Molecular Systems Biology最新文献_第4页

Tissue-aware interpretation of genetic variants advances the etiology of rare diseases. 对基因变异的组织感知解释推进了罕见病的病因学研究。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-09-16 DOI: 10.1038/s44320-024-00061-6

Chanan M Argov,Ariel Shneyour,Juman Jubran,Eric Sabag,Avigdor Mansbach,Yair Sepunaru,Emmi Filtzer,Gil Gruber,Miri Volozhinsky,Yuval Yogev,Ohad Birk,Vered Chalifa-Caspi,Lior Rokach,Esti Yeger-Lotem

{"title":"Tissue-aware interpretation of genetic variants advances the etiology of rare diseases.","authors":"Chanan M Argov,Ariel Shneyour,Juman Jubran,Eric Sabag,Avigdor Mansbach,Yair Sepunaru,Emmi Filtzer,Gil Gruber,Miri Volozhinsky,Yuval Yogev,Ohad Birk,Vered Chalifa-Caspi,Lior Rokach,Esti Yeger-Lotem","doi":"10.1038/s44320-024-00061-6","DOIUrl":"https://doi.org/10.1038/s44320-024-00061-6","url":null,"abstract":"Pathogenic variants underlying Mendelian diseases often disrupt the normal physiology of a few tissues and organs. However, variant effect prediction tools that aim to identify pathogenic variants are typically oblivious to tissue contexts. Here we report a machine-learning framework, denoted \"Tissue Risk Assessment of Causality by Expression for variants\" (TRACEvar, https://netbio.bgu.ac.il/TRACEvar/ ), that offers two advancements. First, TRACEvar predicts pathogenic variants that disrupt the normal physiology of specific tissues. This was achieved by creating 14 tissue-specific models that were trained on over 14,000 variants and combined 84 attributes of genetic variants with 495 attributes derived from tissue omics. TRACEvar outperformed 10 well-established and tissue-oblivious variant effect prediction tools. Second, the resulting models are interpretable, thereby illuminating variants' mode of action. Application of TRACEvar to variants of 52 rare-disease patients highlighted pathogenicity mechanisms and relevant disease processes. Lastly, the interpretation of all tissue models revealed that top-ranking determinants of pathogenicity included attributes of disease-affected tissues, particularly cellular process activities. Collectively, these results show that tissue contexts and interpretable machine-learning models can greatly enhance the etiology of rare diseases.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"1 1","pages":""},"PeriodicalIF":9.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rescuing error control in crosslinking mass spectrometry. 挽救交联质谱中的误差控制。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-08-02 DOI: 10.1038/s44320-024-00057-2

Lutz Fischer, Juri Rappsilber

引用次数: 0

Evolution and stability of complex microbial communities driven by trade-offs. 权衡利弊驱动复杂微生物群落的进化和稳定。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-07-03 DOI: 10.1038/s44320-024-00051-8

Yanqing Huang, Avik Mukherjee, Severin Schink, Nina Catherine Benites, Markus Basan

{"title":"Evolution and stability of complex microbial communities driven by trade-offs.","authors":"Yanqing Huang, Avik Mukherjee, Severin Schink, Nina Catherine Benites, Markus Basan","doi":"10.1038/s44320-024-00051-8","DOIUrl":"10.1038/s44320-024-00051-8","url":null,"abstract":"Microbial communities are ubiquitous in nature and play an important role in ecology and human health. Cross-feeding is thought to be core to microbial communities, though it remains unclear precisely why it emerges. Why have multi-species microbial communities evolved in many contexts and what protects microbial consortia from invasion? Here, we review recent insights into the emergence and stability of coexistence in microbial communities. A particular focus is the long-term evolutionary stability of coexistence, as observed for microbial communities that spontaneously evolved in the E. coli long-term evolution experiment (LTEE). We analyze these findings in the context of recent work on trade-offs between competing microbial objectives, which can constitute a mechanistic basis for the emergence of coexistence. Coexisting communities, rather than monocultures of the 'fittest' single strain, can form stable endpoints of evolutionary trajectories. Hence, the emergence of coexistence might be an obligatory outcome in the evolution of microbial communities. This implies that rather than embodying fragile metastable configurations, some microbial communities can constitute formidable ecosystems that are difficult to disrupt.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"997-1005"},"PeriodicalIF":8.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498464","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}

