Genome Biology最新文献

{"title":"A molecular census to elucidate the demixing mechanism of membraneless organelles","authors":"Cheryn Ali, Fernando Muzzopappa, Fabian Erdel","doi":"10.1186/s13059-025-03806-0","DOIUrl":"https://doi.org/10.1186/s13059-025-03806-0","url":null,"abstract":"Cells contain membraneless organelles that have been proposed to form via phase separation involving dense networks of multivalent intermolecular interactions. As it is notoriously difficult to experimentally distinguish punctate structures formed by phase separation from those formed by other mechanisms, this issue is controversial. To complement experimental assays, we present a computational by-the-numbers approach to phase separation. We mine publicly available datasets to perform a molecular census of prominent subnuclear organelles in mouse embryonic stem cells: nucleoli, transcriptional condensates, heterochromatin foci, and Polycomb bodies. We estimate copy numbers and intermolecular distances and compare the latter to the Debye length, which is the characteristic distance over which intermolecular interactions typically occur. We find that none of the organelles studied here contain any protein species that shows intermolecular distances below the estimated Debye length if molecules in the organelles are randomly distributed, which disfavors the classical one-component phase separation scenario. Considering multiple species based on databases of phase-separating proteins, we find that nucleoli and transcriptional condensates are compatible with multi-component phase separation driven by proteins and RNAs, while heterochromatin foci and Polycomb bodies are better explained by a model in which proteins bind to chromatin without phase-separating via dense multivalent interaction networks. We also provide an interactive tool that allows testing of alternative multi-component scenarios. We introduce a computational by-the-numbers approach to benchmark different demixing models that may explain the assembly of membraneless organelles. Our results suggest that cells use different mechanisms to form subnuclear organelles with different biophysical properties.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"50 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246529","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}

{"title":"Engineered virus-like particle-assembled Vegfa-targeting Cas9 ribonucleoprotein treatment alleviates neovascularization in wet age-related macular degeneration","authors":"Jun Wu, Hyewon Jang, Hyunjong Kwak, Minchae Son, Weiyan Jiang, Hye-Yeon Hwang, Dong Hyun Jo, Daesik Kim, Hyongbum Henry Kim, Jeong Hun Kim","doi":"10.1186/s13059-025-03774-5","DOIUrl":"https://doi.org/10.1186/s13059-025-03774-5","url":null,"abstract":"Age-related macular degeneration, particularly the wet form, is a leading cause of vision loss, characterized by vascular endothelial growth factor A (VEGFA) overproduction. Engineered virus-like particles (eVLPs) combine the efficiency of viral systems with the transient nature of non-viral platforms to offer a potential solution for delivering VEGFA-targeting genome editing enzymes in a safe and efficient manner. Here, we investigate the therapeutic efficacy of eVLPs for transient delivery of Vegfa-targeting Cas9 ribonucleoprotein in a laser-induced choroidal neovascularization mouse model of wet age-related macular degeneration. We find that Cas9-eVLPs enables efficient intracellular delivery in vitro, achieving up to 99% insertion and deletion frequency at Vegfa target locus and significant VEGFA protein downregulation in NIH/3T3 cells. A single subretinal injection of Cas9-eVLPs into the mouse retinal pigment epithelium effectively disrupts Vegfa expression, achieving an average indel efficiency of 16.7%. Compared to control groups, the laser-induced choroidal neovascularization mouse model exhibits significantly reduced choroidal neovascularization formation following Cas9-eVLPs intervention, and decreased VEGFA protein levels are detected in the retinal pigment epithelium. Furthermore, the retinal anatomical and functional toxicity are not affected after treatment. eVLPs exhibit the potential as a safe and efficient delivery platform for Cas9 ribonucleoproteins, achieving precise Vegfa downregulation and significant reduction in choroidal neovascularization in a mouse model of wet age-related macular degeneration. With transient delivery of gene editing enzymes, high editing efficiency, and minimal risk of genomic integration, eVLPs present a promising alternative to conventional delivery systems for advancing genome editing therapies in retinal diseases. ","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"56 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246530","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}

