Pub Date : 2025-10-16DOI: 10.1038/s41580-025-00912-6
Charles Barlowe
Two seminal studies from the 1980s catalysed major advances in the trafficking field, when converging research in yeast and mammalian cells revealed the molecular machinery of the secretory pathway.
{"title":"The secretory pathway gets a molecular framework","authors":"Charles Barlowe","doi":"10.1038/s41580-025-00912-6","DOIUrl":"10.1038/s41580-025-00912-6","url":null,"abstract":"Two seminal studies from the 1980s catalysed major advances in the trafficking field, when converging research in yeast and mammalian cells revealed the molecular machinery of the secretory pathway.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"907-907"},"PeriodicalIF":90.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305695","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 : 2025-10-13DOI: 10.1038/s41580-025-00896-3
Sonia Cruciani, Eva Maria Novoa
Nanopore direct RNA sequencing has enabled the detection of RNA modifications in native RNA molecules, initially through the analysis of signal alterations and base-calling errors. More recently, modification prediction has been integrated into the base-calling step using pretrained, modification-aware base-calling models. So far, such models have been made available for N6-methyladenosine (m6A), inosine (I), pseudouridine (Ψ) and N5-methylcytosine (m5C), enabling RNA modification mapping in single-molecule resolution. However, their performance remains largely unclear. In this Progress, we discuss key limitations and uncertainties associated with base-calling models, including their potential cross-reactivities with other modifications, variability in false positive rates across models, unclear threshold choices for modification calling, insufficient orthogonal validation of model accuracy and lack of standardized analysis pipelines. To illustrate some of these issues, we compared the performance of three base-calling models on identical RNA samples, observing over 20-fold differences in the number of predicted m6A-modified sites. As these models are increasingly adopted, it is crucial to understand their limitations to ensure best practices and avoid misinterpretation of epitranscriptomics data. Nanopore RNA sequencing is a potent technology for the detection of RNA modifications. Nanopore modification-aware base-calling models have been recently developed, and this Progress article discusses their limitations, including modification cross-reactivities, variability in false positive rates and modification-calling threshold choices.
{"title":"The new era of single-molecule RNA modification detection through nanopore base-calling models","authors":"Sonia Cruciani, Eva Maria Novoa","doi":"10.1038/s41580-025-00896-3","DOIUrl":"10.1038/s41580-025-00896-3","url":null,"abstract":"Nanopore direct RNA sequencing has enabled the detection of RNA modifications in native RNA molecules, initially through the analysis of signal alterations and base-calling errors. More recently, modification prediction has been integrated into the base-calling step using pretrained, modification-aware base-calling models. So far, such models have been made available for N6-methyladenosine (m6A), inosine (I), pseudouridine (Ψ) and N5-methylcytosine (m5C), enabling RNA modification mapping in single-molecule resolution. However, their performance remains largely unclear. In this Progress, we discuss key limitations and uncertainties associated with base-calling models, including their potential cross-reactivities with other modifications, variability in false positive rates across models, unclear threshold choices for modification calling, insufficient orthogonal validation of model accuracy and lack of standardized analysis pipelines. To illustrate some of these issues, we compared the performance of three base-calling models on identical RNA samples, observing over 20-fold differences in the number of predicted m6A-modified sites. As these models are increasingly adopted, it is crucial to understand their limitations to ensure best practices and avoid misinterpretation of epitranscriptomics data. Nanopore RNA sequencing is a potent technology for the detection of RNA modifications. Nanopore modification-aware base-calling models have been recently developed, and this Progress article discusses their limitations, including modification cross-reactivities, variability in false positive rates and modification-calling threshold choices.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"10-18"},"PeriodicalIF":90.2,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283457","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 : 2025-10-10DOI: 10.1038/s41580-025-00916-2
Min Zhang
The discovery of a cis-regulatory element required for xenobiotic gene activation highlighted the crucial role of enhancers in drug metabolism.