引用次数: 0

Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics. 时间分辨相互作用组剖析解构了分泌蛋白质量控制动态。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44320-024-00058-1

Madison T Wright, Bibek Timalsina, Valeria Garcia Lopez, Jake N Hermanson, Sarah Garcia, Lars Plate

{"title":"Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics.","authors":"Madison T Wright, Bibek Timalsina, Valeria Garcia Lopez, Jake N Hermanson, Sarah Garcia, Lars Plate","doi":"10.1038/s44320-024-00058-1","DOIUrl":"10.1038/s44320-024-00058-1","url":null,"abstract":"Many cellular processes are governed by protein-protein interactions that require tight spatial and temporal regulation. Accordingly, it is necessary to understand the dynamics of these interactions to fully comprehend and elucidate cellular processes and pathological disease states. To map de novo protein-protein interactions with time resolution at an organelle-wide scale, we developed a quantitative mass spectrometry method, time-resolved interactome profiling (TRIP). We apply TRIP to elucidate aberrant protein interaction dynamics that lead to the protein misfolding disease congenital hypothyroidism. We deconvolute altered temporal interactions of the thyroid hormone precursor thyroglobulin with pathways implicated in hypothyroidism pathophysiology, such as Hsp70-/90-assisted folding, disulfide/redox processing, and N-glycosylation. Functional siRNA screening identified VCP and TEX264 as key protein degradation components whose inhibition selectively rescues mutant prohormone secretion. Ultimately, our results provide novel insight into the temporal coordination of protein homeostasis, and our TRIP method should find broad applications in investigating protein-folding diseases and cellular processes.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1049-1075"},"PeriodicalIF":8.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893815","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}

引用次数: 0

Proteome-scale characterisation of motif-based interactome rewiring by disease mutations. 以蛋白质组尺度描述疾病突变导致的基于主题的相互作用组重配。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI: 10.1038/s44320-024-00055-4

Johanna Kliche, Leandro Simonetti, Izabella Krystkowiak, Hanna Kuss, Marcel Diallo, Emma Rask, Jakob Nilsson, Norman E Davey, Ylva Ivarsson

{"title":"Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.","authors":"Johanna Kliche, Leandro Simonetti, Izabella Krystkowiak, Hanna Kuss, Marcel Diallo, Emma Rask, Jakob Nilsson, Norman E Davey, Ylva Ivarsson","doi":"10.1038/s44320-024-00055-4","DOIUrl":"10.1038/s44320-024-00055-4","url":null,"abstract":"Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1025-1048"},"PeriodicalIF":8.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620413","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}

引用次数: 0

Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer. 体细胞CpG高突变与癌症错配修复缺陷有关。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-07-18 DOI: 10.1038/s44320-024-00054-5

Aidan Flynn, Sebastian M Waszak, Joachim Weischenfeldt

{"title":"Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer.","authors":"Aidan Flynn, Sebastian M Waszak, Joachim Weischenfeldt","doi":"10.1038/s44320-024-00054-5","DOIUrl":"10.1038/s44320-024-00054-5","url":null,"abstract":"Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1006-1024"},"PeriodicalIF":8.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724009","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}

引用次数: 0

Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages. MAPK p38 和 NFκB 在巨噬细胞炎症反应中的动态和组合编码。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-13 DOI: 10.1038/s44320-024-00047-4

Stefanie Luecke, Xiaolu Guo, Katherine M Sheu, Apeksha Singh, Sarina C Lowe, Minhao Han, Jessica Diaz, Francisco Lopes, Roy Wollman, Alexander Hoffmann

