Molecular Systems Biology最新文献_第3页

Proteomic compensation by paralogs preserves protein interaction networks after gene loss in cancer. 类似物的蛋白质组补偿保留了癌症中基因丢失后的蛋白质相互作用网络。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-28 DOI: 10.1038/s44320-025-00122-4

Anjan Venkatesh, Niall Quinn, Swathi Ramachandra Upadhya, Barbara De Kegel, Alfonso Bolado Carrancio, Thomas Lefeivre, Olivier Dennler, Kieran Wynne, Alexander von Kriegsheim, Colm J Ryan

{"title":"Proteomic compensation by paralogs preserves protein interaction networks after gene loss in cancer.","authors":"Anjan Venkatesh, Niall Quinn, Swathi Ramachandra Upadhya, Barbara De Kegel, Alfonso Bolado Carrancio, Thomas Lefeivre, Olivier Dennler, Kieran Wynne, Alexander von Kriegsheim, Colm J Ryan","doi":"10.1038/s44320-025-00122-4","DOIUrl":"https://doi.org/10.1038/s44320-025-00122-4","url":null,"abstract":"Proteins operate within dense interconnected networks, with interactions necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes, but the underlying mechanisms remain poorly understood. Here, we systematically profile the proteomic response of tumours and cell lines to gene loss. We find many examples of proteomic compensation, where loss of one gene causes increased abundance of a paralog, and collateral loss, where gene loss causes reduced paralog abundance. Compensation is enriched among paralog pairs that are central in the protein-protein interaction network and whose interaction partners perform essential functions. Compensation is also significantly more likely to be observed between synthetic lethal pairs. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells may become dependent on the paralog for survival, creating potentially targetable vulnerabilities.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage. 独特的基因家族进化轨迹从基因组分析几乎所有已知物种在一个古老的酵母谱系。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-27 DOI: 10.1038/s44320-025-00118-0

Bo Feng, Yonglin Li, Biyang Xu, Hongyue Liu, Jacob L Steenwyk, Kyle T David, Xiaolin Tian, Carla Gonçalves, Dana A Opulente, Abigail L LaBella, Marie-Claire Harrison, John F Wolters, Shengyuan Shao, Zhaohao Chen, Kaitlin J Fisher, Marizeth Groenewald, Chris Todd Hittinger, Xing-Xing Shen, Shengying Li, Antonis Rokas, Xiaofan Zhou, Yuanning Li

{"title":"Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage.","authors":"Bo Feng, Yonglin Li, Biyang Xu, Hongyue Liu, Jacob L Steenwyk, Kyle T David, Xiaolin Tian, Carla Gonçalves, Dana A Opulente, Abigail L LaBella, Marie-Claire Harrison, John F Wolters, Shengyuan Shao, Zhaohao Chen, Kaitlin J Fisher, Marizeth Groenewald, Chris Todd Hittinger, Xing-Xing Shen, Shengying Li, Antonis Rokas, Xiaofan Zhou, Yuanning Li","doi":"10.1038/s44320-025-00118-0","DOIUrl":"10.1038/s44320-025-00118-0","url":null,"abstract":"Gene gains and losses are a major driver of genome evolution; their precise characterization can provide insights into the origin and diversification of major lineages. Here, we examined gene family evolution of 1154 genomes from nearly all known species in the medically and technologically important yeast subphylum Saccharomycotina. We found that yeast gene family evolution differs from that of plants, animals, and filamentous ascomycetes, and is characterized by smaller overall gene numbers yet larger gene family sizes for a given gene number. Faster-evolving lineages (FELs) in yeasts experienced significantly higher rates of gene losses-commensurate with a narrowing of metabolic niche breadth-but higher speciation rates than their slower-evolving sister lineages (SELs). Gene families most often lost are those involved in mRNA splicing, carbohydrate metabolism, and cell division and are likely associated with intron loss, metabolic breadth, and non-canonical cell cycle processes. Our results highlight the significant role of gene family contractions in the evolution of yeast metabolism, genome function, and speciation, and suggest that gene family evolutionary trajectories have differed markedly across major eukaryotic lineages.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

hu.MAP3.0: atlas of human protein complexes by integration of >25,000 proteomic experiments. hu.MAP3.0：人类蛋白质复合物图谱，通过整合bbbb25 000个蛋白质组学实验。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-27 DOI: 10.1038/s44320-025-00121-5