外源基因激活所需的顺式调控元件的发现突出了增强剂在药物代谢中的关键作用。
{"title":"Cis-regulatory elements that tune transcriptional responses in liver drug metabolism and outcomes","authors":"Min Zhang","doi":"10.1038/s41580-025-00916-2","DOIUrl":"10.1038/s41580-025-00916-2","url":null,"abstract":"The discovery of a cis-regulatory element required for xenobiotic gene activation highlighted the crucial role of enhancers in drug metabolism.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"909-909"},"PeriodicalIF":90.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261531","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 : 2025-10-09DOI: 10.1038/s41580-025-00913-5
Vinicius Maracaja-Coutinho, Helder I. Nakaya
Single-cell genomics and artificial intelligence (AI) hold great promise for precision medicine, yet biased datasets risk deepening health inequities. Latin American and Caribbean initiatives such as LatinCells are generating inclusive, AI-ready data and changing the region’s researchers from being sample providers to leaders that shape a more equitable genomics medicine. Latin American–Caribbean single-cell genomics initiatives are generating inclusive AI-ready data for precision medicine, and empowering the region’s scientists to become researcher leaders.
{"title":"Single-cell research in Latin America and the Caribbean builds genomics datasets for equitable AI-powered precision medicine","authors":"Vinicius Maracaja-Coutinho, Helder I. Nakaya","doi":"10.1038/s41580-025-00913-5","DOIUrl":"10.1038/s41580-025-00913-5","url":null,"abstract":"Single-cell genomics and artificial intelligence (AI) hold great promise for precision medicine, yet biased datasets risk deepening health inequities. Latin American and Caribbean initiatives such as LatinCells are generating inclusive, AI-ready data and changing the region’s researchers from being sample providers to leaders that shape a more equitable genomics medicine. Latin American–Caribbean single-cell genomics initiatives are generating inclusive AI-ready data for precision medicine, and empowering the region’s scientists to become researcher leaders.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"1-3"},"PeriodicalIF":90.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254753","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 : 2025-10-06DOI: 10.1038/s41580-025-00895-4
Carlos Alfonso-Gonzalez, Valérie Hilgers
The maturation of mRNAs is crucial for gene regulation and proteome diversification. Transcripts are processed co-transcriptionally through a complex interplay of mechanisms that involve numerous protein machineries. In eukaryotes, most genes undergo alternative RNA processing through the context-dependent use of transcription start sites (TSSs), splice sites and polyadenylation sites. The accurate measurement of alternative TSS usage, alternative splicing and alternative polyadenylation has been enabled by short-read RNA-sequencing technologies. However, elucidating the timing, coordination and functional outcomes of alternative RNA processing is challenging, especially in vivo. The development of long-read sequencing (LRS) methodologies enables the characterization of various aspects of co-transcriptional RNA processing, each methodology providing unique perspectives and limitations. In this Review, we discuss recent advances in short-read sequencing and LRS technologies that measure transcripts in their nascent and mature state and at single-cell resolution and with whole-molecule read length in the case of LRS. We integrate new findings that functionally link alternative TSS, alternative splicing and alternative polyadenylation, with new implications for diseases such as cancer and neurodevelopmental and neurodegenerative disorders. Finally, we discuss insights gained using CRISPR tools into the coordination of RNA processing events. Co-transcriptional mRNA maturation is a complex, multistep process. This Review focuses on how the development of long-read sequencing methods enabled investigating the timing, coordination and outcomes of alternative uses of transcription start sites, splice sites and polyadenylation sites and their disease implications.
{"title":"Elucidating the coordination of RNA processing using short-read and long-read RNA-sequencing methods","authors":"Carlos Alfonso-Gonzalez, Valérie Hilgers","doi":"10.1038/s41580-025-00895-4","DOIUrl":"10.1038/s41580-025-00895-4","url":null,"abstract":"The maturation of mRNAs is crucial for gene regulation and proteome diversification. Transcripts are processed co-transcriptionally through a complex interplay of mechanisms that involve numerous protein machineries. In eukaryotes, most genes undergo alternative RNA processing through the context-dependent use of transcription start sites (TSSs), splice sites and polyadenylation sites. The accurate measurement of alternative TSS usage, alternative splicing and alternative polyadenylation has been enabled by short-read RNA-sequencing technologies. However, elucidating the timing, coordination and functional outcomes of alternative RNA processing is challenging, especially in vivo. The development of long-read sequencing (LRS) methodologies enables the characterization of various aspects of co-transcriptional RNA processing, each methodology providing unique perspectives and limitations. In this Review, we discuss recent advances in short-read sequencing and LRS technologies that measure transcripts in their nascent and mature state and at single-cell resolution and with whole-molecule read length in the case of LRS. We integrate new findings that functionally link alternative TSS, alternative splicing and alternative polyadenylation, with new implications for diseases such as cancer and neurodevelopmental and neurodegenerative disorders. Finally, we discuss insights gained using CRISPR tools into the coordination of RNA processing events. Co-transcriptional mRNA maturation is a complex, multistep process. This Review focuses on how the development of long-read sequencing methods enabled investigating the timing, coordination and outcomes of alternative uses of transcription start sites, splice sites and polyadenylation sites and their disease implications.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 3","pages":"194-212"},"PeriodicalIF":90.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235540","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 : 2025-10-02DOI: 10.1038/s41580-025-00906-4
Christina Marie Termini
Christina Termini highlights the importance of the identification of haematopoietic stem cell markers.
