Nature genetics最新文献_第4页

Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A–menin to bivalent promoters Kmt2c或Kmt2d的缺失启动了尿路上皮的肿瘤发生，并将KMT2A-menin重新分配给二价启动子

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-01-13 DOI: 10.1038/s41588-024-02015-y

Naitao Wang, Mohini R. Pachai, Dan Li, Cindy J. Lee, Sarah Warda, Makhzuna N. Khudoynazarova, Woo Hyun Cho, Guojia Xie, Sagar R. Shah, Li Yao, Cheng Qian, Elissa W. P. Wong, Juan Yan, Fanny V. Tomas, Wenhuo Hu, Fengshen Kuo, Sizhi P. Gao, Jiaqian Luo, Alison E. Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. Al-Ahmadie, Ping Chi, Yu Chen

{"title":"Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A–menin to bivalent promoters","authors":"Naitao Wang, Mohini R. Pachai, Dan Li, Cindy J. Lee, Sarah Warda, Makhzuna N. Khudoynazarova, Woo Hyun Cho, Guojia Xie, Sagar R. Shah, Li Yao, Cheng Qian, Elissa W. P. Wong, Juan Yan, Fanny V. Tomas, Wenhuo Hu, Fengshen Kuo, Sizhi P. Gao, Jiaqian Luo, Alison E. Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. Al-Ahmadie, Ping Chi, Yu Chen","doi":"10.1038/s41588-024-02015-y","DOIUrl":"10.1038/s41588-024-02015-y","url":null,"abstract":"Members of the KMT2C/D–KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c/d knockout further led to KMT2A–menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c/d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c/d licenses a molecular ‘field effect’ priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities. Loss of Kmt2c or Kmt2d in mice drives the redeployment of KMT2A–menin to bivalent promoters, leading to changes in gene expression. This primes cells for transformation and elicits sensitivity to EGFR inhibitors.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"165-179"},"PeriodicalIF":31.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02015-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968265","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

Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes 人类大脑表型的细胞状态依赖性等位基因效应和上下文孟德尔随机化分析

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-01-10 DOI: 10.1038/s41588-024-02050-9

Alexander Haglund, Verena Zuber, Maya Abouzeid, Yifei Yang, Jeong Hun Ko, Liv Wiemann, Maria Otero-Jimenez, Louwai Muhammed, Rahel Feleke, Alexi Nott, James D. Mills, Liisi Laaniste, Djordje O. Gveric, Daniel Clode, Ann C. Babtie, Susanna Pagni, Ravishankara Bellampalli, Alyma Somani, Karina McDade, Jasper J. Anink, Lucia Mesarosova, Nurun Fancy, Nanet Willumsen, Amy Smith, Johanna Jackson, Javier Alegre-Abarrategui, Eleonora Aronica, Paul M. Matthews, Maria Thom, Sanjay M. Sisodiya, Prashant K. Srivastava, Dheeraj Malhotra, Julien Bryois, Leonardo Bottolo, Michael R. Johnson

{"title":"Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes","authors":"Alexander Haglund, Verena Zuber, Maya Abouzeid, Yifei Yang, Jeong Hun Ko, Liv Wiemann, Maria Otero-Jimenez, Louwai Muhammed, Rahel Feleke, Alexi Nott, James D. Mills, Liisi Laaniste, Djordje O. Gveric, Daniel Clode, Ann C. Babtie, Susanna Pagni, Ravishankara Bellampalli, Alyma Somani, Karina McDade, Jasper J. Anink, Lucia Mesarosova, Nurun Fancy, Nanet Willumsen, Amy Smith, Johanna Jackson, Javier Alegre-Abarrategui, Eleonora Aronica, Paul M. Matthews, Maria Thom, Sanjay M. Sisodiya, Prashant K. Srivastava, Dheeraj Malhotra, Julien Bryois, Leonardo Bottolo, Michael R. Johnson","doi":"10.1038/s41588-024-02050-9","DOIUrl":"https://doi.org/10.1038/s41588-024-02050-9","url":null,"abstract":"Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case and control brains, we report 13,939 genes whose expression correlated with genetic variation, of which 16.7–40.8% (depending on cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a disease dependency, even after adjusting for disease status. To estimate the unconfounded effect of genes on outcomes, we repeated the analysis using nondiseased brains (n = 183) and reported an additional 91 colocalizations not present in the larger mixed disease and control dataset, demonstrating enhanced interpretation of disease-associated variants. Principled implementation of single-cell Mendelian randomization in control-only brains identified 140 putatively causal gene–trait associations, of which 11 were replicated in the UK Biobank, prioritizing candidate peripheral biomarkers predictive of CNS outcomes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"36 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961338","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