Samantha N Fischer, Erin R Claussen, Savvas Kourtis, Sara Sdelci, Sandra Orchard, Henning Hermjakob, Georg Kustatscher, Kevin Drew

{"title":"hu.MAP3.0: atlas of human protein complexes by integration of >25,000 proteomic experiments.","authors":"Samantha N Fischer, Erin R Claussen, Savvas Kourtis, Sara Sdelci, Sandra Orchard, Henning Hermjakob, Georg Kustatscher, Kevin Drew","doi":"10.1038/s44320-025-00121-5","DOIUrl":"10.1038/s44320-025-00121-5","url":null,"abstract":"Macromolecular protein complexes carry out most cellular functions. Unfortunately, we lack the subunit composition for many human protein complexes. To address this gap we integrated >25,000 mass spectrometry experiments using a machine learning approach to identify >15,000 human protein complexes. We show our map of protein complexes is highly accurate and more comprehensive than previous maps, placing nearly 70% of human proteins into their physical contexts. We globally characterize our complexes using mass spectrometry based protein covariation data (ProteomeHD.2) and identify covarying complexes suggesting common functional associations. hu.MAP3.0 generates testable functional hypotheses for 472 uncharacterized proteins which we support using AlphaFold modeling. Additionally, we use AlphaFold modeling to identify 5871 mutually exclusive proteins in hu.MAP3.0 complexes suggesting complexes serve different functional roles depending on their subunit composition. We identify expression as the primary way cells and organisms relieve the conflict of mutually exclusive subunits. Finally, we import our complexes to EMBL-EBI's Complex Portal ( https://www.ebi.ac.uk/complexportal/home ) and provide complexes through our hu.MAP3.0 web interface ( https://humap3.proteincomplexes.org/ ). We expect our resource to be highly impactful to the broader research community.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exogenous prion-like proteins and their potential to trigger cognitive dysfunction. 外源性朊病毒样蛋白及其引发认知功能障碍的可能性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-27 DOI: 10.1038/s44320-025-00114-4

Jofre Seira Curto, Adan Dominguez Martinez, Genis Perez Collell, Estrella Barniol Simon, Marina Romero Ruiz, Berta Franco Bordés, Paula Sotillo Sotillo, Sandra Villegas Hernandez, Maria Rosario Fernandez, Natalia Sanchez de Groot

{"title":"Exogenous prion-like proteins and their potential to trigger cognitive dysfunction.","authors":"Jofre Seira Curto, Adan Dominguez Martinez, Genis Perez Collell, Estrella Barniol Simon, Marina Romero Ruiz, Berta Franco Bordés, Paula Sotillo Sotillo, Sandra Villegas Hernandez, Maria Rosario Fernandez, Natalia Sanchez de Groot","doi":"10.1038/s44320-025-00114-4","DOIUrl":"https://doi.org/10.1038/s44320-025-00114-4","url":null,"abstract":"The gut is exposed to a wide range of proteins, including ingested proteins and those produced by the resident microbiota. While ingested prion-like proteins can propagate across species, their implications for disease development remain largely unknown. Here, we apply a multidisciplinary approach to examine the relationship between the biophysical properties of exogenous prion-like proteins and the phenotypic consequences of ingesting them. Through computational analysis of gut bacterial proteins, we identified an enrichment of prion-like sequences in Helicobacter pylori. Based on these findings, we rationally designed a set of synthetic prion-like sequences that form amyloid fibrils, interfere with amyloid-beta-peptide aggregation, and trigger prion propagation when introduced in the yeast Sup35 model. When C. elegans were fed bacteria expressing these prion-like proteins, they lost associative memory and exhibited increased lipid oxidation. These data suggest a link between memory impairment, the conformational state of aggregates, and oxidative stress. Overall, this work supports gut microbiota as a reservoir of exogenous prion-like sequences, especially H. pylori, and the gut as an entry point for molecules capable of triggering cognitive dysfunction.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mining the heparinome for cryptic antimicrobial peptides that selectively kill Gram-negative bacteria. 挖掘肝素素的隐抗菌肽选择性杀死革兰氏阴性细菌。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-23 DOI: 10.1038/s44320-025-00120-6

