Molecular Systems Biology最新文献_第10页

Genetic effects on molecular network states explain complex traits. 遗传对分子网络状态的影响解释了复杂的性状。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 DOI: 10.15252/msb.202211493

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

{"title":"Genetic effects on molecular network states explain complex traits.","authors":"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","doi":"10.15252/msb.202211493","DOIUrl":"https://doi.org/10.15252/msb.202211493","url":null,"abstract":"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 are confined to small parts of a network versus when they lead to modulation of network states. Integrating multi-omics profiling of genetically heterogeneous budding and fission yeast strains with an array of cellular traits identified a central state transition of the yeast molecular network that is related to PKA and TOR (PT) signaling. Genetic variants affecting this PT state globally shifted the molecular network along a single-dimensional axis, thereby modulating processes including energy and amino acid metabolism, transcription, translation, cell cycle control, and cellular stress response. We propose that genetic effects can propagate through large parts of molecular networks because of the functional requirement to centrally coordinate the activity of fundamental cellular processes.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11493"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10318644","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: 1

Updated benchmarking of variant effect predictors using deep mutational scanning. 利用深度突变扫描更新变异效应预测器的基准。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 Epub Date: 2023-06-13 DOI: 10.15252/msb.202211474

Benjamin J Livesey, Joseph A Marsh

{"title":"Updated benchmarking of variant effect predictors using deep mutational scanning.","authors":"Benjamin J Livesey, Joseph A Marsh","doi":"10.15252/msb.202211474","DOIUrl":"10.15252/msb.202211474","url":null,"abstract":"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 top-performing VEPs are unsupervised methods including EVE, DeepSequence and ESM-1v, a protein language model that ranked first overall. However, the strong performance of recent supervised VEPs, in particular VARITY, shows that developers are taking data circularity and bias issues seriously. We also assess the performance of DMS and unsupervised VEPs for discriminating between known pathogenic and putatively benign missense variants. Our findings are mixed, demonstrating that some DMS datasets perform exceptionally at variant classification, while others are poor. Notably, we observe a striking correlation between VEP agreement with DMS data and performance in identifying clinically relevant variants, strongly supporting the validity of our rankings and the utility of DMS for independent benchmarking.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11474"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9960586","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

Transcription factor expression is the main determinant of variability in gene co-activity. 转录因子的表达是决定基因共同活性变化的主要因素。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-07-11 Epub Date: 2023-05-09 DOI: 10.15252/msb.202211392

Lucas van Duin, Robert Krautz, Sarah Rennie, Robin Andersson

{"title":"Transcription factor expression is the main determinant of variability in gene co-activity.","authors":"Lucas van Duin, Robert Krautz, Sarah Rennie, Robin Andersson","doi":"10.15252/msb.202211392","DOIUrl":"10.15252/msb.202211392","url":null,"abstract":"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 expression data an expression component related to co-activity revealed by genomic positioning. This strategy reveals close to 1,500 co-activity domains, covering most expressed genes, of which the large majority are invariable across individuals. Focusing specifically on domains with high variability in co-activity reveals that contained genes have a higher sharing of eQTLs, a higher variability in enhancer interactions, and an enrichment of binding by variably expressed transcription factors, compared to genes within non-variable domains. Through careful quantification of the relative contributions of regulatory processes underlying co-activity, we find transcription factor expression levels to be the main determinant of gene co-activity. Our results indicate that distal trans effects contribute more than local genetic variation to individual variation in co-activity domains.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 7","pages":"e11392"},"PeriodicalIF":8.5,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9789760","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

Single-cell biology: what does the future hold? 单细胞生物学:未来会怎样?

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-07-11 DOI: 10.15252/msb.202311799

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

引用次数: 1

Large-scale phosphomimetic screening identifies phospho-modulated motif-based protein interactions. 大规模拟磷酸化筛选确定了基于磷酸化调制基团的蛋白质相互作用。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-07-11 Epub Date: 2023-05-23 DOI: 10.15252/msb.202211164

Johanna Kliche, Dimitriya Hristoforova Garvanska, Leandro Simonetti, Dilip Badgujar, Doreen Dobritzsch, Jakob Nilsson, Norman E Davey, Ylva Ivarsson

{"title":"Large-scale phosphomimetic screening identifies phospho-modulated motif-based protein interactions.","authors":"Johanna Kliche, Dimitriya Hristoforova Garvanska, Leandro Simonetti, Dilip Badgujar, Doreen Dobritzsch, Jakob Nilsson, Norman E Davey, Ylva Ivarsson","doi":"10.15252/msb.202211164","DOIUrl":"10.15252/msb.202211164","url":null,"abstract":"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 peptide-phage display library to screen for phosphosites that modulate short linear motif-based interactions. The peptidome covers ~13,500 phospho-serine/threonine sites found in the intrinsically disordered regions of the human proteome. Each phosphosite is represented as wild-type and phosphomimetic variant. We screened 71 protein domains to identify 248 phosphosites that modulate motif-mediated interactions. Affinity measurements confirmed the phospho-modulation of 14 out of 18 tested interactions. We performed a detailed follow-up on a phospho-dependent interaction between clathrin and the mitotic spindle protein hepatoma-upregulated protein (HURP), demonstrating the essentiality of the phospho-dependency to the mitotic function of HURP. Structural characterisation of the clathrin-HURP complex elucidated the molecular basis for the phospho-dependency. Our work showcases the power of phosphomimetic ProP-PD to discover novel phospho-modulated interactions required for cellular function.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 7","pages":"e11164"},"PeriodicalIF":9.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9794572","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 metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability. DNA 损伤反应的代谢图谱确定了 PRDX1 对核 ROS 清除和天冬氨酸供应的控制作用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-07-11 Epub Date: 2023-06-01 DOI: 10.15252/msb.202211267

