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.
{"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}
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.
{"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}
Pub Date : 2025-01-08DOI: 10.1038/s41588-024-02053-6
Johannes Linder, Divyanshi Srivastava, Han Yuan, Vikram Agarwal, David R. Kelley
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.
{"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":"<p>Sequence-based machine-learning models trained on genomics data improve genetic variant interpretation by providing functional predictions describing their impact on the <i>cis</i>-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 <i>cis</i>-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.</p>","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}
Pub Date : 2025-01-08DOI: 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, Human Genome Structural Variation Consortium (HGSVC), Feyza Yilmaz, Pille Hallast, Charles Lee, Tomi Pastinen, Evan E. Eichler
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. Analysis of 170 human genomes assembled using long-read sequencing provides a map of structural variation within regions of segmental duplication and identifies novel candidate protein-coding genes supported by full-length Iso-Seq reads.
{"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, Human Genome Structural Variation Consortium (HGSVC), Feyza Yilmaz, Pille Hallast, Charles Lee, Tomi Pastinen, Evan E. Eichler","doi":"10.1038/s41588-024-02051-8","DOIUrl":"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. Analysis of 170 human genomes assembled using long-read sequencing provides a map of structural variation within regions of segmental duplication and identifies novel candidate protein-coding genes supported by full-length Iso-Seq reads.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"390-401"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02051-8.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1038/s41588-024-02038-5
Tianyuan Liu, Ana Conesa
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.
{"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}
Pub Date : 2025-01-08DOI: 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
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. Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq) isolates rare cells based on RNA marker transcripts for single-cell RNA sequencing profiling of complex tissues, with applicability to a broad variety of samples and cell types.
{"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":"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. Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq) isolates rare cells based on RNA marker transcripts for single-cell RNA sequencing profiling of complex tissues, with applicability to a broad variety of samples and cell types.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"451-460"},"PeriodicalIF":31.7,"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}
Pub Date : 2025-01-07DOI: 10.1038/s41588-024-02039-4
Julianne S. Funk, Maria Klimovich, Daniel Drangenstein, Ole Pielhoop, Pascal Hunold, Anna Borowek, Maxim Noeparast, Evangelos Pavlakis, Michelle Neumann, Dimitrios-Ilias Balourdas, Katharina Kochhan, Nastasja Merle, Imke Bullwinkel, Michael Wanzel, Sabrina Elmshäuser, Julia Teply-Szymanski, Andrea Nist, Tara Procida, Marek Bartkuhn, Katharina Humpert, Marco Mernberger, Rajkumar Savai, Thierry Soussi, Andreas C. Joerger, Thorsten Stiewe
The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy. A large-scale CRISPR-mediated deep mutational scanning approach is used to interrogate the function of mutations in the endogenous locus of TP53 mapping to the DNA-binding domain.
{"title":"Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations","authors":"Julianne S. Funk, Maria Klimovich, Daniel Drangenstein, Ole Pielhoop, Pascal Hunold, Anna Borowek, Maxim Noeparast, Evangelos Pavlakis, Michelle Neumann, Dimitrios-Ilias Balourdas, Katharina Kochhan, Nastasja Merle, Imke Bullwinkel, Michael Wanzel, Sabrina Elmshäuser, Julia Teply-Szymanski, Andrea Nist, Tara Procida, Marek Bartkuhn, Katharina Humpert, Marco Mernberger, Rajkumar Savai, Thierry Soussi, Andreas C. Joerger, Thorsten Stiewe","doi":"10.1038/s41588-024-02039-4","DOIUrl":"10.1038/s41588-024-02039-4","url":null,"abstract":"The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy. A large-scale CRISPR-mediated deep mutational scanning approach is used to interrogate the function of mutations in the endogenous locus of TP53 mapping to the DNA-binding domain.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"140-153"},"PeriodicalIF":31.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02039-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934766","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}
Pub Date : 2025-01-06DOI: 10.1038/s41588-024-02025-w
Elina Wiechens, Flavia Vigliotti, Kanstantsin Siniuk, Robert Schwarz, Katjana Schwab, Konstantin Riege, Alena van Bömmel, Ivonne Görlich, Martin Bens, Arne Sahm, Marco Groth, Morgan A. Sammons, Alexander Loewer, Steve Hoffmann, Martin Fischer
Convergent transcription, that is, the collision of sense and antisense transcription, is ubiquitous in mammalian genomes and believed to diminish RNA expression. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent. However, functional characteristics of affected promoters are poorly investigated. Here we show that convergent transcription marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, we identified co-regulated constituent promoters connected through a distinct chromatin structure. Within these cis-regulatory domains, transcription factors can regulate both constituting promoters by binding to only one of them. Convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs—an RNA class believed previously to be rare. Visualization of nascent RNA molecules reveals convergent cotranscription at these loci. Together, our results demonstrate that co-regulated convergent promoters substantially expand the cis-regulatory repertoire, reveal limitations of the transcription interference model and call for adjusting the promoter concept. Genome-wide analysis and genetic manipulation at loci regulated by p53, E2F4 and RFX7 show that convergent promoters with similar epigenetic features can be co-regulated and simultaneously expressed in the same direction.
