Molecular Systems Biology最新文献

{"title":"Bacterial population dynamics during colonization of solid tumors.","authors":"Serkan Sayin, Motasem ElGamel, Brittany Rosener, Michael Brehm, Andrew Mugler, Amir Mitchell","doi":"10.1038/s44320-025-00175-5","DOIUrl":"10.1038/s44320-025-00175-5","url":null,"abstract":"<p><p>Bacterial colonization of tumors is widespread, yet the dynamics during colonization remain underexplored. Here we discover strong variability in the sizes of intratumor bacterial clones and use this variability to infer the mechanisms of colonization. We monitored bacterial population dynamics in murine tumors after introducing millions of genetically barcoded Escherichia coli cells. Results from intravenous injection revealed that roughly a hundred bacteria seeded a tumor and that colonizers underwent rapid, yet highly nonuniform growth. Within a day, bacteria reached a steady-state and then sustained load and clone diversity. Intratumor injections, circumventing colonization bottlenecks, revealed that the nonuniformity persists and that the sizes of bacterial progenies followed a scale-free distribution. Theory suggested that our observations are compatible with a growth model constrained by a local niche load, global resource competition, and noise. Our work provides the first dynamical model of tumor colonization and may allow distinguishing genuine tumor microbiomes from contamination.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"412-434"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763277","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":"Limited proteolysis-coupled mass spectrometry captures proteome-wide protein structural alterations and biomolecular condensation in living cells.","authors":"Franziska Elsässer, Roberta Florea, Felix Räsch, Mostafa Zedan, Nesli-Ece Sen, Tim Pflästerer, Tatjana Kleele, Robbie Loewith, Karsten Weis, Natalie de Souza, Paola Picotti","doi":"10.1038/s44320-025-00182-6","DOIUrl":"10.1038/s44320-025-00182-6","url":null,"abstract":"<p><p>The function of a protein is determined by its structure, which may change dynamically in response to post-translational modifications, interaction with other molecules, or environmental factors like temperature. Limited proteolysis-coupled mass spectrometry (LiP-MS) captures such structural alterations on a proteome-wide scale via the detection of altered protease susceptibility patterns of proteins. However, this technique has so far required cell lysis, which exposes proteins to non-native conditions and can disrupt labile interactions such as those occurring within biomolecular condensates. To study protein structures directly within cells, we developed in-cell LiP-MS. We optimized conditions for introduction of proteinase K into human cells using electroporation and validated that intracellular cleavage occurs. In-cell LiP-MS captured the known binding of rapamycin to FKBP1A within the cell. Moreover, it detected global protein structural alterations upon sodium arsenite treatment and captured the structural dynamics of hundreds of proteins from biomolecular condensates with peptide level resolution and within live human cells. The data allowed monitoring of structural alterations of individual sites on the involved proteins, such as known RNA-binding and intrinsically-disordered regions, and dissected the timing of the different events. We detected known (G3BP1) and novel structural alterations of proteins from stress granules as well as from nuclear speckles and validated alteration of nuclear speckles by fluorescence microscopy and of the protein SERBP1 by polysome profiling. Our dataset further provides a resource describing the structural changes of human proteins in response to a cellular stress leading to biomolecular condensation and pinpoints structurally altered regions. Comparison of LiP-based structural fingerprints before and after cell lysis revealed which human proteins are susceptible to structural change upon cell lysis, therefore guiding the design of future experiments requiring native protein structures.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"337-368"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958776","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":"Genetics-mediated regulation of intestinal gene expression on microbiome contributes to human disease heritability.","authors":"Haochuan Wang, Chengyu Li, Zhen Hu, Haonan Feng, Luowei Chen, Ke Ding, Jiuhong Nan, Yuhan Wu, Jinghao Sheng, Xushen Xiong","doi":"10.1038/s44320-025-00173-7","DOIUrl":"10.1038/s44320-025-00173-7","url":null,"abstract":"<p><p>The gut microbiome plays fundamental roles in physiological and pathological processes, yet its interaction with host gene expression and contribution to disease remain underexplored. Here, we integrate the genetic regulatory maps of 116 microbial genera with gene expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) in three intestinal tissues to dissect host-microbiome interaction. We identify 6088, 5810, and 2398 gene-to-microbiome regulatory loci in the transverse colon, sigmoid colon, and ileum, respectively. Among these, 13.2% of genes show broad regulatory effects on multiple genera, with functional enrichments in developmental, metabolic, and immune-related pathways. Integrative analysis with genome-wide association studies (GWASs) reveals 283 microbiome-dependent disease loci. We observe pleiotropic effects mediated by the gene-to-microbiome regulation at both microbiome and disease layers. Notably, we predict and experimentally validate the suppressive effect of Allisonella on depression through regulating bile acid abundance, and the regulation of Parasutterella on short-chain fatty acid and its contribution to allergic rhinitis. The gene-microbiome-disease regulatory maps are available at our interactive database ( https://xiongxslab.github.io/microbiomeMR/ ).