{"title":"Pan-S-locus analysis reveals insights into the origin and evolution of self-incompatibility in the orange subfamily","authors":"Jianbing Hu, Zezhen Du, Chenchen Liu, Hao Wen, Cong Liu, Peng Chen, Chunmei Shi, Junli Ye, QianHua Ji, Xiuxin Deng, Maurice Bosch, Zongcheng Lin, Wen-Biao Jiao, Lijun Chai","doi":"10.1186/s13059-025-03817-x","DOIUrl":"https://doi.org/10.1186/s13059-025-03817-x","url":null,"abstract":"Self-incompatibility is controlled by a highly polymorphic supergene complex, the S-locus, which is structurally complex, rich in repetitive sequences, and varies in length from hundreds of kilobases to tens of megabases across different plant families. Due to these challenges, the S-locus has been fully reconstructed in only a few species, limiting our understanding of its evolutionary dynamics. This study systematically explores the evolutionary mechanisms and structural characteristics of the self-incompatibility system mediated by S-RNase in the Aurantioideae (orange subfamily) of Rutaceae. We construct a pan-S-locus framework spanning 11 genera within the orange subfamily from 14 newly assembled genomes from representative accessions and the analysis of 41 published citrus genomes. Our analyses reveal significant structural variations and transposable element (TE)-driven pseudogenization of SLF genes. By constructing a comprehensive library of S-RNases and developing a novel genotyping pipeline, we reveal divergent frequencies of S-RNases between self-incompatible and self-compatible populations. Comparative analyses demonstrate a unique evolutionary trajectory marked by asynchronous core nonS-genes duplication and TE-mediated structural diversification, distinct from other families. Innovatively, we identified TE-induced self-incompatibility loss as the primary driver of self-compatibility transition, which implies the uniqueness of the origin and evolution of self-incompatibility in the orange subfamily. Through the construction and characterization of the pan-S-locus, this study provides profound insight into the origin and evolution of the S-locus in the orange subfamily. These findings not only advance our understanding of self-incompatibility mechanisms, but also establish a foundational framework for investigating the evolution of the gametophytic self-incompatibility systems in other families.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"20 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235972","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}

{"title":"A ternary-code DNA methylome atlas of mouse tissues","authors":"Sol Moe Lee, David C. Goldberg, Cameron Cloud, Jared B. Parker, Christopher Krapp, Christian E. Loo, Elliot Kim, Ivan Zhao, Chengcheng Jin, Rishi Porecha, Marisa S. Bartolomei, Rahul M. Kohli, Wanding Zhou","doi":"10.1186/s13059-025-03808-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03808-y","url":null,"abstract":"DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of traditional profiling methods based on bisulfite conversion. Here, we leverage the combined bisulfite and enzymatic (bACE) conversion with the Mouse Methylation BeadChip to generate 265 base-resolution ternary-code modification maps of 5mC and 5hmC across 29 mouse tissue types spanning 8–76 weeks of age and both sexes. Our atlas reveals a complex grammar of 5hmC distribution, jointly shaped by cell mitotic activity, chromatin states, and interplay with 5mC at the same and neighboring CpG sites. Of note, we demonstrate that 5hmC significantly complements 5mC-based biomarkers in delineating cell identity in both brain and non-brain tissues. Each modification state, including 5hmC alone, accurately discriminates tissue types, enabling high-precision machine learning classification of epigenetic identity. Furthermore, the ternary methylome variations extensively implicate gene transcriptional variation, with age-related changes correlated with gene expression in a tissue-dependent manner. Our work reveals how tissue, sex, and age jointly govern the dynamics of the two cytosine modifications, augments the scope of DNA modification biomarker discovery, and provides a reference atlas to explore epigenetic dynamics in development and disease.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"18 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235643","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}

