Pub Date : 2024-09-02DOI: 10.1038/s41576-024-00767-1
Matthew J. Meier, Joshua Harrill, Kamin Johnson, Russell S. Thomas, Weida Tong, Julia E. Rager, Carole L. Yauk
Toxicogenomics measures molecular features, such as transcripts, proteins, metabolites and epigenomic modifications, to understand and predict the toxicological effects of environmental and pharmaceutical exposures. Transcriptomics has become an integral tool in contemporary toxicology research owing to innovations in gene expression profiling that can provide mechanistic and quantitative information at scale. These data can be used to predict toxicological hazards through the use of transcriptomic biomarkers, network inference analyses, pattern-matching approaches and artificial intelligence. Furthermore, emerging approaches, such as high-throughput dose–response modelling, can leverage toxicogenomic data for human health protection even in the absence of predicting specific hazards. Finally, single-cell transcriptomics and multi-omics provide detailed insights into toxicological mechanisms. Here, we review the progress since the inception of toxicogenomics in applying transcriptomics towards toxicology testing and highlight advances that are transforming risk assessment.
{"title":"Progress in toxicogenomics to protect human health","authors":"Matthew J. Meier, Joshua Harrill, Kamin Johnson, Russell S. Thomas, Weida Tong, Julia E. Rager, Carole L. Yauk","doi":"10.1038/s41576-024-00767-1","DOIUrl":"https://doi.org/10.1038/s41576-024-00767-1","url":null,"abstract":"<p>Toxicogenomics measures molecular features, such as transcripts, proteins, metabolites and epigenomic modifications, to understand and predict the toxicological effects of environmental and pharmaceutical exposures. Transcriptomics has become an integral tool in contemporary toxicology research owing to innovations in gene expression profiling that can provide mechanistic and quantitative information at scale. These data can be used to predict toxicological hazards through the use of transcriptomic biomarkers, network inference analyses, pattern-matching approaches and artificial intelligence. Furthermore, emerging approaches, such as high-throughput dose–response modelling, can leverage toxicogenomic data for human health protection even in the absence of predicting specific hazards. Finally, single-cell transcriptomics and multi-omics provide detailed insights into toxicological mechanisms. Here, we review the progress since the inception of toxicogenomics in applying transcriptomics towards toxicology testing and highlight advances that are transforming risk assessment.</p>","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"14 1","pages":""},"PeriodicalIF":42.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118117","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 : 2024-08-29DOI: 10.1038/s41576-024-00770-6
Merly C. Vogt
Merly C. Vogt recalls a seminal paper by Greer et al., who demonstrated the transgenerational inheritance of longevity, a complex trait, in Caenorhabditis elegans by manipulating the trimethylation of histone H3 lysine 4 (H3K4me3) in the parental generation.
{"title":"The complex non-genetic inheritance of complex traits","authors":"Merly C. Vogt","doi":"10.1038/s41576-024-00770-6","DOIUrl":"10.1038/s41576-024-00770-6","url":null,"abstract":"Merly C. Vogt recalls a seminal paper by Greer et al., who demonstrated the transgenerational inheritance of longevity, a complex trait, in Caenorhabditis elegans by manipulating the trimethylation of histone H3 lysine 4 (H3K4me3) in the parental generation.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 10","pages":"678-678"},"PeriodicalIF":39.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090006","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 : 2024-08-22DOI: 10.1038/s41576-024-00771-5
Henry Ertl
Satterlee et al. employ several approaches to demonstrate that prickle evolution has a common genetic basis among several plant lineages.
Satterlee 等人采用多种方法证明，皮刺的进化在多个植物品系中具有共同的遗传基础。
{"title":"Convergent evolution of prickles across crops","authors":"Henry Ertl","doi":"10.1038/s41576-024-00771-5","DOIUrl":"10.1038/s41576-024-00771-5","url":null,"abstract":"Satterlee et al. employ several approaches to demonstrate that prickle evolution has a common genetic basis among several plant lineages.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 10","pages":"676-676"},"PeriodicalIF":39.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036402","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 : 2024-08-21DOI: 10.1038/s41576-024-00762-6
Marcos Malumbres, Carolina Villarroya-Beltri
Mosaic variegated aneuploidy (MVA) is a rare condition in which abnormal chromosome counts (that is, aneuploidies), affecting different chromosomes in each cell (making it variegated) are found only in a certain number of cells (making it mosaic). MVA is characterized by various developmental defects and, despite its rarity, presents a unique clinical scenario to understand the consequences of chromosomal instability and copy number variation in humans. Research from patients with MVA, genetically engineered mouse models and functional cellular studies have found the genetic causes to be mutations in components of the spindle-assembly checkpoint as well as in related proteins involved in centrosome dynamics during mitosis. MVA is accompanied by tumour susceptibility (depending on the genetic basis) as well as cellular and systemic stress, including chronic immune response and the associated clinical implications. Mosaic variegated aneuploidy is a rare condition in which the copy number of different chromosomes varies across some cells within an individual. In this Review, the authors discuss the genetic underpinnings and clinical manifestations of this condition and relate these findings to the consequences of chromosomal instability more broadly.