Roberto Bello-Madruga, Daniel Sandín, Javier Valle, Jordi Gómez, Laura Comas, María Nieves Larrosa, Juan José González-López, María Ángeles Jiménez, David Andreu, Marc Torrent

{"title":"Mining the heparinome for cryptic antimicrobial peptides that selectively kill Gram-negative bacteria.","authors":"Roberto Bello-Madruga, Daniel Sandín, Javier Valle, Jordi Gómez, Laura Comas, María Nieves Larrosa, Juan José González-López, María Ángeles Jiménez, David Andreu, Marc Torrent","doi":"10.1038/s44320-025-00120-6","DOIUrl":"https://doi.org/10.1038/s44320-025-00120-6","url":null,"abstract":"Glycosaminoglycan (GAG)-binding proteins regulating essential processes such as cell growth and migration are essential for cell homeostasis. As both GAGs and the lipid A disaccharide core of Gram-negative bacteria contain negatively charged disaccharide units, we hypothesized that GAG-binding proteins could also recognize LPS and enclose cryptic antibiotic motifs. Here, we report novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs), with specific activity against Gram-negative bacteria and high LPS binding. We used computational tools to locate antimicrobial regions in 82% of HBPs, most of those colocalizing with putative heparin-binding sites. To validate these results, we synthesized five candidates [HBP-1-5] that showed remarkable activity against Gram-negative bacteria, as well as a strong correlation between heparin and LPS binding. Structural characterization of these AMPs shows that heparin or LPS recognition promotes a conformational arrangement that favors binding. Among all analogs, HBP-5 displayed the highest affinity for both heparin and LPS, with antimicrobial activities against Gram-negative bacteria at the nanomolar range. These results suggest that GAG-binding proteins are involved in LPS recognition, which allows them to act also as antimicrobial proteins. Some of the peptides reported here, particularly HBP-5, constitute a new class of AMPs with specific activity against Gram-negative bacteria.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An enzyme activation network reveals extensive regulatory crosstalk between metabolic pathways. 酶激活网络揭示了代谢途径之间广泛的调控串扰。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-22 DOI: 10.1038/s44320-025-00111-7

Sultana Mohammed Al Zubaidi, Muhammad Ibtisam Nasar, Richard A Notebaart, Markus Ralser, Mohammad Tauqeer Alam