</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"369-394"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687700","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":"The DNA dialect: a comprehensive guide to pretrained genomic language models.","authors":"Marcell Veiner, Fran Supek","doi":"10.1038/s44320-025-00184-4","DOIUrl":"10.1038/s44320-025-00184-4","url":null,"abstract":"<p><p>Following their success in natural language processing and protein biology, pretrained large language models have started appearing in genomics in large numbers. These genomic language models (gLMs), trained on diverse DNA and RNA sequences, promise improved performance on a variety of downstream prediction and understanding tasks. In this review, we trace the rapid evolution of gLMs, analyze current trends, and offer an overview of their application in genomic research. We investigate each gLM component in detail, from training data curation to the architecture, and highlight the present trends of increasing model complexity. We review major benchmarking efforts, suggesting that no single model dominates, and that task-specific design and pretraining data often outweigh general model scale or architecture. In addition, we discuss requirements for making gLMs practically useful for genomic research. While several applications, ranging from genome annotation to DNA sequence generation, showcase the potential of gLMs, their use highlights gaps and pitfalls that remain unresolved. This guide aims to equip researchers with a grounded understanding of gLM capabilities, limitations, and best practices for their effective use in genomics.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"309-332"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003753","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":"Decoding non-coding SNPs: systems genomics modelling dissects the heterogeneity of IBD.","authors":"Dezső Módos, John P Thomas, Johanne Brooks-Warburton, Martina Poletti, Balazs Bohar, Yufan Liu, Matthew Madgwick, Luca Csabai, Wen-Xin Kang, Benjamin Alexander-Dann, Azedine Zoufir, Padhmanand Sudhakar, Domenico Cozzetto, David Fazekas, Shamith Samarajiwa, Simon R Carding, Nicholas Powell, Bram Verstockt, Andreas Bender, Tamas Korcsmaros","doi":"10.1038/s44320-025-00169-3","DOIUrl":"10.1038/s44320-025-00169-3","url":null,"abstract":"<p><p>Genome-wide association studies have identified numerous susceptibility loci in complex diseases, such as chronic immune-mediated inflammatory disorders (IMIDs), yet their impact on pathomechanisms remains poorly understood. Low effect sizes, polygenicity, and predominance within non-coding genomic regions remain major challenges to the functional interpretation of IMID-associated single-nucleotide polymorphisms (SNPs). To address this, we present a novel systems genomics approach which models the cumulative impact of non-coding SNPs on downstream cellular signalling and gene regulatory networks. Applying this to the prototypical chronic IMIDs of Crohn's disease (CD) and ulcerative colitis (UC), both forms of inflammatory bowel disease (IBD), we individually analysed 2,636 patient genomes. Signals from non-coding SNPs were found to propagate towards well-established and novel CD- and UC-associated pathogenic pathways through the signalling and gene regulatory layers. The SNP-propagated gene regulatory networks stratified CD and UC patients into distinct clusters corresponding to cell type-specific gene dysregulation and potential therapeutic response. This approach bridges the gap between genotype and phenotype, laying the foundations for accelerating precision medicine in complex diseases.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"259-280"},"PeriodicalIF":7.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636216","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":"Expansion omics: from expansion microscopy to spatial omics.","authors":"Zhen Dong, Weirong Xiang, Wenhao Jiang, Tiannan Guo","doi":"10.1038/s44320-025-00171-9","DOIUrl":"10.1038/s44320-025-00171-9","url":null,"abstract":"<p><p>Tissue expansion, originally developed for super-resolution imaging, has become a foundation for expansion omics (ExO), a growing field that uses physical tissue expansion to enable spatially resolved omics profiling. In this perspective, we explore how ExO integrates multi-omics through chemical anchoring strategies that ensure selective retention of diverse molecular species, together with improved spatial resolution from the subcellular resolution for profiling to the sub-nanometer scale for imaging, allowing precise detection of biomolecules and their link with biological function. These capabilities have empowered tissue expansion to be successfully applied across multiple spatial omics modalities, including epigenomics, transcriptomics, proteomics, and lipidomics, enabling high-resolution mapping of chromatin states, gene expression, protein localization, and lipid distributions. Moreover, ExO supports spatial multi-omics approaches that jointly capture and correlate multiple biomolecular dimensions within the same tissue context. However, challenges remain in expansion resolution, molecular retention, hydrogel adaptability, data scalability, and AI-driven analysis. As tissue expansion evolves, its integration of super-resolution imaging and spatial omics establishes it as a core technology for whole-slide, single-cell multi-omics and the development of the Artificial Intelligence Virtual Cell, advancing spatial biology and medicine.