{"title":"Mosaic variegated aneuploidy in development, ageing and cancer","authors":"Marcos Malumbres, Carolina Villarroya-Beltri","doi":"10.1038/s41576-024-00762-6","DOIUrl":"10.1038/s41576-024-00762-6","url":null,"abstract":"Mosaic variegated aneuploidy (MVA) is a rare condition in which abnormal chromosome counts (that is, aneuploidies), affecting different chromosomes in each cell (making it variegated) are found only in a certain number of cells (making it mosaic). MVA is characterized by various developmental defects and, despite its rarity, presents a unique clinical scenario to understand the consequences of chromosomal instability and copy number variation in humans. Research from patients with MVA, genetically engineered mouse models and functional cellular studies have found the genetic causes to be mutations in components of the spindle-assembly checkpoint as well as in related proteins involved in centrosome dynamics during mitosis. MVA is accompanied by tumour susceptibility (depending on the genetic basis) as well as cellular and systemic stress, including chronic immune response and the associated clinical implications. Mosaic variegated aneuploidy is a rare condition in which the copy number of different chromosomes varies across some cells within an individual. In this Review, the authors discuss the genetic underpinnings and clinical manifestations of this condition and relate these findings to the consequences of chromosomal instability more broadly.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 12","pages":"864-878"},"PeriodicalIF":39.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013800","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 : 2024-08-13DOI: 10.1038/s41576-024-00759-1
Lee H. Wong, David J. Tremethick
Histones are integral components of eukaryotic chromatin that have a pivotal role in the organization and function of the genome. The dynamic regulation of chromatin involves the incorporation of histone variants, which can dramatically alter its structural and functional properties. Contrary to an earlier view that limited individual histone variants to specific genomic functions, new insights have revealed that histone variants exert multifaceted roles involving all aspects of genome function, from governing patterns of gene expression at precise genomic loci to participating in genome replication, repair and maintenance. This conceptual change has led to a new understanding of the intricate interplay between chromatin and DNA-dependent processes and how this connection translates into normal and abnormal cellular functions.
组蛋白是真核染色质不可或缺的组成部分，在基因组的组织和功能中发挥着关键作用。染色质的动态调控涉及组蛋白变体的结合，而组蛋白变体可显著改变染色质的结构和功能特性。早先的观点认为，单个组蛋白变体仅限于发挥特定的基因组功能，与此相反，新的研究发现，组蛋白变体发挥着多方面的作用，涉及基因组功能的方方面面，从管理精确基因组位点的基因表达模式，到参与基因组的复制、修复和维护。这种概念上的变化使人们对染色质和 DNA 依赖过程之间错综复杂的相互作用以及这种联系如何转化为正常和异常的细胞功能有了新的认识。
{"title":"Multifunctional histone variants in genome function","authors":"Lee H. Wong, David J. Tremethick","doi":"10.1038/s41576-024-00759-1","DOIUrl":"https://doi.org/10.1038/s41576-024-00759-1","url":null,"abstract":"<p>Histones are integral components of eukaryotic chromatin that have a pivotal role in the organization and function of the genome. The dynamic regulation of chromatin involves the incorporation of histone variants, which can dramatically alter its structural and functional properties. Contrary to an earlier view that limited individual histone variants to specific genomic functions, new insights have revealed that histone variants exert multifaceted roles involving all aspects of genome function, from governing patterns of gene expression at precise genomic loci to participating in genome replication, repair and maintenance. This conceptual change has led to a new understanding of the intricate interplay between chromatin and DNA-dependent processes and how this connection translates into normal and abnormal cellular functions.</p>","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"142 1","pages":""},"PeriodicalIF":42.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973775","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 : 2024-08-12DOI: 10.1038/s41576-024-00760-8
Zachary D. Smith, Sara Hetzel, Alexander Meissner
The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype. In this Review, Smith et al. describe DNA methylation landscapes that emerge over mammalian development and within key disease states, as well as how different methyltransferases interface with histone modifications and other proteins to create and maintain them.