A scalable variational inference approach for increased mixed-model association power 一种提高混合模型关联能力的可伸缩变分推理方法

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-01-09 DOI: 10.1038/s41588-024-02044-7

Hrushikesh Loya, Georgios Kalantzis, Fergus Cooper, Pier Francesco Palamara

{"title":"A scalable variational inference approach for increased mixed-model association power","authors":"Hrushikesh Loya, Georgios Kalantzis, Fergus Cooper, Pier Francesco Palamara","doi":"10.1038/s41588-024-02044-7","DOIUrl":"https://doi.org/10.1038/s41588-024-02044-7","url":null,"abstract":"The rapid growth of modern biobanks is creating new opportunities for large-scale genome-wide association studies (GWASs) and the analysis of complex traits. However, performing GWASs on millions of samples often leads to trade-offs between computational efficiency and statistical power, reducing the benefits of large-scale data collection efforts. We developed Quickdraws, a method that increases association power in quantitative and binary traits without sacrificing computational efficiency, leveraging a spike-and-slab prior on variant effects, stochastic variational inference and graphics processing unit acceleration. We applied Quickdraws to 79 quantitative and 50 binary traits in 405,088 UK Biobank samples, identifying 4.97% and 3.25% more associations than REGENIE and 22.71% and 7.07% more than FastGWA. Quickdraws had costs comparable to REGENIE, FastGWA and SAIGE on the UK Biobank Research Analysis Platform service, while being substantially faster than BOLT-LMM. These results highlight the promise of leveraging machine learning techniques for scalable GWASs without sacrificing power or robustness.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"44 4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937081","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

Pangenome graphs and their applications in biodiversity genomics 泛基因组图谱及其在生物多样性基因组学中的应用

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02029-6

Simona Secomandi, Guido Roberto Gallo, Riccardo Rossi, Carlos Rodríguez Fernandes, Erich D. Jarvis, Andrea Bonisoli-Alquati, Luca Gianfranceschi, Giulio Formenti

{"title":"Pangenome graphs and their applications in biodiversity genomics","authors":"Simona Secomandi, Guido Roberto Gallo, Riccardo Rossi, Carlos Rodríguez Fernandes, Erich D. Jarvis, Andrea Bonisoli-Alquati, Luca Gianfranceschi, Giulio Formenti","doi":"10.1038/s41588-024-02029-6","DOIUrl":"10.1038/s41588-024-02029-6","url":null,"abstract":"Complete datasets of genetic variants are key to biodiversity genomic studies. Long-read sequencing technologies allow the routine assembly of highly contiguous, haplotype-resolved reference genomes. However, even when complete, reference genomes from a single individual may bias downstream analyses and fail to adequately represent genetic diversity within a population or species. Pangenome graphs assembled from aligned collections of high-quality genomes can overcome representation bias by integrating sequence information from multiple genomes from the same population, species or genus into a single reference. Here, we review the available tools and data structures to build, visualize and manipulate pangenome graphs while providing practical examples and discussing their applications in biodiversity and conservation genomics across the tree of life. Pangenomes integrate multiple genomes to mitigate reference bias. This Review presents tools to build, visualize and manipulate pangenome graphs and also highlights pangenome applications in biodiversity and conservation genomics.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"13-26"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936062","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

Tandem kinase proteins across the plant kingdom 植物界的串联激酶蛋白

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02032-x

Tamara Reveguk, Andrii Fatiukha, Evgenii Potapenko, Ivan Reveguk, Hanan Sela, Valentyna Klymiuk, Yinghui Li, Curtis Pozniak, Thomas Wicker, Gitta Coaker, Tzion Fahima

{"title":"Tandem kinase proteins across the plant kingdom","authors":"Tamara Reveguk, Andrii Fatiukha, Evgenii Potapenko, Ivan Reveguk, Hanan Sela, Valentyna Klymiuk, Yinghui Li, Curtis Pozniak, Thomas Wicker, Gitta Coaker, Tzion Fahima","doi":"10.1038/s41588-024-02032-x","DOIUrl":"10.1038/s41588-024-02032-x","url":null,"abstract":"Plant pathogens pose a continuous threat to global food production. Recent discoveries in plant immunity research unveiled a unique protein family characterized by an unusual resistance protein structure that combines two kinase domains. This study demonstrates the widespread occurrence of tandem kinase proteins (TKPs) across the plant kingdom. An examination of 104 plant species’ genomes uncovered 2,682 TKPs. The majority (95.6%) of these kinase domains are part of the receptor-like kinase–Pelle family, which is crucial for cell surface responses in plant immunity. Notably, 90% of TKPs comprise dual kinase domains, with over 50% being pseudokinases. Over 56% of these proteins harbor 127 different integrated domains, and over 47% include a transmembrane domain. TKP pseudokinases and/or integrated domains probably serve as decoys, engaging with pathogen effectors to trigger plant immunity. The TKP Atlas we created sheds light on the mechanisms of TKP convergent molecular evolution and potential function. This genomic analysis of tandem kinase proteins across 104 plant species highlights their mechanisms of convergent molecular evolution and potential roles in plant immunity.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"254-262"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936243","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