{"title":"An enzyme activation network reveals extensive regulatory crosstalk between metabolic pathways.","authors":"Sultana Mohammed Al Zubaidi, Muhammad Ibtisam Nasar, Richard A Notebaart, Markus Ralser, Mohammad Tauqeer Alam","doi":"10.1038/s44320-025-00111-7","DOIUrl":"https://doi.org/10.1038/s44320-025-00111-7","url":null,"abstract":"Enzyme activation by cellular metabolites plays a pivotal role in regulating metabolic processes. Nevertheless, our comprehension of such activation events on a global network scale remains incomplete. In this study, we conducted a comprehensive investigation into the optimization of cell-intrinsic activation interactions using Saccharomyces cerevisiae metabolic network as the basis of the analysis. To achieve this, we integrated a genome-scale metabolic model with cross-species enzyme kinetic data sourced from the BRENDA database, and to use this model as a basis to estimate the distribution of enzyme activators throughout the cellular network. Our findings indicate that the vast majority of biochemical pathways encompass enzyme activators, frequently originating from disparate pathways, thus revealing extensive regulatory crosstalk between metabolic pathways. Notably, activators have short pathway lengths, indicating they are activated quickly upon nutrient shifts, and in most instances, these activators target key enzymatic reactions to facilitate downstream metabolic processes. Interestingly, highly activated enzymes are substantially enriched with non-essential enzymes compared to their essential counterparts. This observation suggests that cells employ enzyme activators to finely regulate secondary metabolic pathways that are only required under specific conditions. Conversely, the activator metabolites themselves are more likely to be essential components, and their activation levels surpass those of non-essential activators. In summary, our study unveils the widespread importance of enzymatic activators and suggests that feed-forward activation of conditional metabolic pathways through essential metabolites mediates metabolic plasticity.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer. 阻断癌-成纤维细胞的相互作用抑制内分泌治疗抵抗性乳腺癌的增殖。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-08 DOI: 10.1038/s44320-025-00104-6

Jason I Griffiths, Feng Chi, Elena Farmaki, Eric F Medina, Patrick A Cosgrove, Kimya L Karimi, Jinfeng Chen, Vince K Grolmusz, Frederick R Adler, Qamar J Khan, Aritro Nath, Jeffrey T Chang, Andrea H Bild

{"title":"Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer.","authors":"Jason I Griffiths, Feng Chi, Elena Farmaki, Eric F Medina, Patrick A Cosgrove, Kimya L Karimi, Jinfeng Chen, Vince K Grolmusz, Frederick R Adler, Qamar J Khan, Aritro Nath, Jeffrey T Chang, Andrea H Bild","doi":"10.1038/s44320-025-00104-6","DOIUrl":"https://doi.org/10.1038/s44320-025-00104-6","url":null,"abstract":"In early-stage estrogen receptor-positive (ER + ) breast cancer, resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) often involve a shift away from estrogen-driven proliferation. The nature and source of compensatory growth signals driving cancer proliferation remain unknown but represent direct therapeutic targets of resistant cells. By analyzing single-cell RNA-sequencing data from serial biopsies of patient tumors, we elucidated compensatory growth signaling pathways activated in ET + CDK4/6i-resistant cancer cells, along with the intercellular growth signal communications within the tumor microenvironment. In most patient tumors, resistant cancer cells increased ERBB growth pathway activity during treatment, only partially through ERBB receptor upregulation. Concurrently, fibroblasts within the tumor increased ERBB ligand communication with cancer cells, as they differentiated to a proliferative and mesenchymal phenotype in response to TGF <math><mi>β</mi></math> signals from cancer cells. In vitro model systems demonstrated molecularly how therapy induces a mutualistic cycle of crosstalk between cancer cells and fibroblasts, fostering a growth factor-rich tumor microenvironment circumventing estrogen reliance. We show that ERBB inhibition can break this cancer-fibroblasts mutualism, targeting an acquired sensitivity of resistant cancer cells.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extensive folding variability between homologous chromosomes in mammalian cells. 哺乳动物细胞中同源染色体之间广泛的折叠变异性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-06 DOI: 10.1038/s44320-025-00107-3

Ibai Irastorza-Azcarate, Alexander Kukalev, Rieke Kempfer, Christoph J Thieme, Guido Mastrobuoni, Julia Markowski, Gesa Loof, Thomas M Sparks, Emily Brookes, Kedar Nath Natarajan, Stephan Sauer, Amanda G Fisher, Mario Nicodemi, Bing Ren, Roland F Schwarz, Stefan Kempa, Ana Pombo

