NPJ Systems Biology and Applications最新文献_第5页

Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways. 多组学揭示了果糖胺-3-激酶（FN3K）与核心代谢途径之间的新联系。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-06-03 DOI: 10.1038/s41540-024-00390-0

Safal Shrestha, Rahil Taujale, Samiksha Katiyar, Natarajan Kannan

{"title":"Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.","authors":"Safal Shrestha, Rahil Taujale, Samiksha Katiyar, Natarajan Kannan","doi":"10.1038/s41540-024-00390-0","DOIUrl":"10.1038/s41540-024-00390-0","url":null,"abstract":"Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the Tree of Life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) HepG2 cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), and carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3K and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. Our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance and NAD-dependent metabolic processes are altered.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Integrated omics of Saccharomyces cerevisiae CENPK2-1C reveals pleiotropic drug resistance and lipidomic adaptations to cannabidiol. 酿酒酵母 CENPK2-1C 的综合全局分析揭示了对大麻二酚的多向性耐药性和脂质体适应性。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-31 DOI: 10.1038/s41540-024-00382-0

Erin Noel Jordan, Ramin Shirali Hossein Zade, Stephanie Pillay, Paul van Lent, Thomas Abeel, Oliver Kayser

{"title":"Integrated omics of Saccharomyces cerevisiae CENPK2-1C reveals pleiotropic drug resistance and lipidomic adaptations to cannabidiol.","authors":"Erin Noel Jordan, Ramin Shirali Hossein Zade, Stephanie Pillay, Paul van Lent, Thomas Abeel, Oliver Kayser","doi":"10.1038/s41540-024-00382-0","DOIUrl":"10.1038/s41540-024-00382-0","url":null,"abstract":"Yeast metabolism can be engineered to produce xenobiotic compounds, such as cannabinoids, the principal isoprenoids of the plant Cannabis sativa, through heterologous metabolic pathways. However, yeast cell factories continue to have low cannabinoid production. This study employed an integrated omics approach to investigate the physiological effects of cannabidiol on S. cerevisiae CENPK2-1C yeast cultures. We treated the experimental group with 0.5 mM CBD and monitored CENPK2-1C cultures. We observed a latent-stationary phase post-diauxic shift in the experimental group and harvested samples in the inflection point of this growth phase for transcriptomic and metabolomic analysis. We compared the transcriptomes of the CBD-treated yeast and the positive control, identifying eight significantly overexpressed genes with a log fold change of at least 1.5 and a significant adjusted p-value. Three notable genes were PDR5 (an ABC-steroid and cation transporter), CIS1, and YGR035C. These genes are all regulated by pleiotropic drug resistance linked promoters. Knockout and rescue of PDR5 showed that it is a causal factor in the post-diauxic shift phenotype. Metabolomic analysis revealed 48 significant spectra associated with CBD-fed cell pellets, 20 of which were identifiable as non-CBD compounds, including fatty acids, glycerophospholipids, and phosphate-salvage indicators. Our results suggest that mitochondrial regulation and lipidomic remodeling play a role in yeast's response to CBD, which are employed in tandem with pleiotropic drug resistance (PDR). We conclude that bioengineers should account for off-target product C-flux, energy use from ABC-transport, and post-stationary phase cell growth when developing cannabinoid-biosynthetic yeast strains.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11143246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of drug responsive enhancers by predicting chromatin accessibility change from perturbed gene expression profiles. 通过预测扰乱基因表达谱的染色质可及性变化来识别药物反应增强子。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-30 DOI: 10.1038/s41540-024-00388-8

Yongcui Wang, Yong Wang

{"title":"Identification of drug responsive enhancers by predicting chromatin accessibility change from perturbed gene expression profiles.","authors":"Yongcui Wang, Yong Wang","doi":"10.1038/s41540-024-00388-8","DOIUrl":"10.1038/s41540-024-00388-8","url":null,"abstract":"Individual may response to drug treatment differently due to their genetic variants located in enhancers. These variants can alter transcription factor's (TF) binding strength, affect enhancer's chromatin activity or interaction, and eventually change expression level of downstream gene. Here, we propose a computational framework, PERD, to Predict the Enhancers Responsive to Drug. A machine learning model was trained to predict the genome-wide chromatin accessibility from transcriptome data using the paired expression and chromatin accessibility data collected from ENCODE and ROADMAP. Then the model was applied to the perturbed gene expression data from Connectivity Map (CMAP) and Cancer Drug-induced gene expression Signature DataBase (CDS-DB) and identify drug responsive enhancers with significantly altered chromatin accessibility. Furthermore, the drug responsive enhancers were related to the pharmacogenomics genome-wide association studies (PGx GWAS). Stepping on the traditional drug-associated gene signatures, PERD holds the promise to enhance the causality of drug perturbation by providing candidate regulatory element of those drug associated genes.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The art of modeling gene regulatory circuits. 基因调控回路建模艺术。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-29 DOI: 10.1038/s41540-024-00380-2