Telomere-to-telomere sheep genome assembly identifies variants associated with wool fineness 端粒到端粒羊基因组组装鉴定与羊毛细度相关的变异

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02037-6

Ling-Yun Luo, Hui Wu, Li-Ming Zhao, Ya-Hui Zhang, Jia-Hui Huang, Qiu-Yue Liu, Hai-Tao Wang, Dong-Xin Mo, He-Hua EEr, Lian-Quan Zhang, Hai-Liang Chen, Shan-Gang Jia, Wei-Min Wang, Meng-Hua Li

{"title":"Telomere-to-telomere sheep genome assembly identifies variants associated with wool fineness","authors":"Ling-Yun Luo, Hui Wu, Li-Ming Zhao, Ya-Hui Zhang, Jia-Hui Huang, Qiu-Yue Liu, Hai-Tao Wang, Dong-Xin Mo, He-Hua EEr, Lian-Quan Zhang, Hai-Liang Chen, Shan-Gang Jia, Wei-Min Wang, Meng-Hua Li","doi":"10.1038/s41588-024-02037-6","DOIUrl":"10.1038/s41588-024-02037-6","url":null,"abstract":"Ongoing efforts to improve sheep reference genome assemblies still leave many gaps and incomplete regions, resulting in a few common failures and errors in genomic studies. Here, we report a 2.85-Gb gap-free telomere-to-telomere genome of a ram (T2T-sheep1.0), including all autosomes and the X and Y chromosomes. This genome adds 220.05 Mb of previously unresolved regions and 754 new genes to the most updated reference assembly ARS-UI_Ramb_v3.0; it contains four types of repeat units (SatI, SatII, SatIII and CenY) in centromeric regions. T2T-sheep1.0 has a base accuracy of more than 99.999%, corrects several structural errors in previous reference assemblies and improves structural variant detection in repetitive sequences. Alignment of whole-genome short-read sequences of global domestic and wild sheep against T2T-sheep1.0 identifies 2,664,979 new single-nucleotide polymorphisms in previously unresolved regions, which improves the population genetic analyses and detection of selective signals for domestication (for example, ABCC4) and wool fineness (for example, FOXQ1). A gap-free telomere-to-telomere genome assembly for a ram of Hu sheep uncovers genes and variants associated with domestication and selection for wool fineness.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"218-230"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936102","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

Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation 从DNA序列预测RNA-seq覆盖作为基因调控的统一模型

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02053-6

Johannes Linder, Divyanshi Srivastava, Han Yuan, Vikram Agarwal, David R. Kelley

{"title":"Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation","authors":"Johannes Linder, Divyanshi Srivastava, Han Yuan, Vikram Agarwal, David R. Kelley","doi":"10.1038/s41588-024-02053-6","DOIUrl":"https://doi.org/10.1038/s41588-024-02053-6","url":null,"abstract":"Sequence-based machine-learning models trained on genomics data improve genetic variant interpretation by providing functional predictions describing their impact on the cis-regulatory code. However, current tools do not predict RNA-seq expression profiles because of modeling challenges. Here, we introduce Borzoi, a model that learns to predict cell-type-specific and tissue-specific RNA-seq coverage from DNA sequence. Using statistics derived from Borzoi’s predicted coverage, we isolate and accurately score DNA variant effects across multiple layers of regulation, including transcription, splicing and polyadenylation. Evaluated on quantitative trait loci, Borzoi is competitive with and often outperforms state-of-the-art models trained on individual regulatory functions. By applying attribution methods to the derived statistics, we extract cis-regulatory motifs driving RNA expression and post-transcriptional regulation in normal tissues. The wide availability of RNA-seq data across species, conditions and assays profiling specific aspects of regulation emphasizes the potential of this approach to decipher the mapping from DNA sequence to regulatory function.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"66 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936100","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

