Molecular Systems Biology最新文献_第5页

Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression. 动态多组学和机制建模方法揭示了肾纤维化进展的新机制。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-06-05 DOI: 10.1038/s44320-025-00116-2

Nadine Tuechler, Mira Lea Burtscher, Martin Garrido-Rodriguez, Muzamil Majid Khan, Dénes Türei, Christian Tischer, Sarah Kaspar, Jennifer Jasmin Schwarz, Frank Stein, Mandy Rettel, Rafael Kramann, Mikhail M Savitski, Julio Saez-Rodriguez, Rainer Pepperkok

{"title":"Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression.","authors":"Nadine Tuechler, Mira Lea Burtscher, Martin Garrido-Rodriguez, Muzamil Majid Khan, Dénes Türei, Christian Tischer, Sarah Kaspar, Jennifer Jasmin Schwarz, Frank Stein, Mandy Rettel, Rafael Kramann, Mikhail M Savitski, Julio Saez-Rodriguez, Rainer Pepperkok","doi":"10.1038/s44320-025-00116-2","DOIUrl":"10.1038/s44320-025-00116-2","url":null,"abstract":"Kidney fibrosis, characterized by excessive extracellular matrix deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. This study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells aimed at unraveling disease mechanisms. Using transcriptomics, proteomics, phosphoproteomics, and secretomics, we quantified over 14,000 biomolecules across seven time points following TGF-β stimulation. This revealed distinct temporal patterns in the expression and activity of known and potential kidney fibrosis markers and modulators. Data integration resulted in time-resolved multi-omic network models which allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and regulatory mechanisms underlying kidney fibrosis. In particular, we show that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a resource to be further leveraged by the community.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1030-1065"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234581","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

Spatial entropy drives the maintenance and dissemination of transferable plasmids. 空间熵驱动可转移质粒的维持和传播。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-07-01 Epub Date: 2025-04-29 DOI: 10.1038/s44320-025-00110-8

Wenzhi Xue, Juken Hong, Runmeng Zhao, Huaxiong Yao, Yi Zhang, Zhuojun Dai, Teng Wang

{"title":"Spatial entropy drives the maintenance and dissemination of transferable plasmids.","authors":"Wenzhi Xue, Juken Hong, Runmeng Zhao, Huaxiong Yao, Yi Zhang, Zhuojun Dai, Teng Wang","doi":"10.1038/s44320-025-00110-8","DOIUrl":"10.1038/s44320-025-00110-8","url":null,"abstract":"The dissemination of transferable plasmids, a major type of mobile genetic elements (MGEs), is one main driver of antibiotic resistance outbreaks. While the plasmid persistence condition in well-mixed environments has been extensively studied, most microbiota in nature are spatially heterogeneous. However, our knowledge regarding how spatial landscape shapes plasmid maintenance and dissemination remains limited. Here we establish a theoretical framework describing plasmid spread over a metacommunity of multiple patches. By analyzing the gene flow dynamics on randomly generated landscapes, we show that plasmid survival and dispersal are dictated by a simple feature of the landscape, spatial entropy. Reducing entropy speeds up plasmid range expansion and allows the global maintenance of many plasmids that are predicted to be lost by classic theories. The entropy's effects are experimentally validated in E. coli metacommunities transferring a conjugative plasmid. We further examine a vast collection of prokaryotic genomes and show that prokaryotes from low-entropy environments indeed carry more abundant MGEs and antibiotic resistance genes. Our work provides critical insights into the management and control of antimicrobial resistance.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"856-869"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013882","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

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 : 2025-07-01 Epub 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":"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":"889-910"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223310/pdf/","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":"OA","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 : 2025-07-01 Epub 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":"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":"825-855"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222798/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse. 结直肠肿瘤的蛋白质组学鉴定CAVIN1在肿瘤复发中的作用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-07-01 Epub Date: 2025-04-23 DOI: 10.1038/s44320-025-00102-8

Ana Martinez-Val, Leander Van der Hoeven, Dorte B Bekker-Jensen, Margarita Melnikova Jørgensen, Jesper Nors, Giulia Franciosa, Claus L Andersen, Jesper B Bramsen, Jesper V Olsen

{"title":"Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse.","authors":"Ana Martinez-Val, Leander Van der Hoeven, Dorte B Bekker-Jensen, Margarita Melnikova Jørgensen, Jesper Nors, Giulia Franciosa, Claus L Andersen, Jesper B Bramsen, Jesper V Olsen","doi":"10.1038/s44320-025-00102-8","DOIUrl":"10.1038/s44320-025-00102-8","url":null,"abstract":"Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"776-806"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002186","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

BaCoN (Balanced Correlation Network) improves prediction of gene buffering. BaCoN （Balanced Correlation Network）改进了基因缓冲的预测。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-07-01 Epub Date: 2025-04-22 DOI: 10.1038/s44320-025-00103-7

Thomas Rohde, Talip Yasir Demirtas, Sebastian Süsser, Angela Helen Shaw, Manuel Kaulich, Maximilian Billmann

{"title":"BaCoN (Balanced Correlation Network) improves prediction of gene buffering.","authors":"Thomas Rohde, Talip Yasir Demirtas, Sebastian Süsser, Angela Helen Shaw, Manuel Kaulich, Maximilian Billmann","doi":"10.1038/s44320-025-00103-7","DOIUrl":"10.1038/s44320-025-00103-7","url":null,"abstract":"Buffering between genes, where one gene can compensate for the loss of another gene, is fundamental for robust cellular functions. While experimentally testing all possible gene pairs is infeasible, gene buffering can be predicted genome-wide under the assumption that a gene's buffering capacity depends on its expression level and its absence primes a severe fitness phenotype of the buffered gene. We developed BaCoN (Balanced Correlation Network), a post hoc unsupervised correction method that amplifies specific signals in expression-vs-fitness correlation networks. We quantified 147 million potential buffering relationships by associating CRISPR-Cas9-screening fitness effects with transcriptomic data across 1019 Cancer Dependency Map (DepMap) cell lines. BaCoN outperformed state-of-the-art methods, including multiple linear regression based on our compiled gene buffering prediction metrics. Combining BaCoN with batch correction or Cholesky data whitening further boosts predictive performance. We characterized 808 high-confidence buffering predictions and found that in contrast to buffering gene pairs overall, buffering paralogs were on different chromosomes. BaCoN performance increases with more screens and genes considered, making it a valuable tool for gene buffering predictions from the growing DepMap.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"807-824"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002017","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

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 : 2025-07-01 Epub 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":"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":"870-888"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222706/pdf/","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":"OA","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 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-07-01 Epub 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":"911-943"},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222714/pdf/","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":"OA","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 : 2025-07-01 Epub 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":"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":"735-775"},"PeriodicalIF":8.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222873/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial proteomics in translational and clinical research. 空间蛋白质组学在转化和临床研究中的应用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-01 Epub Date: 2025-04-14 DOI: 10.1038/s44320-025-00101-9

Peter Horvath, Fabian Coscia

引用次数: 0