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"165-178"},"PeriodicalIF":6.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654912","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":"Aging-linked systemic lipid signature is reprogrammed by caloric restriction in rhesus monkeys.","authors":"Salma I Abou Elhassan, Josef P Clark, Di Kuang, Timothy W Rhoads, Ricki J Colman, Joshua J Coon, Rozalyn M Anderson, Katherine A Overmyer","doi":"10.1038/s44320-025-00177-3","DOIUrl":"10.1038/s44320-025-00177-3","url":null,"abstract":"<p><p>Caloric restriction (CR) without malnutrition delays aging in diverse species, including primates, with metabolic changes implicated in this process. To facilitate exploration of CR metabolism with aging, we developed a 15-minute LC-MS/MS metabolomics and lipidomics method, leveraging monophasic extractions and wide elution-strength solvents. We analyzed 494 plasma samples collected over 25 years from male and female rhesus monkeys (Macaca mulatta) on a Control or CR (30% restricted) diet. Quantitation of 359 biomolecules revealed that aging, followed by sex and diet, had the largest impact on metabolite abundances. In both sexes, aging was associated with significantly lower plasma levels of sphingomyelins (SMs) and higher levels of diglycerides (DGs) and triglycerides (TGs), each of which was opposed by CR. Sex dimorphism was evident by the increased abundance of phosphocholine (PC)-containing lipids in females. These results highlight the utility of a rapid metabolomics and lipidomics approach to elucidate complex biology in large-scale studies.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"281-305"},"PeriodicalIF":7.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724849","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":"Author Correction: Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets.","authors":"Anuar Makhmut, Mihnea P Dragomir, Sonja Fritzsche, Markus Moebs, Wolfgang D Schmitt, Eliane T Taube, Fabian Coscia","doi":"10.1038/s44320-025-00178-2","DOIUrl":"10.1038/s44320-025-00178-2","url":null,"abstract":"","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"306"},"PeriodicalIF":7.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774971","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":"Cell cycle criticality as a mechanism for robust cell population control.","authors":"Benjamin D Simons, Omer Karin","doi":"10.1038/s44320-025-00164-8","DOIUrl":"10.1038/s44320-025-00164-8","url":null,"abstract":"<p><p>Tissue homeostasis requires a precise balance between stem cell self-renewal and differentiation. While fate decisions are known to be closely linked with cell cycle progression, the functional significance of this relationship is unclear. We propose a mechanistic framework to analyse cellular dynamics when cell fate is coupled to cell cycle duration. Our model highlights a unique aspect of cell cycle regulation where mitogens serve as control parameters for a bifurcation governing the G1-S transition. Under competitive feedback from cell-cell interactions, the cell cycle regulatory network fine-tunes near the critical point of this bifurcation. Critical positioning lengthens G1 while amplifying cell-to-cell variability in mitogenic signalling and biochemical states. Such regulation confers significant advantages for controlling cell population dynamics, with alternative topologies enabling rapid tissue growth and repair or efficient mutant rejection. Counter-intuitively, we propose that stem cells may couple prolonged G1 with increased self-renewal propensity to efficiently suppress mis-sensing mutants. Our theory provides a distinct explanation to dynamical and statistical patterns of G1 lengthening and predicts regulatory strategies across development, homeostasis, and ageing.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"241-258"},"PeriodicalIF":6.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459290","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":"LimbNET: collaborative platform for simulating spatial patterns of gene networks in limb development.","authors":"Antoni Matyjaszkiewicz, James Sharpe","doi":"10.1038/s44320-025-00128-y","DOIUrl":"10.1038/s44320-025-00128-y","url":null,"abstract":"<p><p>Successful computational modelling of complex biological phenomena will depend on the seamless sharing of models and hypotheses between researchers of all backgrounds-experimental and theoretical. LimbNET, a new online tool for modelling, simulating and visualising spatiotemporal patterning in limb development, aims to facilitate this process within the limb development community. LimbNET enables remote users to define and simulate arbitrary gene regulatory network (GRN) models of 2D spatiotemporal developmental patterning processes. Researchers can test and compare each others' hypotheses within a common framework. A database of previously created models empowers users to simulate, explore, and extend each others' work. Spatiotemporally varying gene expression intensities, derived from image-based data, are mapped into a standardised computational description of limb growth, integrated within our modelling framework. This enables direct comparison not only between datasets but between data and simulation outputs, closing the feedback loop between experiments and simulation via parameter optimisation. All functionality is accessible through a web browser ( https://limbnet.embl.es ), requiring no special software, and opening the field of image-driven modelling to the full scientific community.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"228-240"},"PeriodicalIF":7.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678247","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}