Mariana Gómez-Schiavon, Isabel Montejano-Montelongo, F Sophia Orozco-Ruiz, Cristina Sotomayor-Vivas

引用次数: 0

Inferring upstream regulatory genes of FOXP3 in human regulatory T cells from time-series transcriptomic data. 从时间序列转录组数据推断人类调节性 T 细胞中 FOXP3 的上游调控基因

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-29 DOI: 10.1038/s41540-024-00387-9

Stefano Magni, Rucha Sawlekar, Christophe M Capelle, Vera Tslaf, Alexandre Baron, Ni Zeng, Laurent Mombaerts, Zuogong Yue, Ye Yuan, Feng Q Hefeng, Jorge Gonçalves

{"title":"Inferring upstream regulatory genes of FOXP3 in human regulatory T cells from time-series transcriptomic data.","authors":"Stefano Magni, Rucha Sawlekar, Christophe M Capelle, Vera Tslaf, Alexandre Baron, Ni Zeng, Laurent Mombaerts, Zuogong Yue, Ye Yuan, Feng Q Hefeng, Jorge Gonçalves","doi":"10.1038/s41540-024-00387-9","DOIUrl":"10.1038/s41540-024-00387-9","url":null,"abstract":"The discovery of upstream regulatory genes of a gene of interest still remains challenging. Here we applied a scalable computational method to unbiasedly predict candidate regulatory genes of critical transcription factors by searching the whole genome. We illustrated our approach with a case study on the master regulator FOXP3 of human primary regulatory T cells (Tregs). While target genes of FOXP3 have been identified, its upstream regulatory machinery still remains elusive. Our methodology selected five top-ranked candidates that were tested via proof-of-concept experiments. Following knockdown, three out of five candidates showed significant effects on the mRNA expression of FOXP3 across multiple donors. This provides insights into the regulatory mechanisms modulating FOXP3 transcriptional expression in Tregs. Overall, at the genome level this represents a high level of accuracy in predicting upstream regulatory genes of key genes of interest.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Mechanisms of cell size regulation in slow-growing Escherichia coli cells: discriminating models beyond the adder. 缓慢生长的大肠杆菌细胞大小调节机制：加法器之外的判别模型。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-29 DOI: 10.1038/s41540-024-00383-z

César Nieto, César Augusto Vargas-García, Juan Manuel Pedraza, Abhyudai Singh

{"title":"Mechanisms of cell size regulation in slow-growing Escherichia coli cells: discriminating models beyond the adder.","authors":"César Nieto, César Augusto Vargas-García, Juan Manuel Pedraza, Abhyudai Singh","doi":"10.1038/s41540-024-00383-z","DOIUrl":"10.1038/s41540-024-00383-z","url":null,"abstract":"Under ideal conditions, Escherichia coli cells divide after adding a fixed cell size, a strategy known as the adder. This concept applies to various microbes and is often explained as the division that occurs after a certain number of stages, associated with the accumulation of precursor proteins at a rate proportional to cell size. However, under poor media conditions, E. coli cells exhibit a different size regulation. They are smaller and follow a sizer-like division strategy where the added size is inversely proportional to the size at birth. We explore three potential causes for this deviation: degradation of the precursor protein and two models where the propensity for accumulation depends on the cell size: a nonlinear accumulation rate, and accumulation starting at a threshold size termed the commitment size. These models fit the mean trends but predict different distributions given the birth size. To quantify the precision of the models to explain the data, we used the Akaike information criterion and compared them to open datasets of slow-growing E. coli cells in different media. We found that none of the models alone can consistently explain the data. However, the degradation model better explains the division strategy when cells are larger, whereas size-related models (power-law and commitment size) account for smaller cells. Our methodology proposes a data-based method in which different mechanisms can be tested systematically.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Flexible modeling of regulatory networks improves transcription factor activity estimation. 灵活的调控网络建模改进了转录因子活性估计。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-28 DOI: 10.1038/s41540-024-00386-w

