is prototypical of oncogenes that can be targeted therapeutically and the treatment of BRAFV600E melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring generates a drug adapted state thought to be involved in acquired resistance and disease recurrence. In this article, we study mechanisms of adaptive rewiring in BRAFV600E melanoma cells using an
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Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-01-23 Abel Sousa, Aurelien Dugourd, Danish Memon, Borgthor Petursson, Evangelia Petsalaki, Julio Saez-Rodriguez, Pedro Beltrao
Genetic alterations in cancer cells trigger oncogenic transformation, a process largely mediated by the dysregulation of kinase and transcription factor (TF) activities. While the mutational profiles of thousands of tumours have been extensively characterised, the measurements of protein activities have been technically limited until recently. We compiled public data of matched genomics and (phospho)proteomics
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A toolbox for systematic discovery of stable and transient protein interactors in baker's yeast Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-01-18 Emma J Fenech, Nir Cohen, Meital Kupervaser, Zohar Gazi, Maya Schuldiner
Identification of both stable and transient interactions is essential for understanding protein function and regulation. While assessing stable interactions is more straightforward, capturing transient ones is challenging. In recent years, sophisticated tools have emerged to improve transient interactor discovery, with many harnessing the power of evolved biotin ligases for proximity labelling. However
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Bacterial expression of a designed single-chain IL-10 prevents severe lung inflammation Mol. Syst. Biol. (IF 9.9) Pub Date : 2023-01-04 Ariadna Montero-Blay, Javier Delgado Blanco, Irene Rodriguez-Arce, Claire Lastrucci, Carlos Piñero-Lambea, Maria Lluch-Senar, Luis Serrano
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is active as a swapped domain dimer and is used in bacterial therapy of gut inflammation. IL-10 can be used as treatment of a wide range of pulmonary diseases. Here we have developed a non-pathogenic chassis (CV8) of the human lung bacterium Mycoplasma pneumoniae (MPN) to treat lung diseases. We find that IL-10 expression by MPN has a limited
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Vertical and horizontal gene transfer tradeoffs direct plasmid fitness Mol. Syst. Biol. (IF 9.9) Pub Date : 2022-12-27 Jonathan H Bethke, Helena R Ma, Ryan Tsoi, Li Cheng, Minfeng Xiao, Lingchong You
Plasmid fitness is directed by two orthogonal processes—vertical transfer through cell division and horizontal transfer through conjugation. When considered individually, improvements in either mode of transfer can promote how well a plasmid spreads and persists. Together, however, the metabolic cost of conjugation could create a tradeoff that constrains plasmid evolution. Here, we present evidence
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A single-cell RNA labeling strategy for measuring stress response upon tissue dissociation Mol. Syst. Biol. (IF 9.9) Pub Date : 2022-12-27 Anika Neuschulz, Olga Bakina, Victor Badillo-Lisakowski, Pedro Olivares-Chauvet, Thomas Conrad, Michael Gotthardt, Helmut Kettenmann, Jan Philipp Junker
Tissue dissociation, a crucial step in single-cell sample preparation, can alter the transcriptional state of a sample through the intrinsic cellular stress response. Here we demonstrate a general approach for measuring transcriptional response during sample preparation. In our method, transcripts made during dissociation are labeled for later identification upon sequencing. We found general as well
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Analysis of proteome adaptation reveals a key role of the bacterial envelope in starvation survival Mol. Syst. Biol. (IF 9.9) Pub Date : 2022-12-07 Severin Schink, Constantin Ammar, Yu-Fang Chang, Ralf Zimmer, Markus Basan
Bacteria reorganize their physiology upon entry to stationary phase. What part of this reorganization improves starvation survival is a difficult question because the change in physiology includes a global reorganization of the proteome, envelope, and metabolism of the cell. In this work, we used several trade-offs between fast growth and long survival to statistically score over 2,000 Escherichia
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Coordination of MAPK and p53 dynamics in the cellular responses to DNA damage and oxidative stress Mol. Syst. Biol. (IF 9.9) Pub Date : 2022-12-06 Ryan L Hanson, Eric Batchelor
In response to different cellular stresses, the transcription factor p53 undergoes different dynamics. p53 dynamics, in turn, control cell fate. However, distinct stresses can generate the same p53 dynamics but different cell fate outcomes, suggesting integration of dynamic information from other pathways is important for cell fate regulation. To determine how MAPK activities affect p53-mediated responses
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Enhancing nutritional niche and host defenses by modifying the gut microbiome Mol. Syst. Biol. (IF 9.9) Pub Date : 2022-11-15 Qing Sun, Nic M Vega, Bernardo Cervantes, Christopher P Mancuso, Ning Mao, Megan N Taylor, James J Collins, Ahmad S Khalil, Jeff Gore, Timothy K Lu
The gut microbiome is essential for processing complex food compounds and synthesizing nutrients that the host cannot digest or produce, respectively. New model systems are needed to study how the metabolic capacity provided by the gut microbiome impacts the nutritional status of the host, and to explore possibilities for altering host metabolic capacity via the microbiome. Here, we colonized the nematode