{"title":"Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages.","authors":"Stefanie Luecke, Xiaolu Guo, Katherine M Sheu, Apeksha Singh, Sarina C Lowe, Minhao Han, Jessica Diaz, Francisco Lopes, Roy Wollman, Alexander Hoffmann","doi":"10.1038/s44320-024-00047-4","DOIUrl":"10.1038/s44320-024-00047-4","url":null,"abstract":"Macrophages sense pathogens and orchestrate specific immune responses. Stimulus specificity is thought to be achieved through combinatorial and dynamical coding by signaling pathways. While NFκB dynamics are known to encode stimulus information, dynamical coding in other signaling pathways and their combinatorial coordination remain unclear. Here, we established live-cell microscopy to investigate how NFκB and p38 dynamics interface in stimulated macrophages. Information theory and machine learning revealed that p38 dynamics distinguish cytokine TNF from pathogen-associated molecular patterns and high doses from low, but contributed little to information-rich NFκB dynamics when both pathways are considered. This suggests that immune response genes benefit from decoding immune signaling dynamics or combinatorics, but not both. We found that the heterogeneity of the two pathways is surprisingly uncorrelated. Mathematical modeling revealed potential sources of uncorrelated heterogeneity in the branched pathway network topology and predicted it to drive gene expression variability. Indeed, genes dependent on both p38 and NFκB showed high scRNAseq variability and bimodality. These results identify combinatorial signaling as a mechanism to restrict NFκB-AND-p38-responsive inflammatory cytokine expression to few cells.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"898-932"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317837","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}

引用次数: 0

A 'rich-get-richer' mechanism drives patchy dynamics and resistance evolution in antibiotic-treated bacteria. 富者愈富 "的机制推动了抗生素处理过的细菌的斑块动态和耐药性进化。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1038/s44320-024-00046-5

Emrah Şimşek, Kyeri Kim, Jia Lu, Anita Silver, Nan Luo, Charlotte T Lee, Lingchong You

{"title":"A 'rich-get-richer' mechanism drives patchy dynamics and resistance evolution in antibiotic-treated bacteria.","authors":"Emrah Şimşek, Kyeri Kim, Jia Lu, Anita Silver, Nan Luo, Charlotte T Lee, Lingchong You","doi":"10.1038/s44320-024-00046-5","DOIUrl":"10.1038/s44320-024-00046-5","url":null,"abstract":"Bacteria in nature often form surface-attached communities that initially comprise distinct subpopulations, or patches. For pathogens, these patches can form at infection sites, persist during antibiotic treatment, and develop into mature biofilms. Evidence suggests that patches can emerge due to heterogeneity in the growth environment and bacterial seeding, as well as cell-cell signaling. However, it is unclear how these factors contribute to patch formation and how patch formation might affect bacterial survival and evolution. Here, we demonstrate that a 'rich-get-richer' mechanism drives patch formation in bacteria exhibiting collective survival (CS) during antibiotic treatment. Modeling predicts that the seeding heterogeneity of these bacteria is amplified by local CS and global resource competition, leading to patch formation. Increasing the dose of a non-eradicating antibiotic treatment increases the degree of patchiness. Experimentally, we first demonstrated the mechanism using engineered Escherichia coli and then demonstrated its applicability to a pathogen, Pseudomonas aeruginosa. We further showed that the formation of P. aeruginosa patches promoted the evolution of antibiotic resistance. Our work provides new insights into population dynamics and resistance evolution during surface-attached bacterial growth.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"880-897"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321261","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}

引用次数: 0

Molecular causality in the advent of foundation models. 基础模型出现时的分子因果关系。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-18 DOI: 10.1038/s44320-024-00041-w

Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez

引用次数: 0

µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics. μPhos：高维磷酸化蛋白质组学的可扩展灵敏平台。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-21 DOI: 10.1038/s44320-024-00050-9

Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier

{"title":"µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics.","authors":"Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier","doi":"10.1038/s44320-024-00050-9","DOIUrl":"10.1038/s44320-024-00050-9","url":null,"abstract":"Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations is crucial for further illuminating the functionality of the phosphoproteome. Here we describe µPhos ('microPhos'), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture and small tissue amounts in <8 h total processing time. By greatly minimizing transfer steps and liquid volumes, we demonstrate increased sensitivity, >90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify ~17,000 Class I phosphosites in a human cancer cell line using 20 µg starting material, and confidently localize ~6200 phosphosites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable. We employ µPhos to study drug- and time-dependent response signatures in a leukemia cell line, and by quantifying 30,000 Class I phosphosites in the mouse brain we reveal distinct spatial kinase activities in subregions of the hippocampal formation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"972-995"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437256","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}

引用次数: 0