Structural polymorphism and diversity of human segmental duplications 人类片段复制的结构多态性和多样性

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02051-8

Hyeonsoo Jeong, Philip C. Dishuck, DongAhn Yoo, William T. Harvey, Katherine M. Munson, Alexandra P. Lewis, Jennifer Kordosky, Gage H. Garcia, Feyza Yilmaz, Pille Hallast, Charles Lee, Tomi Pastinen, Evan E. Eichler

{"title":"Structural polymorphism and diversity of human segmental duplications","authors":"Hyeonsoo Jeong, Philip C. Dishuck, DongAhn Yoo, William T. Harvey, Katherine M. Munson, Alexandra P. Lewis, Jennifer Kordosky, Gage H. Garcia, Feyza Yilmaz, Pille Hallast, Charles Lee, Tomi Pastinen, Evan E. Eichler","doi":"10.1038/s41588-024-02051-8","DOIUrl":"https://doi.org/10.1038/s41588-024-02051-8","url":null,"abstract":"Segmental duplications (SDs) contribute significantly to human disease, evolution and diversity but have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies (from 85 samples representing 38 Africans and 47 non-Africans) in which the majority of autosomal SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms and sex chromosomes, we identify 173.2 Mb of duplicated sequence (47.4 Mb not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable, with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy numbers than non-African samples. Comparison to a resource of 563 million full-length isoform sequencing reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"74 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936103","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

Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing 转录特异性富集可以通过单细胞RNA测序来分析罕见的细胞状态

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02036-7

Tsion Abay, Robert R. Stickels, Meril T. Takizawa, Benan N. Nalbant, Yu-Hsin Hsieh, Sidney Hwang, Catherine Snopkowski, Kenny Kwok Hei Yu, Zaki Abou-Mrad, Viviane Tabar, Brooke E. Howitt, Leif S. Ludwig, Ronan Chaligné, Ansuman T. Satpathy, Caleb A. Lareau

{"title":"Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing","authors":"Tsion Abay, Robert R. Stickels, Meril T. Takizawa, Benan N. Nalbant, Yu-Hsin Hsieh, Sidney Hwang, Catherine Snopkowski, Kenny Kwok Hei Yu, Zaki Abou-Mrad, Viviane Tabar, Brooke E. Howitt, Leif S. Ludwig, Ronan Chaligné, Ansuman T. Satpathy, Caleb A. Lareau","doi":"10.1038/s41588-024-02036-7","DOIUrl":"https://doi.org/10.1038/s41588-024-02036-7","url":null,"abstract":"Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. In the present report, we addressed these limitations by developing Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations defined by the abundance of specific RNA transcripts. Across immune populations (n = 184,126 cells) and fresh-frozen and formalin-fixed, paraffin-embedded brain tissue (n = 33,145 nuclei), we demonstrated that programmable sorting logic via RNA-based cytometry can isolate rare cell populations and uncover phenotypic heterogeneity via downstream, high-throughput, single-cell genomics analyses.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"83 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936099","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

Profiling the epigenome using long-read sequencing 使用长读测序分析表观基因组

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-01-08 DOI: 10.1038/s41588-024-02038-5

Tianyuan Liu, Ana Conesa

{"title":"Profiling the epigenome using long-read sequencing","authors":"Tianyuan Liu, Ana Conesa","doi":"10.1038/s41588-024-02038-5","DOIUrl":"10.1038/s41588-024-02038-5","url":null,"abstract":"The advent of single-molecule, long-read sequencing (LRS) technologies by Oxford Nanopore Technologies and Pacific Biosciences has revolutionized genomics, transcriptomics and, more recently, epigenomics research. These technologies offer distinct advantages, including the direct detection of methylated DNA and simultaneous assessment of DNA sequences spanning multiple kilobases along with their modifications at the single-molecule level. This has enabled the development of new assays for analyzing chromatin states and made it possible to integrate data for DNA methylation, chromatin accessibility, transcription factor binding and histone modifications, thereby facilitating comprehensive epigenomic profiling. Owing to recent advancements, alternative, nascent and translating transcripts can be detected using LRS approaches. This Review discusses LRS-based experimental and computational strategies for characterizing chromatin states and highlights their advantages over short-read sequencing methods. Furthermore, we demonstrate how various long-read methods can be integrated to design multi-omics studies to investigate the relationship between chromatin states and transcriptional dynamics. Long-read sequencing technologies have revolutionized genomics and transcriptomics, and more recently enabled comprehensive epigenomic profiling. These advances now also allow investigation of the relationship between chromatin states and transcriptional dynamics.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"27-41"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936272","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