Mathis Wolter, Erica T Grant, Marie Boudaud, Nicholas A Pudlo, Gabriel V Pereira, Kathryn A Eaton, Eric C Martens, Mahesh S Desai
{"title":"Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility.","authors":"Mathis Wolter, Erica T Grant, Marie Boudaud, Nicholas A Pudlo, Gabriel V Pereira, Kathryn A Eaton, Eric C Martens, Mahesh S Desai","doi":"10.1038/s44320-024-00036-7","DOIUrl":"10.1038/s44320-024-00036-7","url":null,"abstract":"<p><p>The erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen, Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show that Akkermansia muciniphila renders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence of A. muciniphila reduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities of A. muciniphila and other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"596-625"},"PeriodicalIF":8.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922754","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}
Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli
{"title":"An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors.","authors":"Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli","doi":"10.1038/s44320-024-00040-x","DOIUrl":"10.1038/s44320-024-00040-x","url":null,"abstract":"<p><p>More than 500 kinases are implicated in the control of most cellular process in mammals, and deregulation of their activity is linked to cancer and inflammatory disorders. 80 clinical kinase inhibitors (CKIs) have been approved for clinical use and hundreds are in various stages of development. However, CKIs inhibit other kinases in addition to the intended target(s), causing both enhanced clinical effects and undesired side effects that are only partially predictable based on in vitro selectivity profiling. Here, we report an integrative approach grounded on the use of chromatin modifications as unbiased, information-rich readouts of the functional effects of CKIs on macrophage activation. This approach exceeded the performance of transcriptome-based approaches and allowed us to identify similarities and differences among CKIs with identical intended targets, to recognize novel CKI specificities and to pinpoint CKIs that may be repurposed to control inflammation, thus supporting the utility of this strategy to improve selection and use of CKIs in clinical settings.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"626-650"},"PeriodicalIF":9.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897948","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}
Ian Hoskins, Shilpa Rao, Charisma Tante, Can Cenik
{"title":"Integrated multiplexed assays of variant effect reveal determinants of catechol-O-methyltransferase gene expression.","authors":"Ian Hoskins, Shilpa Rao, Charisma Tante, Can Cenik","doi":"10.1038/s44320-024-00018-9","DOIUrl":"10.1038/s44320-024-00018-9","url":null,"abstract":"<p><p>Multiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase or decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped the cis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alter COMT expression. Finally, we trained machine learning models to map signatures of variant effects on COMT gene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants in COMT and highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"481-505"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735666","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}
Pedro Tomaz da Silva, Yujie Zhang, Evangelos Theodorakis, Laura D Martens, Vicente A Yépez, Vicent Pelechano, Julien Gagneur
{"title":"Cellular energy regulates mRNA degradation in a codon-specific manner.","authors":"Pedro Tomaz da Silva, Yujie Zhang, Evangelos Theodorakis, Laura D Martens, Vicente A Yépez, Vicent Pelechano, Julien Gagneur","doi":"10.1038/s44320-024-00026-9","DOIUrl":"10.1038/s44320-024-00026-9","url":null,"abstract":"<p><p>Codon optimality is a major determinant of mRNA translation and degradation rates. However, whether and through which mechanisms its effects are regulated remains poorly understood. Here we show that codon optimality associates with up to 2-fold change in mRNA stability variations between human tissues, and that its effect is attenuated in tissues with high energy metabolism and amplifies with age. Mathematical modeling and perturbation data through oxygen deprivation and ATP synthesis inhibition reveal that cellular energy variations non-uniformly alter the effect of codon usage. This new mode of codon effect regulation, independent of tRNA regulation, provides a fundamental mechanistic link between cellular energy metabolism and eukaryotic gene expression.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"506-520"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140485","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}
Angel F Cisneros, Lou Nielly-Thibault, Saurav Mallik, Emmanuel D Levy, Christian R Landry