{"title":"Structural and evolutionary features of red algal UV sex chromosomes","authors":"Agnieszka P. Lipinska, Guillaume Cossard, Paul Epperlein, Tobias Woertwein, Cecile Molinier, Olivier Godfroy, Sabrina Carli, Ligia Ayres-Ostrock, Emma Lavaut, Fabiana Marchi, Stephane Mauger, Christophe Destombe, Mariana C. Oliveira, Estela M. Plastino, Stacy A. Krueger-Hadfield, Marie-Laure Guillemin, Myriam Valero, Susana M. Coelho","doi":"10.1186/s13059-025-03797-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03797-y","url":null,"abstract":"Sex chromosomes in red algae have remained relatively understudied, despite their fundamental role in understanding the evolution of sex determination across eukaryotes. In this study, we investigate the structure, gene composition, and evolutionary history of the U and V sex chromosomes in four Gracilaria species, which diverged approximately 100 million years ago. Our findings reveal that UV sex chromosomes, previously identified in green and brown algae as well as bryophytes, have also evolved in red algae, contributing to the diversity of sex determination systems across eukaryotes. The shared orthology of conserved sex-determining region genes between Gracilaria and distantly related red algae suggests that this system may have originated approximately 390 million years ago, making it one of the oldest known sex chromosome systems. The sex-determining region in Gracilaria is relatively small but contains conserved gametologs and V-specific genes involved in transcriptional regulation and signaling, suggesting their essential role in sexual differentiation. Unlike the conserved V-specific genes, U-specific genes appear absent, pointing to a dominant role of the V chromosome in sex determination. Despite their ancient origin, the sex chromosomes show low levels of degeneration, likely due to haploid purifying selection during the gametophytic phase of the life cycle. This study provides the first large-scale comparative genomic and transcriptomic analysis of the U and V sex chromosomes across multiple red algal species, preparing the ground for future studies on reproductive life cycles and speciation in this understudied group of eukaryotes.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"107 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235974","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}

{"title":"High-precision cell-type mapping and annotation of single-cell spatial transcriptomics with STAMapper","authors":"Qunlun Shen, Kangning Dong, Shuqin Zhang, Shihua Zhang","doi":"10.1186/s13059-025-03773-6","DOIUrl":"https://doi.org/10.1186/s13059-025-03773-6","url":null,"abstract":"In this paper, we develop a heterogeneous graph neural network, STAMapper, to transfer the cell-type labels from single-cell RNA-sequencing (scRNA-seq) data to single-cell spatial transcriptomics (scST) data. We collect 81 scST datasets consisting of 344 slices and 16 paired scRNA-seq datasets from eight technologies and five tissues to validate the efficiency of STAMapper. STAMapper achieves the best performance on 75 out of 81 datasets compared to competing methods in accuracy. STAMapper demonstrates enhanced performance over manual annotations, particularly at the boundaries of cell clusters, enables the unknown cell-type detection in scST data, and exhibits precise cell subtype annotations.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"123 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235644","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}

{"title":"A nucleoporin-associated signaling cascade controls plant immunity via histone modification","authors":"Leiwen Pan, Shun Peng, Yuehui Zhang, Huan Chang, Yi Yang, Dongbei Guo, Yuan Guo, Yakun Han, Ting Mao, Yuchen Huang, Shui Wang","doi":"10.1186/s13059-025-03814-0","DOIUrl":"https://doi.org/10.1186/s13059-025-03814-0","url":null,"abstract":"Plants undergo massive transcriptional reprogramming upon pathogen infection. The transcription factors SAR DEFICIENT1 (SARD1) and CAM-BINDING PROTEIN 60-LIKE G (CBP60g) are master regulators of this process. However, the regulation of SARD1 and CBP60g transcription remains unclear. We discover a signaling complex centered on the plant-specific nucleoporins CONSTITUTIVE EXPRESSION OF PR GENES 5 (CPR5) and GUANYLATE-BINDING PROTEIN-LIKE GTPASE 3 (GBPL3), which critically regulates SARD1 and CBP60g transcription. We establish that the RNA processing complexes NineTeen Complex (NTC) and CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR (CPSF) act downstream of CPR5 to activate immunity. A genetic screen identifies GBPL3 and key histone modification complex components as suppressors of the autoimmune phenotype in cpr5 mutants, functioning downstream of NTC/CPSF. Transcriptomic and genetic analyses demonstrate that SARD1 and CBP60g are fully responsible for autoimmune activation in cpr5. Crucially, GBPL3 and the histone modifiers physically interact, bind directly to the SARD1 and CBP60g loci, and repress their expression. Pathogen infection substantially reduces this binding. Consistently, the active histone mark H3K4me3 at SARD1 and CBP60g is modulated by the CPR5-NTC/CPSF-GBPL3/histone modifiers cascade and accumulates significantly upon pathogen infection. Our findings reveal a CPR5-NTC/CPSF-GBPL3/histone modifiers signaling cascade that controls the transcription of the SARD1 and CBP60g via histone modification, thereby modulating the transcriptional reprogramming during plant immune responses.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"32 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228854","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}

