Molecular Systems Biology最新文献_第8页

Hotspot propensity across mutational processes. 不同突变过程中的热点倾向

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-01-01 Epub Date: 2023-12-20 DOI: 10.1038/s44320-023-00001-w

Claudia Arnedo-Pac, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas

{"title":"Hotspot propensity across mutational processes.","authors":"Claudia Arnedo-Pac, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas","doi":"10.1038/s44320-023-00001-w","DOIUrl":"10.1038/s44320-023-00001-w","url":null,"abstract":"The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"20 1","pages":"6-27"},"PeriodicalIF":9.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098307","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

What we can learn from deep space communication for reproducible bioimaging and data analysis 我们能从深空通信中学到什么，以实现可重现的生物成像和数据分析

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-13 DOI: 10.1038/s44320-023-00002-9

Tatiana Woller, Christopher J Cawthorne, Romain Raymond Agnes Slootmaekers, Ingrid Barcena Roig, Alexander Botzki, Sebastian Munck

引用次数: 0

A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration. 多层网络模型确定Akt1是神经退行性变的共同调节剂。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-20 DOI: 10.15252/msb.202311801

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

{"title":"A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.","authors":"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","doi":"10.15252/msb.202311801","DOIUrl":"10.15252/msb.202311801","url":null,"abstract":"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 protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3β), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11801"},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176810","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

Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data. 评估E。大肠杆菌基因组规模代谢模型的准确性与高通量突变适应度数据。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-10-27 DOI: 10.15252/msb.202311566

David B Bernstein, Batu Akkas, Morgan N Price, Adam P Arkin

{"title":"Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data.","authors":"David B Bernstein, Batu Akkas, Morgan N Price, Adam P Arkin","doi":"10.15252/msb.202311566","DOIUrl":"10.15252/msb.202311566","url":null,"abstract":"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 25 different carbon sources. This evaluation demonstrated the utility of the area under a precision-recall curve relative to alternative accuracy metrics. An analysis of errors in the latest (iML1515) model identified several vitamins/cofactors that are likely available to mutants despite being absent from the experimental growth medium and highlighted isoenzyme gene-protein-reaction mapping as a key source of inaccurate predictions. A machine learning approach further identified metabolic fluxes through hydrogen ion exchange and specific central metabolism branch points as important determinants of model accuracy. This work outlines improved practices for the assessment of GEM accuracy with high-throughput mutant fitness data and highlights promising areas for future model refinement in E. coli and beyond.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11566"},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230090","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

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":" ","pages":"e11987"},"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":" ","pages":"e11462"},"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":" ","pages":"e11782"},"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":" ","pages":"e11657"},"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":" ","pages":"e11510"},"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

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