{"title":"Mutational biases favor complexity increases in protein interaction networks after gene duplication.","authors":"Angel F Cisneros, Lou Nielly-Thibault, Saurav Mallik, Emmanuel D Levy, Christian R Landry","doi":"10.1038/s44320-024-00030-z","DOIUrl":"10.1038/s44320-024-00030-z","url":null,"abstract":"<p><p>Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"549-572"},"PeriodicalIF":8.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158556","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}
Mie Monti, Reyme Herman, Leonardo Mancini, Charlotte Capitanchik, Karen Davey, Charlotte S Dawson, Jernej Ule, Gavin H Thomas, Anne E Willis, Kathryn S Lilley, Eneko Villanueva
{"title":"Interrogation of RNA-protein interaction dynamics in bacterial growth.","authors":"Mie Monti, Reyme Herman, Leonardo Mancini, Charlotte Capitanchik, Karen Davey, Charlotte S Dawson, Jernej Ule, Gavin H Thomas, Anne E Willis, Kathryn S Lilley, Eneko Villanueva","doi":"10.1038/s44320-024-00031-y","DOIUrl":"10.1038/s44320-024-00031-y","url":null,"abstract":"<p><p>Characterising RNA-protein interaction dynamics is fundamental to understand how bacteria respond to their environment. In this study, we have analysed the dynamics of 91% of the Escherichia coli expressed proteome and the RNA-interaction properties of 271 RNA-binding proteins (RBPs) at different growth phases. We find that 68% of RBPs differentially bind RNA across growth phases and characterise 17 previously unannotated proteins as bacterial RBPs including YfiF, a ncRNA-binding protein. While these new RBPs are mostly present in Proteobacteria, two of them are orthologs of human mitochondrial proteins associated with rare metabolic disorders. Moreover, we reveal novel RBP functions for proteins such as the chaperone HtpG, a new stationary phase tRNA-binding protein. For the first time, the dynamics of the bacterial RBPome have been interrogated, showcasing how this approach can reveal the function of uncharacterised proteins and identify critical RNA-protein interactions for cell growth which could inform new antimicrobial therapies.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"573-589"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140294055","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}
Anastasia Razdaibiedina, Alexander Brechalov, Helena Friesen, Mojca Mattiazzi Usaj, Myra Paz David Masinas, Harsha Garadi Suresh, Kyle Wang, Charles Boone, Jimmy Ba, Brenda Andrews
{"title":"PIFiA: self-supervised approach for protein functional annotation from single-cell imaging data.","authors":"Anastasia Razdaibiedina, Alexander Brechalov, Helena Friesen, Mojca Mattiazzi Usaj, Myra Paz David Masinas, Harsha Garadi Suresh, Kyle Wang, Charles Boone, Jimmy Ba, Brenda Andrews","doi":"10.1038/s44320-024-00029-6","DOIUrl":"10.1038/s44320-024-00029-6","url":null,"abstract":"<p><p>Fluorescence microscopy data describe protein localization patterns at single-cell resolution and have the potential to reveal whole-proteome functional information with remarkable precision. Yet, extracting biologically meaningful representations from cell micrographs remains a major challenge. Existing approaches often fail to learn robust and noise-invariant features or rely on supervised labels for accurate annotations. We developed PIFiA (Protein Image-based Functional Annotation), a self-supervised approach for protein functional annotation from single-cell imaging data. We imaged the global yeast ORF-GFP collection and applied PIFiA to generate protein feature profiles from single-cell images of fluorescently tagged proteins. We show that PIFiA outperforms existing approaches for molecular representation learning and describe a range of downstream analysis tasks to explore the information content of the feature profiles. Specifically, we cluster extracted features into a hierarchy of functional organization, study cell population heterogeneity, and develop techniques to distinguish multi-localizing proteins and identify functional modules. Finally, we confirm new PIFiA predictions using a colocalization assay, suggesting previously unappreciated biological roles for several proteins. Paired with a fully interactive website ( https://thecellvision.org/pifia/ ), PIFiA is a resource for the quantitative analysis of protein organization within the cell.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"521-548"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110698","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}