{"title":"Extensive folding variability between homologous chromosomes in mammalian cells.","authors":"Ibai Irastorza-Azcarate, Alexander Kukalev, Rieke Kempfer, Christoph J Thieme, Guido Mastrobuoni, Julia Markowski, Gesa Loof, Thomas M Sparks, Emily Brookes, Kedar Nath Natarajan, Stephan Sauer, Amanda G Fisher, Mario Nicodemi, Bing Ren, Roland F Schwarz, Stefan Kempa, Ana Pombo","doi":"10.1038/s44320-025-00107-3","DOIUrl":"https://doi.org/10.1038/s44320-025-00107-3","url":null,"abstract":"Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single-nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer-promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, and with Polycomb occupancy. We show that histone genes are expressed with allelic imbalance in mESCs, and are involved in haplotype-specific chromatin contacts marked by H3K27me3. Conditional knockouts of Polycomb enzymatic subunits, Ezh2 or Ring1, show that one-third of ASE genes, including histone genes, is regulated through Polycomb repression. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Constraints on the optimization of gene product diversity. 基因产物多样性优化的制约因素。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-01 Epub Date: 2025-04-10 DOI: 10.1038/s44320-025-00095-4

Daohan Jiang, Nevraj Kejiou, Yi Qiu, Alexander F Palazzo, Matt Pennell

{"title":"Constraints on the optimization of gene product diversity.","authors":"Daohan Jiang, Nevraj Kejiou, Yi Qiu, Alexander F Palazzo, Matt Pennell","doi":"10.1038/s44320-025-00095-4","DOIUrl":"https://doi.org/10.1038/s44320-025-00095-4","url":null,"abstract":"RNA and proteins can have diverse isoforms due to post-transcriptional and post-translational modifications. A fundamental question is whether these isoforms are mostly beneficial or the result of noisy molecular processes. To assess the plausibility of these explanations, we developed mathematical models depicting different regulatory architectures and investigated isoform evolution under multiple population genetic regimes. We found that factors beyond selection, such as effective population size and the number of cis-acting loci, significantly influence evolutionary outcomes. We found that sub-optimal phenotypes are more likely to evolve when populations are small and/or when the number of cis-loci is large. We also discovered that opposing selection on cis- and trans-acting loci can constrain adaptation, leading to a non-monotonic relationship between effective population size and optimization. More generally, our models provide a quantitative framework for developing statistical tests to analyze empirical data; as a demonstration of this, we analyzed A-to-I RNA editing levels in coleoids and found these to be largely consistent with non-adaptive explanations.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"21 5","pages":"472-491"},"PeriodicalIF":8.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044914","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

Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II. 小鼠启动子的特点是RNA聚合酶II的低占用和高周转。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-05-01 Epub Date: 2025-03-31 DOI: 10.1038/s44320-025-00094-5

Kasit Chatsirisupachai, Christina J I Moene, Rozemarijn Kleinendorst, Elisa Kreibich, Nacho Molina, Arnaud Krebs

{"title":"Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II.","authors":"Kasit Chatsirisupachai, Christina J I Moene, Rozemarijn Kleinendorst, Elisa Kreibich, Nacho Molina, Arnaud Krebs","doi":"10.1038/s44320-025-00094-5","DOIUrl":"10.1038/s44320-025-00094-5","url":null,"abstract":"The general transcription machinery and its occupancy at promoters are highly conserved across metazoans. This contrasts with the kinetics of mRNA production that considerably differ between model species such as Drosophila and mouse. The molecular basis for these kinetic differences is currently unknown. Here, we used Single-Molecule Footprinting to measure RNA Polymerase II (Pol II) occupancy, the fraction of DNA molecules bound, at promoters in mouse and Drosophila cell lines. Single-molecule data reveals that Pol II occupancy is on average 3-5 times more frequent at transcriptionally active Drosophila promoters than active mouse promoters. Kinetic modelling of the occupancy states suggests that these differences in Pol II occupancy are determined by the ratio between the transcription initiation and Pol II turnover rates. We used chemical perturbation of transcription initiation to determine Pol II turnover rate in both species. Integration of these data into the model shows that infrequent Pol II occupancy in mouse is explained by the combination of high Pol II turnover and low transcription initiation rates.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"447-471"},"PeriodicalIF":8.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753626","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