{"title":"Silent mutations in coding regions of Hepatitis C virus affect patterns of HCV RNA structures and attenuate viral replication and pathogenesis","authors":"Roba Dabour, Shaked Bergman, Zohar Zafrir, Ateret Davidovitch, Michal Werbner, Meital Gal-Tanamy, Tamir Tuller","doi":"10.1186/s13059-025-03816-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03816-y","url":null,"abstract":"Vaccines based on live attenuated viruses are the most effective strategy for controlling infections, since they elicit long-lasting natural and effective immune response, but entail challenges for safety and virulence. Hepatitis C Virus (HCV) causes liver diseases and liver cancer, with millions infected each year and hundreds of thousands of annual fatalities; but no vaccine is currently available for the virus. Here, we present a novel computational approach for the accurate prediction of virus attenuation. We rationally design viral variants by inserting a large number of synonymous mutations in the NS5A/B coding region to disrupt the viral RNA’s secondary structure and regulatory sequences important for the viral life cycle. By measuring RNA levels and virus spread in an HCV infection model, we show that some variants have lower viral fitness relative to the wild-type virus, with gradient of attenuation in concordance with the prediction model. Deep sequencing of replicating viruses demonstrates relative genomic stability of the attenuated variant. Differential expression analysis and evaluation of cancer-related phenotypes reveal that some variants have a lower pathogenic influence on the host cells, compared to the wildtype virus. These rationally designed variants reveal novel information on key functional elements in HCV RNA important for virus fitness, that may be further considered as a promising direction for a viable HCV vaccine. Importantly, the computational approach described here is based on the most fundamental viral regulatory motifs and therefore may be applied for almost all viruses as a new strategy for vaccine development.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"93 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228855","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}

{"title":"Potential synthetic associations created by epistasis","authors":"Hai-Jun Liu, Jingxian Fu, Shuhua Xu, Magnus Nordborg","doi":"10.1186/s13059-025-03807-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03807-z","url":null,"abstract":"The prevalence of synthetic associations in GWAS, where non-causal variants become significant by tagging multiple undetected causal variants and not necessarily in strong linkage disequilibrium with any single one, remains unexplored. We introduce a novel machine-learning approach using only genotype data to infer such associations in human GWAS. Our analysis reveals that 3–5% of GWAS Catalog peaks may represent potential synthetic associations, often arising from epistatic interactions between common variants rather than multiple rare variants acting independently. Our findings highlight the need for multi-locus models and emphasize careful GWAS interpretation and follow-up analyses like fine-mapping and trait prediction.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"46 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228856","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}

{"title":"Cisformer: a scalable cross-modality generation framework for decoding transcriptional regulation at single-cell resolution","authors":"Luzhang Ji, Qihang Zou, Ke Tang, Chenfei Wang","doi":"10.1186/s13059-025-03823-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03823-z","url":null,"abstract":"Single-cell multiomic technologies enable the joint analysis of different modalities, but face challenges due to experimental complexity. Current computational methods for single-cell cross-modality translation lack biological interpretability. Here, we present Cisformer, a cross-attention-based generative model tailored for cross-modality generation between gene expression and chromatin accessibility at single-cell resolution. Systematic benchmarking demonstrates the superior accuracy and generalization of Cisformer against existing methods. Cisformer leverages its inherent interpretability to precisely link cis-regulatory elements to target genes, facilitating the identification of functional transcription factors associated with tumorigenesis and aging. Overall, Cisformer is a powerful tool for single-cell multiomic data analysis.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"39 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228830","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}