Chen Chen, Megha Padi

{"title":"Flexible modeling of regulatory networks improves transcription factor activity estimation.","authors":"Chen Chen, Megha Padi","doi":"10.1038/s41540-024-00386-w","DOIUrl":"10.1038/s41540-024-00386-w","url":null,"abstract":"Transcriptional regulation plays a crucial role in determining cell fate and disease, yet inferring the key regulators from gene expression data remains a significant challenge. Existing methods for estimating transcription factor (TF) activity often rely on static TF-gene interaction databases and cannot adapt to changes in regulatory mechanisms across different cell types and disease conditions. Here, we present a new algorithm - Transcriptional Inference using Gene Expression and Regulatory data (TIGER) - that overcomes these limitations by flexibly modeling activation and inhibition events, up-weighting essential edges, shrinking irrelevant edges towards zero through a sparse Bayesian prior, and simultaneously estimating both TF activity levels and changes in the underlying regulatory network. When applied to yeast and cancer TF knock-out datasets, TIGER outperforms comparable methods in terms of prediction accuracy. Moreover, our application of TIGER to tissue- and cell-type-specific RNA-seq data demonstrates its ability to uncover differences in regulatory mechanisms. Collectively, our findings highlight the utility of modeling context-specific regulation when inferring transcription factor activities.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11133322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Enhancing mass spectrometry imaging accessibility using convolutional autoencoders for deriving hypoxia-associated peptides from tumors. 利用卷积自动编码器提高质谱成像的可及性，从肿瘤中提取缺氧相关肽。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-27 DOI: 10.1038/s41540-024-00385-x

Verena Bitto, Pia Hönscheid, María José Besso, Christian Sperling, Ina Kurth, Michael Baumann, Benedikt Brors

{"title":"Enhancing mass spectrometry imaging accessibility using convolutional autoencoders for deriving hypoxia-associated peptides from tumors.","authors":"Verena Bitto, Pia Hönscheid, María José Besso, Christian Sperling, Ina Kurth, Michael Baumann, Benedikt Brors","doi":"10.1038/s41540-024-00385-x","DOIUrl":"10.1038/s41540-024-00385-x","url":null,"abstract":"Mass spectrometry imaging (MSI) allows to study cancer's intratumoral heterogeneity through spatially-resolved peptides, metabolites and lipids. Yet, in biomedical research MSI is rarely used for biomarker discovery. Besides its high dimensionality and multicollinearity, mass spectrometry (MS) technologies typically output mass-to-charge ratio values but not the biochemical compounds of interest. Our framework makes particularly low-abundant signals in MSI more accessible. We utilized convolutional autoencoders to aggregate features associated with tumor hypoxia, a parameter with significant spatial heterogeneity, in cancer xenograft models. We highlight that MSI captures these low-abundant signals and that autoencoders can preserve them in their latent space. The relevance of individual hyperparameters is demonstrated through ablation experiments, and the contribution from original features to latent features is unraveled. Complementing MSI with tandem MS from the same tumor model, multiple hypoxia-associated peptide candidates were derived. Compared to random forests alone, our autoencoder approach yielded more biologically relevant insights for biomarker discovery.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Extending PROXIMAL to predict degradation pathways of phenolic compounds in the human gut microbiota. 扩展 PROXIMAL 预测人类肠道微生物群中酚类化合物的降解途径。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-27 DOI: 10.1038/s41540-024-00381-1

Francesco Balzerani, Telmo Blasco, Sergio Pérez-Burillo, Luis V Valcarcel, Soha Hassoun, Francisco J Planes

{"title":"Extending PROXIMAL to predict degradation pathways of phenolic compounds in the human gut microbiota.","authors":"Francesco Balzerani, Telmo Blasco, Sergio Pérez-Burillo, Luis V Valcarcel, Soha Hassoun, Francisco J Planes","doi":"10.1038/s41540-024-00381-1","DOIUrl":"10.1038/s41540-024-00381-1","url":null,"abstract":"Despite significant advances in reconstructing genome-scale metabolic networks, the understanding of cellular metabolism remains incomplete for many organisms. A promising approach for elucidating cellular metabolism is analysing the full scope of enzyme promiscuity, which exploits the capacity of enzymes to bind to non-annotated substrates and generate novel reactions. To guide time-consuming costly experimentation, different computational methods have been proposed for exploring enzyme promiscuity. One relevant algorithm is PROXIMAL, which strongly relies on KEGG to define generic reaction rules and link specific molecular substructures with associated chemical transformations. Here, we present a completely new pipeline, PROXIMAL2, which overcomes the dependency on KEGG data. In addition, PROXIMAL2 introduces two relevant improvements with respect to the former version: i) correct treatment of multi-step reactions and ii) tracking of electric charges in the transformations. We compare PROXIMAL and PROXIMAL2 in recovering annotated products from substrates in KEGG reactions, finding a highly significant improvement in the level of accuracy. We then applied PROXIMAL2 to predict degradation reactions of phenolic compounds in the human gut microbiota. The results were compared to RetroPath RL, a different and relevant enzyme promiscuity method. We found a significant overlap between these two methods but also complementary results, which open new research directions into this relevant question in nutrition.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 negative feedback loop underlies the Warburg effect. 负反馈回路是沃伯格效应的基础。

IF 4 2区生物学

NPJ Systems Biology and Applications Pub Date : 2024-05-24 DOI: 10.1038/s41540-024-00377-x

Alok Jaiswal, Raghvendra Singh

引用次数: 0