Molecular Systems Biology最新文献_第8页

Paralog dispensability shapes homozygous deletion patterns in tumor genomes. 平行可有可无的形状纯合缺失模式在肿瘤基因组。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-14 DOI: 10.15252/msb.202311987

Barbara De Kegel, Colm J Ryan

{"title":"Paralog dispensability shapes homozygous deletion patterns in tumor genomes.","authors":"Barbara De Kegel, Colm J Ryan","doi":"10.15252/msb.202311987","DOIUrl":"10.15252/msb.202311987","url":null,"abstract":"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 are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of > 10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that genes with paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non-essential paralogs. Overall, our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107591804","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: 5

Integrated systems biology approach identifies gene targets for endothelial dysfunction. 综合系统生物学方法确定内皮功能障碍的基因靶标。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-30 DOI: 10.15252/msb.202211462

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

{"title":"Integrated systems biology approach identifies gene targets for endothelial dysfunction.","authors":"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","doi":"10.15252/msb.202211462","DOIUrl":"10.15252/msb.202211462","url":null,"abstract":"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, high content imaging and network analysis to prioritise key ED genes and identify a pro- and anti-ED network. We found 26 genes that, upon silencing, exacerbated the ED phenotypes tested, and network propagation identified a pro-ED network enriched in functions associated with inflammatory responses. Conversely, 31 genes ameliorated ED phenotypes, pointing to potential ED targets, and the respective anti-ED network was enriched in hypoxia, angiogenesis and cancer-related processes. An independent screen with 17 drugs found general agreement with the trends from our siRNA screen and further highlighted DUSP1, IL6 and CCL2 as potential candidates for targeting ED. Overall, our results demonstrate the potential of integrated system biology approaches in discovering disease-specific candidate drug targets for endothelial dysfunction.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138461112","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

Phosphatase specificity principles uncovered by MRBLE:Dephos and global substrate identification. MRBLE揭示的磷酸酶特异性原理：Dephos和全局底物鉴定。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-02 DOI: 10.15252/msb.202311782

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

{"title":"Phosphatase specificity principles uncovered by MRBLE:Dephos and global substrate identification.","authors":"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","doi":"10.15252/msb.202311782","DOIUrl":"10.15252/msb.202311782","url":null,"abstract":"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 of the residues surrounding the dephosphorylation site for PP1 and PP2A-B55, which reveals common and unique preferences. To compare the MRBLE:Dephos results to cellular substrates, we focused on mitotic exit that requires extensive dephosphorylation by PP1 and PP2A-B55. We use specific inhibition of PP1 and PP2A-B55 in mitotic exit lysates coupled with phosphoproteomics to identify more than 2,000 regulated sites. Importantly, the sites dephosphorylated during mitotic exit reveal key signatures that are consistent with MRBLE:Dephos. Furthermore, integration of our phosphoproteomic data with mitotic interactomes of PP1 and PP2A-B55 provides insight into how binding of phosphatases to substrates shapes dephosphorylation. Collectively, we develop novel approaches to investigate protein phosphatases that provide insight into mitotic exit regulation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425190","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

Dimensionality reduction methods for extracting functional networks from large-scale CRISPR screens. 从大规模CRISPR屏幕中提取功能网络的降维方法。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-11-09 Epub Date: 2023-09-26 DOI: 10.15252/msb.202311657

Arshia Zernab Hassan, Henry N Ward, Mahfuzur Rahman, Maximilian Billmann, Yoonkyu Lee, Chad L Myers

{"title":"Dimensionality reduction methods for extracting functional networks from large-scale CRISPR screens.","authors":"Arshia Zernab Hassan, Henry N Ward, Mahfuzur Rahman, Maximilian Billmann, Yoonkyu Lee, Chad L Myers","doi":"10.15252/msb.202311657","DOIUrl":"10.15252/msb.202311657","url":null,"abstract":"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, and thus, methods for normalizing this dominant signal to improve co-essentiality networks are of interest. In this study, we explore three unsupervised dimensionality reduction methods-autoencoders, robust, and classical principal component analyses (PCA)-for normalizing the DepMap to improve functional networks extracted from these data. We propose a novel \"onion\" normalization technique to combine several normalized data layers into a single network. Benchmarking analyses reveal that robust PCA combined with onion normalization outperforms existing methods for normalizing the DepMap. Our work demonstrates the value of removing low-dimensional signals from the DepMap before constructing functional gene networks and provides generalizable dimensionality reduction-based normalization tools.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":8.5,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134039","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

Modeling unveils sex differences of signaling networks in mouse embryonic stem cells. 模型揭示了小鼠胚胎干细胞中信号网络的性别差异。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-11-09 Epub Date: 2023-09-21 DOI: 10.15252/msb.202211510

Zeba Sultana, Mathurin Dorel, Bertram Klinger, Anja Sieber, Ilona Dunkel, Nils Blüthgen, Edda G Schulz