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

{"title":"A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.","authors":"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","doi":"10.15252/msb.202211267","DOIUrl":"10.15252/msb.202211267","url":null,"abstract":"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 of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 7","pages":"e11267"},"PeriodicalIF":8.5,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9795797","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

Multisite assessment of reproducibility in high-content cell migration imaging data. 高含量细胞迁移成像数据再现性的多位点评估。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-06-12 Epub Date: 2023-04-17 DOI: 10.15252/msb.202211490

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

{"title":"Multisite assessment of reproducibility in high-content cell migration imaging data.","authors":"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","doi":"10.15252/msb.202211490","DOIUrl":"10.15252/msb.202211490","url":null,"abstract":"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 and usefulness of meta-analysis of results from live-cell microscopy, have not been systematically investigated. Here, using high-content data describing features of cell migration and morphology, we determine the sources of variability across different scales, including between laboratories, persons, experiments, technical repeats, cells, and time points. Significant technical variability occurred between laboratories and, to lesser extent, between persons, providing low value to direct meta-analysis on the data from different laboratories. However, batch effect removal markedly improved the possibility to combine image-based datasets of perturbation experiments. Thus, reproducible quantitative high-content cell image analysis of perturbation effects and meta-analysis depend on standardized procedures combined with batch correction.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 6","pages":"e11490"},"PeriodicalIF":9.9,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9669327","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: 1

GRaNIE and GRaNPA: inference and evaluation of enhancer-mediated gene regulatory networks. GRaNIE和GRaNPA:增强子介导的基因调控网络的推断和评估。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-06-12 Epub Date: 2023-04-19 DOI: 10.15252/msb.202311627

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

{"title":"GRaNIE and GRaNPA: inference and evaluation of enhancer-mediated gene regulatory networks.","authors":"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","doi":"10.15252/msb.202311627","DOIUrl":"10.15252/msb.202311627","url":null,"abstract":"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 them in cell-type-specific gene regulatory networks (GRN). Equally important, we lack an unbiased way of assessing the biological significance of inferred GRNs since no complete ground truth exists. To address these gaps, we present GRaNIE (Gene Regulatory Network Inference including Enhancers) and GRaNPA (Gene Regulatory Network Performance Analysis). GRaNIE (https://git.embl.de/grp-zaugg/GRaNIE) builds enhancer-mediated GRNs based on covariation of chromatin accessibility and RNA-seq across samples (e.g. individuals), while GRaNPA (https://git.embl.de/grp-zaugg/GRaNPA) assesses the performance of GRNs for predicting cell-type-specific differential expression. We demonstrate their power by investigating gene regulatory mechanisms underlying the response of macrophages to infection, cancer and common genetic traits including autoimmune diseases. Finally, our methods identify the TF PURA as a putative regulator of pro-inflammatory macrophage polarisation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 6","pages":"e11627"},"PeriodicalIF":9.9,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9725110","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: 18

A self-propagating, barcoded transposon system for the dynamic rewiring of genomic networks. 一个自我繁殖的条形码转座子系统，用于基因组网络的动态重新布线。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-06-12 DOI: 10.15252/msb.202211398

Max A English, Miguel A Alcantar, James J Collins

{"title":"A self-propagating, barcoded transposon system for the dynamic rewiring of genomic networks.","authors":"Max A English, Miguel A Alcantar, James J Collins","doi":"10.15252/msb.202211398","DOIUrl":"https://doi.org/10.15252/msb.202211398","url":null,"abstract":"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 populations toward diverse carbon source utilization and antibiotic resistance phenotypes. We then develop a modular, combinatorial assembly pipeline for the functionalization of transposons with synthetic or endogenous gene regulatory elements (e.g., inducible promoters) as well as DNA barcodes. We compare parallel evolutions across alternating carbon sources and demonstrate the emergence of inducible, multigenic phenotypes and the ease with which barcoded transposons can be tracked longitudinally to identify the causative rewiring of gene networks. This work establishes a synthetic transposon platform that can be used to optimize strains for industrial and therapeutic applications, for example, by rewiring gene networks to improve growth on diverse feedstocks, as well as help address fundamental questions about the dynamic processes that have sculpted extant gene networks.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 6","pages":"e11398"},"PeriodicalIF":9.9,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9671024","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: 1

Predicting cellular responses to complex perturbations in high-throughput screens. 在高通量筛选中预测细胞对复杂扰动的反应。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-06-12 DOI: 10.15252/msb.202211517

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

{"title":"Predicting cellular responses to complex perturbations in high-throughput screens.","authors":"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","doi":"10.15252/msb.202211517","DOIUrl":"https://doi.org/10.15252/msb.202211517","url":null,"abstract":"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 (CPA), which combines the interpretability of linear models with the flexibility of deep-learning approaches for single-cell response modeling. CPA learns to in silico predict transcriptional perturbation response at the single-cell level for unseen dosages, cell types, time points, and species. Using newly generated single-cell drug combination data, we validate that CPA can predict unseen drug combinations while outperforming baseline models. Additionally, the architecture's modularity enables incorporating the chemical representation of the drugs, allowing the prediction of cellular response to completely unseen drugs. Furthermore, CPA is also applicable to genetic combinatorial screens. We demonstrate this by imputing in silico 5,329 missing combinations (97.6% of all possibilities) in a single-cell Perturb-seq experiment with diverse genetic interactions. We envision CPA will facilitate efficient experimental design and hypothesis generation by enabling in silico response prediction at the single-cell level and thus accelerate therapeutic applications using single-cell technologies.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 6","pages":"e11517"},"PeriodicalIF":9.9,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9663033","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: 16