Nature genetics最新文献

{"title":"Epigenetic heterogeneity in AML","authors":"Chiara Anania","doi":"10.1038/s41588-026-02720-w","DOIUrl":"10.1038/s41588-026-02720-w","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1749-1749"},"PeriodicalIF":25.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689537","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":"Universal cell embedding for single-cell biology","authors":"Wei Li","doi":"10.1038/s41588-026-02718-4","DOIUrl":"10.1038/s41588-026-02718-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1749-1749"},"PeriodicalIF":25.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689615","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 spatial snapshot of hair follicle development","authors":"Hui Hua","doi":"10.1038/s41588-026-02717-5","DOIUrl":"10.1038/s41588-026-02717-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1749-1749"},"PeriodicalIF":25.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689617","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-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells in immune disease risk","authors":"Valeriya Malysheva, Helen Ray-Jones, Nora Lakes, Rachel A. Brown, Tareian A. Cazares, Owen Clay, David E. Ohayon, Pavel Artemov, Joseph A. Wayman, Zi F. Yang, Monica Della Rosa, Carmen Petitjean, Clarissa Booth, Joseph I. J. Ellaway, Jenna R. Barnes, Andrew W. Dangel, Ankita Saini, William R. Orchard, Xiaoting Chen, Sreeja Parameswaran, Frances Burden, Mattia Frontini, Takashi Nagano, Peter Fraser, Stefan Schoenfelder, Matthew T. Weirauch, Leah C. Kottyan, David F. Smith, Nick Powell, Jill M. Weimer, Eugene M. Oltz, Chris Wallace, Emily R. Miraldi, Stephen N. Waggoner, Mikhail Spivakov","doi":"10.1038/s41588-026-02681-0","DOIUrl":"10.1038/s41588-026-02681-0","url":null,"abstract":"Innate lymphoid cells (ILCs) are rare tissue-resident lymphocytes that functionally mirror cells of CD4+ T helper lineage but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched at barrier sites, regulating inflammation and promoting tissue integrity. Here we profile the promoter-anchored chromosomal contacts of primary human ILC3s using low-input, high-resolution targeted chromosome conformation capture and compare them with those in CD4+ T cells. We use these data to link Crohn’s disease genome-wide association study variants with target genes, implicating both known and unanticipated candidates, including CLN3, a causal gene for Batten disease. We show that Cln3 overexpression in a mouse ILC3-like cell line alters stimulation-induced transcriptional programs and cytokine secretion. Extending our approach to five additional immune genome-wide association study traits reveals enrichment for regulators of ILC3 activation. Our work develops methods, maps long-range gene regulation in ILC3s, and prioritizes immune disease risk genes with roles in this clinically relevant immune cell type. High-resolution mapping of promoter-anchored chromosomal contacts in type 3 innate lymphoid cells (ILC3s), coupled with GWAS effector gene prioritization and functional studies, identifies ILC3-linked genes as potential mediators of risk for several immune diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1953-1966"},"PeriodicalIF":25.5,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02681-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674139","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":"Histone marks are conserved across eukaryotes but chromatin states are diversified","authors":"","doi":"10.1038/s41588-026-02683-y","DOIUrl":"10.1038/s41588-026-02683-y","url":null,"abstract":"Eukaryotes share many ancient histone post-translational modifications, but whether they use them in the same way remains unknown. By profiling some of these modifications across diverse eukaryotic lineages, we find that active chromatin states are deeply conserved, whereas repressive heterochromatin has diversified extensively.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2081-2082"},"PeriodicalIF":25.