{"title":"Modeling unveils sex differences of signaling networks in mouse embryonic stem cells.","authors":"Zeba Sultana, Mathurin Dorel, Bertram Klinger, Anja Sieber, Ilona Dunkel, Nils Blüthgen, Edda G Schulz","doi":"10.15252/msb.202211510","DOIUrl":"10.15252/msb.202211510","url":null,"abstract":"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 dissect X-dosage effects on the signaling network in mESCs, we combine systematic perturbation experiments with mathematical modeling. We quantify the response to a variety of inhibitors and growth factors for cells with one (XO) or two X chromosomes (XX). We then build models of the signaling networks in XX and XO cells through a semi-quantitative modeling approach based on modular response analysis. We identify a novel negative feedback in the PI3K/AKT pathway through GSK3. Moreover, the presence of a single active X makes mESCs more sensitive to the differentiation-promoting Activin A signal and leads to a stronger RAF1-mediated negative feedback in the FGF-triggered MAPK pathway. The differential response to these differentiation-promoting pathways can explain the impaired differentiation propensity of female mESCs.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41145546","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

CellNeighborEX: deciphering neighbor-dependent gene expression from spatial transcriptomics data. CellNeighborEX：从空间转录组学数据中破译邻居依赖性基因表达。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-11-09 Epub Date: 2023-10-10 DOI: 10.15252/msb.202311670

Hyobin Kim, Amit Kumar, Cecilia Lövkvist, António M Palma, Patrick Martin, Junil Kim, Praveen Bhoopathi, Jose Trevino, Paul Fisher, Esha Madan, Rajan Gogna, Kyoung Jae Won

{"title":"CellNeighborEX: deciphering neighbor-dependent gene expression from spatial transcriptomics data.","authors":"Hyobin Kim, Amit Kumar, Cecilia Lövkvist, António M Palma, Patrick Martin, Junil Kim, Praveen Bhoopathi, Jose Trevino, Paul Fisher, Esha Madan, Rajan Gogna, Kyoung Jae Won","doi":"10.15252/msb.202311670","DOIUrl":"10.15252/msb.202311670","url":null,"abstract":"Cells have evolved their communication methods to sense their microenvironments and send biological signals. In addition to communication using ligands and receptors, cells use diverse channels including gap junctions to communicate with their immediate neighbors. Current approaches, however, cannot effectively capture the influence of various microenvironments. Here, we propose a novel approach to investigate cell neighbor-dependent gene expression (CellNeighborEX) in spatial transcriptomics (ST) data. To categorize cells based on their microenvironment, CellNeighborEX uses direct cell location or the mixture of transcriptome from multiple cells depending on ST technologies. For each cell type, CellNeighborEX identifies diverse gene sets associated with partnering cell types, providing further insight. We found that cells express different genes depending on their neighboring cell types in various tissues including mouse embryos, brain, and liver cancer. Those genes are associated with critical biological processes such as development or metastases. We further validated that gene expression is induced by neighboring partners via spatial visualization. The neighbor-dependent gene expression suggests new potential genes involved in cell-cell interactions beyond what ligand-receptor co-expression can discover.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41183096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enablers and challenges of spatial omics, a melting pot of technologies. 空间组学的推动者和挑战，一个技术熔炉。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-11-09 Epub Date: 2023-10-16 DOI: 10.15252/msb.202110571

Theodore Alexandrov, Julio Saez-Rodriguez, Sinem K Saka

引用次数: 0

Canalisation and plasticity on the developmental manifold of Caenorhabditis elegans. 秀丽隐杆线虫发育多样性的渠道化和可塑性。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-11-09 Epub Date: 2023-10-18 DOI: 10.15252/msb.202311835

David J Jordan, Eric A Miska

{"title":"Canalisation and plasticity on the developmental manifold of Caenorhabditis elegans.","authors":"David J Jordan, Eric A Miska","doi":"10.15252/msb.202311835","DOIUrl":"10.15252/msb.202311835","url":null,"abstract":"How do the same mechanisms that faithfully regenerate complex developmental programmes in spite of environmental and genetic perturbations also allow responsiveness to environmental signals, adaptation and genetic evolution? Using the nematode Caenorhabditis elegans as a model, we explore the phenotypic space of growth and development in various genetic and environmental contexts. Our data are growth curves and developmental parameters obtained by automated microscopy. Using these, we show that among the traits that make up the developmental space, correlations within a particular context are predictive of correlations among different contexts. Furthermore, we find that the developmental variability of this animal can be captured on a relatively low-dimensional phenotypic manifold and that on this manifold, genetic and environmental contributions to plasticity can be deconvolved independently. Our perspective offers a new way of understanding the relationship between robustness and flexibility in complex systems, suggesting that projection and concentration of dimension can naturally align these forces as complementary rather than competing.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comprehensive quantitative modeling of translation efficiency in a genome-reduced bacterium. 基因组减少细菌翻译效率的综合定量建模。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-10-12 Epub Date: 2023-08-29 DOI: 10.15252/msb.202211301

Marc Weber, Adrià Sogues, Eva Yus, Raul Burgos, Carolina Gallo, Sira Martínez, Maria Lluch-Senar, Luis Serrano

引用次数: 1

Turning up the heat on essential E. coli genes. 加大对大肠杆菌基本基因的研究力度。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-10-12 Epub Date: 2023-09-18 DOI: 10.15252/msb.202311933

Arun Kumar, Peter C Stirling

引用次数: 0