{"title":"Systematic identification of 20S proteasome substrates.","authors":"Monika Pepelnjak, Rivkah Rogawski, Galina Arkind, Yegor Leushkin, Irit Fainer, Gili Ben-Nissan, Paola Picotti, Michal Sharon","doi":"10.1038/s44320-024-00015-y","DOIUrl":"10.1038/s44320-024-00015-y","url":null,"abstract":"<p><p>For years, proteasomal degradation was predominantly attributed to the ubiquitin-26S proteasome pathway. However, it is now evident that the core 20S proteasome can independently target proteins for degradation. With approximately half of the cellular proteasomes comprising free 20S complexes, this degradation mechanism is not rare. Identifying 20S-specific substrates is challenging due to the dual-targeting of some proteins to either 20S or 26S proteasomes and the non-specificity of proteasome inhibitors. Consequently, knowledge of 20S proteasome substrates relies on limited hypothesis-driven studies. To comprehensively explore 20S proteasome substrates, we employed advanced mass spectrometry, along with biochemical and cellular analyses. This systematic approach revealed hundreds of 20S proteasome substrates, including proteins undergoing specific N- or C-terminal cleavage, possibly for regulation. Notably, these substrates were enriched in RNA- and DNA-binding proteins with intrinsically disordered regions, often found in the nucleus and stress granules. Under cellular stress, we observed reduced proteolytic activity in oxidized proteasomes, with oxidized protein substrates exhibiting higher structural disorder compared to unmodified proteins. Overall, our study illuminates the nature of 20S substrates, offering crucial insights into 20S proteasome biology.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"403-427"},"PeriodicalIF":9.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576211","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}
Amrisha Bhosle, Sena Bae, Yancong Zhang, Eunyoung Chun, Julian Avila-Pacheco, Ludwig Geistlinger, Gleb Pishchany, Jonathan N Glickman, Monia Michaud, Levi Waldron, Clary B Clish, Ramnik J Xavier, Hera Vlamakis, Eric A Franzosa, Wendy S Garrett, Curtis Huttenhower
{"title":"Integrated annotation prioritizes metabolites with bioactivity in inflammatory bowel disease.","authors":"Amrisha Bhosle, Sena Bae, Yancong Zhang, Eunyoung Chun, Julian Avila-Pacheco, Ludwig Geistlinger, Gleb Pishchany, Jonathan N Glickman, Monia Michaud, Levi Waldron, Clary B Clish, Ramnik J Xavier, Hera Vlamakis, Eric A Franzosa, Wendy S Garrett, Curtis Huttenhower","doi":"10.1038/s44320-024-00027-8","DOIUrl":"10.1038/s44320-024-00027-8","url":null,"abstract":"<p><p>Microbial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP/HMP2) metabolomes, using a newly developed methodology for bioactive compound prioritization from microbial communities. This suggested >1000 metabolic features as potentially bioactive in IBD and associated ~43% of prevalent, unannotated features with at least one well-characterized metabolite, thereby providing initial information for further characterization of a significant portion of the fecal metabolome. Prioritized features included known IBD-linked chemical families such as bile acids and short-chain fatty acids, and less-explored bilirubin, polyamine, and vitamin derivatives, and other microbial products. One of these, nicotinamide riboside, reduced colitis scores in DSS-treated mice. The method, MACARRoN, is generalizable with the potential to improve microbial community characterization and provide therapeutic candidates.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"338-361"},"PeriodicalIF":8.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101972","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}
Andreas Tsouris, Gauthier Brach, Anne Friedrich, Jing Hou, Joseph Schacherer
{"title":"Diallel panel reveals a significant impact of low-frequency genetic variants on gene expression variation in yeast.","authors":"Andreas Tsouris, Gauthier Brach, Anne Friedrich, Jing Hou, Joseph Schacherer","doi":"10.1038/s44320-024-00021-0","DOIUrl":"10.1038/s44320-024-00021-0","url":null,"abstract":"<p><p>Unraveling the genetic sources of gene expression variation is essential to better understand the origins of phenotypic diversity in natural populations. Genome-wide association studies identified thousands of variants involved in gene expression variation, however, variants detected only explain part of the heritability. In fact, variants such as low-frequency and structural variants (SVs) are poorly captured in association studies. To assess the impact of these variants on gene expression variation, we explored a half-diallel panel composed of 323 hybrids originated from pairwise crosses of 26 natural Saccharomyces cerevisiae isolates. Using short- and long-read sequencing strategies, we established an exhaustive catalog of single nucleotide polymorphisms (SNPs) and SVs for this panel. Combining this dataset with the transcriptomes of all hybrids, we comprehensively mapped SNPs and SVs associated with gene expression variation. While SVs impact gene expression variation, SNPs exhibit a higher effect size with an overrepresentation of low-frequency variants compared to common ones. These results reinforce the importance of dissecting the heritability of complex traits with a comprehensive catalog of genetic variants at the population level.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"362-373"},"PeriodicalIF":8.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735665","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}