DNA 甲基化领域已经从发现和基因组特征描述阶段成熟到寻求对这种修饰如何促进发育、衰老和疾病的更深入的功能性理解阶段。尤其是在过去的十年中，许多令人振奋的机理发现大大扩展了我们对这一古老的进化修饰如何被纳入强大的表观遗传密码的认识。在此，我们总结了目前对哺乳动物生命周期中出现的不同 DNA 甲基化景观的理解，并讨论了它们如何与其他调控层相互作用以支持不同的基因组功能。然后，我们回顾了人们对衰老和体细胞向癌症转化过程中发现的替代模式日益增长的兴趣。随着单细胞和长读程测序技术的进步，这些领域的共同见解为将 DNA 甲基化的生化和遗传特征与细胞生理、发育潜能和表型联系起来提供了新的机会。
{"title":"DNA methylation in mammalian development and disease","authors":"Zachary D. Smith, Sara Hetzel, Alexander Meissner","doi":"10.1038/s41576-024-00760-8","DOIUrl":"10.1038/s41576-024-00760-8","url":null,"abstract":"The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype. In this Review, Smith et al. describe DNA methylation landscapes that emerge over mammalian development and within key disease states, as well as how different methyltransferases interface with histone modifications and other proteins to create and maintain them.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 1","pages":"7-30"},"PeriodicalIF":39.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918822","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 : 2024-08-12DOI: 10.1038/s41576-024-00769-z
Kirsty Minton
Duttke et al. show that transcription factors have position-dependent effects relative to their distance from the transcription start site, which suggests that a ''spatial grammar'' could be used to encode multiple gene-regulatory programmes.
{"title":"Position-dependent effects of transcription factor binding","authors":"Kirsty Minton","doi":"10.1038/s41576-024-00769-z","DOIUrl":"10.1038/s41576-024-00769-z","url":null,"abstract":"Duttke et al. show that transcription factors have position-dependent effects relative to their distance from the transcription start site, which suggests that a ''spatial grammar'' could be used to encode multiple gene-regulatory programmes.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 10","pages":"675-675"},"PeriodicalIF":39.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918819","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 : 2024-08-05DOI: 10.1038/s41576-024-00766-2
Pablo Librado
In this Tools of the Trade article, Pablo Librado describes a novel computational method to infer the time between successive generations from genomic data, including ancient genomes, which offers new insights into the timing of evolutionary and demographic events.
{"title":"Reconstructing generation intervals over time","authors":"Pablo Librado","doi":"10.1038/s41576-024-00766-2","DOIUrl":"10.1038/s41576-024-00766-2","url":null,"abstract":"In this Tools of the Trade article, Pablo Librado describes a novel computational method to infer the time between successive generations from genomic data, including ancient genomes, which offers new insights into the timing of evolutionary and demographic events.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 11","pages":"745-746"},"PeriodicalIF":39.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891852","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 : 2024-07-29DOI: 10.1038/s41576-024-00761-7
Xuelan Chen, Albert S. Agustinus, Jun Li, Melody DiBona, Samuel F. Bakhoum
Chromosomal instability (CIN) refers to an increased propensity of cells to acquire structural and numerical chromosomal abnormalities during cell division, which contributes to tumour genetic heterogeneity. CIN has long been recognized as a hallmark of cancer, and evidence over the past decade has strongly linked CIN to tumour evolution, metastasis, immune evasion and treatment resistance. Until recently, the mechanisms by which CIN propels cancer progression have remained elusive. Beyond the generation of genomic copy number heterogeneity, recent work has unveiled additional tumour-promoting consequences of abnormal chromosome segregation. These mechanisms include complex chromosomal rearrangements, epigenetic reprogramming and the induction of cancer cell-intrinsic inflammation, emphasizing the multifaceted role of CIN in cancer. Chromosomal instability (CIN) drives cancer progression through diverse mechanisms. The authors review the molecular consequences of CIN in advanced cancer, such as genomic and phenotypic heterogeneity and cancer cell-intrinsic inflammation.
{"title":"Chromosomal instability as a driver of cancer progression","authors":"Xuelan Chen, Albert S. Agustinus, Jun Li, Melody DiBona, Samuel F. Bakhoum","doi":"10.1038/s41576-024-00761-7","DOIUrl":"10.1038/s41576-024-00761-7","url":null,"abstract":"Chromosomal instability (CIN) refers to an increased propensity of cells to acquire structural and numerical chromosomal abnormalities during cell division, which contributes to tumour genetic heterogeneity. CIN has long been recognized as a hallmark of cancer, and evidence over the past decade has strongly linked CIN to tumour evolution, metastasis, immune evasion and treatment resistance. Until recently, the mechanisms by which CIN propels cancer progression have remained elusive. Beyond the generation of genomic copy number heterogeneity, recent work has unveiled additional tumour-promoting consequences of abnormal chromosome segregation. These mechanisms include complex chromosomal rearrangements, epigenetic reprogramming and the induction of cancer cell-intrinsic inflammation, emphasizing the multifaceted role of CIN in cancer. Chromosomal instability (CIN) drives cancer progression through diverse mechanisms. The authors review the molecular consequences of CIN in advanced cancer, such as genomic and phenotypic heterogeneity and cancer cell-intrinsic inflammation.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 1","pages":"31-46"},"PeriodicalIF":39.1,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791103","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":"Epigenetic editing works like a CHARM","authors":"Kirsty Minton","doi":"10.1038/s41576-024-00765-3","DOIUrl":"10.1038/s41576-024-00765-3","url":null,"abstract":"Neumann, Bertozzi et al. describe a novel epigenetic editor termed CHARM and report its use to silence prion protein expression in the brain.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 9","pages":"600-600"},"PeriodicalIF":39.1,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141737017","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}
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