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670295","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":"Mapping enhancer–gene regulatory interactions from single-cell data","authors":"Maya U. Sheth, Wei-Lin Qiu, X. Rosa Ma, Andreas R. Gschwind, Evelyn Jagoda, Anthony S. Tan, James Galante, Judhajeet Ray, Dulguun Amgalan, Hjörleifur Einarsson, Bram L. Gorissen, Danilo Dubocanin, Christopher S. McGinnis, Jacob Huang, Glen Munson, Kayla Brand, Ansuman T. Satpathy, Thouis R. Jones, Lars M. Steinmetz, Anshul Kundaje, Berk Ustun, Jesse M. Engreitz, Robin Andersson","doi":"10.1038/s41588-026-02695-8","DOIUrl":"10.1038/s41588-026-02695-8","url":null,"abstract":"Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation and human disease genetics. However, accurately predicting enhancer–gene regulatory interactions from single-cell datasets has been challenging. Here we introduce a family of classification models, scE2G, to predict enhancer–gene regulation. These models use features from single-cell assay for transposase-accessible chromatin with sequencing (ATAC-seq) or multiomic RNA and ATAC-seq data, and are trained on a CRISPR perturbation dataset including >10,000 evaluated element–gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped expression quantitative trait loci and genome-wide association study variant–gene associations and demonstrate state-of-the-art performance at prediction tasks across several cell types and categories of perturbations. We apply scE2G to build maps of enhancer–gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking INPP4B and IL15 to lymphocyte count. The scE2G models will enable accurate mapping of enhancer–gene regulatory interactions across thousands of human cell types. scE2G is a family of models that predict enhancer–gene regulatory interactions from single-cell datasets and enable mapping of these interactions across diverse cell types and tissues.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1941-1952"},"PeriodicalIF":25.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02695-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670344","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":"Diversity and evolution of chromatin regulatory states across eukaryotes","authors":"Cristina Navarrete, Sean A. Montgomery, Julen Mendieta, Ewa Księżopolska, Jim Renema, Cristina Chiva, Eduard Sabidó, David Lara-Astiaso, Arnau Sebé-Pedrós","doi":"10.1038/s41588-026-02672-1","DOIUrl":"10.1038/s41588-026-02672-1","url":null,"abstract":"Histone post-translational modifications (hPTMs) are key regulators of chromatin states, influencing gene expression, epigenetic memory and transposable element repression across eukaryotic genomes. While many hPTMs are evolutionarily conserved, the extent to which the chromatin states they define are similarly preserved remains unclear. Here we developed a combinatorial indexing chromatin immunoprecipitation followed by sequencing method to simultaneously profile specific hPTMs across diverse eukaryotic lineages, including amoebozoans, rhizarians, discobans and cryptomonads. Our analyses revealed highly conserved euchromatin states at active gene promoters and gene bodies. In contrast, we observed diverse configurations of repressive heterochromatin states associated with silenced genes and transposable elements, characterized by various combinations of hPTMs such as H3K9me3, H3K27me3 and/or different H3K79 methylations. These findings suggest that, while core hPTMs are ancient and broadly conserved, their functional readout has diversified throughout eukaryotic evolution, shaping lineage-specific chromatin landscapes. This study introduces iChIP2, a low-input chromatin immunoprecipitation followed by sequencing method that profiles histone post-translational modifications (hPTMs) simultaneously across diverse eukaryotic species. Despite the conservation of hPTMs across eukaryotes, the functional chromatin states they define are not always conserved.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2134-2140"},"PeriodicalIF":25.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670309","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":"Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples","authors":"Nicola Calonaci, Eriseld Krasniqi, Daniel Colic, Stefano Scalera, Giorgia Gandolfi, Salvatore Milite, Konstantin Bräutigam, Andrea Sottoriva, Trevor A. Graham, Leonardo Egidi, Biagio Ricciuti, Marcello Maugeri-Saccà, Giulio Caravagna","doi":"10.1038/s41588-026-02666-z","DOIUrl":"10.1038/s41588-026-02666-z","url":null,"abstract":"The interplay between somatic mutations and copy number alterations influences tumor evolution and prognosis. These alterations are often treated independently, overlooking gene mutant dosage (GMD)—a key property of their interaction. Here we develop a computational framework that infers mutation copy number and multiplicity from targeted sequencing panels without requiring matched normal samples. We derive GMD for over 500,000 mutations across 60,000 pan-cancer samples. By stratifying more than 20,000 patients according to GMD across multiple genes, we identify 46 tumor-type-specific biomarkers predictive of survival, 13 of which were undetectable using binary mutant/wild-type models, 26 were associated with metastatic spread and 20 predicted metastatic tropism. Our method reveals GMD patterns as independent predictors of disease prognosis, metastatic potential and site-specific dissemination across diverse tumor types. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis and holds the potential to substantially enhance biomarker discovery. The authors present INCOMMON, an open-source Bayesian inference tool that determines the multiplicity and copy number of driver mutations from tumor sequencing datasets.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1906-1917"},"PeriodicalIF":25.5,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02666-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648808","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":"Cumulative transcription factor binding and p300-mediated histone acetylation drive enhancer activation frequency","authors":"Valentina Baderna, Guido Barzaghi, Rozemarijn Kleinendorst, Kasit Chatsirisupachai, Laura Moniot-Perron, Colm Doyle, Meike Schopp, Tino Hochepied, Claude Libert, Duncan T. Odom, Judith B. Zaugg, Arnaud R. Krebs","doi":"10.1038/s41588-026-02703-x","DOIUrl":"10.1038/s41588-026-02703-x","url":null,"abstract":"In eukaryotes, transcription factors (TFs) must continuously compete with nucleosomes to access their binding sites, leading to cell-to-cell variability in chromatin accessibility at regulatory regions. Although critical to understand enhancer function in transcription, the mechanisms that define how frequently an enhancer is active in a cell population remain unclear. Here we used single-molecule footprinting to quantify the frequency at which chromatin is accessible at enhancers in response to TF perturbations and changes in their chromatin environment. We find that, individually, most TFs open chromatin in a small fraction of cells, and that cumulative TF binding controls enhancer activation frequency. Moreover, testing the functionality of hundreds of enhancers when inserted at an ectopic genomic location indicates that p300 activity is required for their full activation. Our data support a model in which enhancer activation frequency depends on the cumulative function of multiple TFs and is modulated by p300 activity. This study uses single-molecule footprinting to quantify chromatin accessibility at enhancers and promoters in mouse embryonic stem cells and to dissect the contributions of transcription factor binding and chromatin context.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1976-1987"},"PeriodicalIF":25.5,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02703-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648561","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":"Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions","authors":"Jonathan Levinsohn, Samuel Grindel, Bernhard Dumoulin, Amin Abedini, Carolina Conte, Aria Zheyuan Huang, Rena Levin-Klein, Boaz Weisz, Grace Rabinowitz, Andi M. Bergeson, Eunji Ha, Konstantin A. Klötzer, Nancy Zhang, Paul Titchenell, Mingyao Li, Joo-Seop Park, Juan Pablo Arroyo, Laura S. Finn, Kotaro Sasaki, Pazit Beckerman, Oren Pleniceanu, Paola Romagnani, Alex J. Hughes, Katalin Susztak","doi":"10.1038/s41588-026-02665-0","DOIUrl":"10.1038/s41588-026-02665-0","url":null,"abstract":"Evolution has used cell–cell communication as a strategy to coordinate organ development, enabling the reproducible generation of intricate structures. Classically, these interactions have been studied one at a time in model organisms, limiting our understanding of how cellular interplay coordinates human development. We investigated human kidney development using single-cell RNA sequencing and spatial transcriptomics, analyzing over 700,000 cells. By mapping gene expression and differentiation trajectories in space, we define the spatial organization of kidney development. Our analysis revealed unrecognized plasticity, showing that cell fate established during early patterning can be later revised. This plasticity provides a potential mechanism for how cell fate is robustly established in complex patterned tissues. Additionally, through a genome-wide, spatially aware cell–cell interaction analysis, we link localized ligand signals to cell fate decisions. We also define biologically meaningful cellular neighborhoods based on aggregated extracellular cues, providing a blueprint to understand the coordination of human development at scale. The spatial organization of human kidney development is explored using single-cell RNA sequencing and spatial transcriptomics, highlighting the crucial role of microenvironmental signals in guiding cell fate.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1877-1890"},"PeriodicalIF":25.5,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02665-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148612626","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}