{"title":"Gene regulation by convergent promoters","authors":"Elina Wiechens, Flavia Vigliotti, Kanstantsin Siniuk, Robert Schwarz, Katjana Schwab, Konstantin Riege, Alena van Bömmel, Ivonne Görlich, Martin Bens, Arne Sahm, Marco Groth, Morgan A. Sammons, Alexander Loewer, Steve Hoffmann, Martin Fischer","doi":"10.1038/s41588-024-02025-w","DOIUrl":"10.1038/s41588-024-02025-w","url":null,"abstract":"Convergent transcription, that is, the collision of sense and antisense transcription, is ubiquitous in mammalian genomes and believed to diminish RNA expression. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent. However, functional characteristics of affected promoters are poorly investigated. Here we show that convergent transcription marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, we identified co-regulated constituent promoters connected through a distinct chromatin structure. Within these cis-regulatory domains, transcription factors can regulate both constituting promoters by binding to only one of them. Convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs—an RNA class believed previously to be rare. Visualization of nascent RNA molecules reveals convergent cotranscription at these loci. Together, our results demonstrate that co-regulated convergent promoters substantially expand the cis-regulatory repertoire, reveal limitations of the transcription interference model and call for adjusting the promoter concept. Genome-wide analysis and genetic manipulation at loci regulated by p53, E2F4 and RFX7 show that convergent promoters with similar epigenetic features can be co-regulated and simultaneously expressed in the same direction.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"206-217"},"PeriodicalIF":31.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02025-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937083","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}
Pub Date : 2025-01-03DOI: 10.1038/s41588-024-02030-z
Frederik Prip, Philippe Lamy, Sia Viborg Lindskrog, Trine Strandgaard, Iver Nordentoft, Karin Birkenkamp-Demtröder, Nicolai Juul Birkbak, Nanna Kristjánsdóttir, Asbjørn Kjær, Tine G. Andreasen, Johanne Ahrenfeldt, Jakob Skou Pedersen, Asta Mannstaedt Rasmussen, Gregers G. Hermann, Karin Mogensen, Astrid C. Petersen, Arndt Hartmann, Marc-Oliver Grimm, Marcus Horstmann, Roman Nawroth, Ulrika Segersten, Danijel Sikic, Kim E. M. van Kessel, Ellen C. Zwarthoff, Tobias Maurer, Tatjana Simic, Per-Uno Malmström, Núria Malats, Jørgen Bjerggaard Jensen, UROMOL Consortium, Francisco X. Real, Lars Dyrskjøt
Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification. A genomic and transcriptomic analysis of nonmuscle-invasive bladder cancer identifies four molecular subtypes, and associates whole-genome duplication and immune exhaustion with tumor progression.
{"title":"Comprehensive genomic characterization of early-stage bladder cancer","authors":"Frederik Prip, Philippe Lamy, Sia Viborg Lindskrog, Trine Strandgaard, Iver Nordentoft, Karin Birkenkamp-Demtröder, Nicolai Juul Birkbak, Nanna Kristjánsdóttir, Asbjørn Kjær, Tine G. Andreasen, Johanne Ahrenfeldt, Jakob Skou Pedersen, Asta Mannstaedt Rasmussen, Gregers G. Hermann, Karin Mogensen, Astrid C. Petersen, Arndt Hartmann, Marc-Oliver Grimm, Marcus Horstmann, Roman Nawroth, Ulrika Segersten, Danijel Sikic, Kim E. M. van Kessel, Ellen C. Zwarthoff, Tobias Maurer, Tatjana Simic, Per-Uno Malmström, Núria Malats, Jørgen Bjerggaard Jensen, UROMOL Consortium, Francisco X. Real, Lars Dyrskjøt","doi":"10.1038/s41588-024-02030-z","DOIUrl":"10.1038/s41588-024-02030-z","url":null,"abstract":"Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification. A genomic and transcriptomic analysis of nonmuscle-invasive bladder cancer identifies four molecular subtypes, and associates whole-genome duplication and immune exhaustion with tumor progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"115-125"},"PeriodicalIF":31.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02030-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917043","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：