Christina Termini强调了鉴定造血干细胞标记物的重要性。
{"title":"SLAM passes the haematopoietic stem cell identity test","authors":"Christina Marie Termini","doi":"10.1038/s41580-025-00906-4","DOIUrl":"10.1038/s41580-025-00906-4","url":null,"abstract":"Christina Termini highlights the importance of the identification of haematopoietic stem cell markers.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"9-9"},"PeriodicalIF":90.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209286","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 : 2025-10-01DOI: 10.1038/s41580-025-00910-8
Kim Baumann
Colon stem cells expressing the surface markers NOX1 and NPY1R can give rise to colon cancer in mice.
表达表面标记物NOX1和NPY1R的结肠干细胞可引起小鼠结肠癌。
{"title":"Stem cell sources of colon cancer in mice","authors":"Kim Baumann","doi":"10.1038/s41580-025-00910-8","DOIUrl":"10.1038/s41580-025-00910-8","url":null,"abstract":"Colon stem cells expressing the surface markers NOX1 and NPY1R can give rise to colon cancer in mice.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 11","pages":"823-823"},"PeriodicalIF":90.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203556","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 : 2025-10-01DOI: 10.1038/s41580-025-00905-5
Sean Munro
The advent of laser-scanning confocal microscopy revolutionized cell biology, offering unprecedented resolution and depth and enabling scientists to visualize cellular structures in 3D.
Pub Date : 2025-09-30DOI: 10.1038/s41580-025-00882-9
Tony Tiganis, Nicholas K. Tonks
Aberrations in protein tyrosine phosphorylation-dependent cell signalling contribute to a wide variety of human diseases. Drugs targeting protein tyrosine kinases have had a major impact on human health; by contrast, protein tyrosine phosphatases (PTPs), which serve unique functions and together with protein tyrosine kinases coordinate tyrosine phosphorylation-dependent cell signalling, have been underexploited therapeutically. In this Review, we discuss key breakthroughs in our understanding of how PTPs are regulated, highlight their capacity to coordinate signalling and provide examples of their complex roles in physiology and pathophysiology, including diabetes, obesity and cancer. Also, we discuss the development of PTP-targeted therapeutics that are in clinical trials or poised for clinical translation. We argue that the emergence of this class of enzymes from the shadows lays the foundation for a more complete understanding of the regulation of cell signalling and heralds a new era of drug development opportunities to combat important human diseases. Protein tyrosine phosphatases (PTPs) regulate cell signalling and contribute to a wide range of human diseases. This Review discusses mechanistic insights into PTP function and regulation, their physiological roles and the development of PTP-targeted therapeutics.
{"title":"Mechanisms, functions and therapeutic targeting of protein tyrosine phosphatases","authors":"Tony Tiganis, Nicholas K. Tonks","doi":"10.1038/s41580-025-00882-9","DOIUrl":"10.1038/s41580-025-00882-9","url":null,"abstract":"Aberrations in protein tyrosine phosphorylation-dependent cell signalling contribute to a wide variety of human diseases. Drugs targeting protein tyrosine kinases have had a major impact on human health; by contrast, protein tyrosine phosphatases (PTPs), which serve unique functions and together with protein tyrosine kinases coordinate tyrosine phosphorylation-dependent cell signalling, have been underexploited therapeutically. In this Review, we discuss key breakthroughs in our understanding of how PTPs are regulated, highlight their capacity to coordinate signalling and provide examples of their complex roles in physiology and pathophysiology, including diabetes, obesity and cancer. Also, we discuss the development of PTP-targeted therapeutics that are in clinical trials or poised for clinical translation. We argue that the emergence of this class of enzymes from the shadows lays the foundation for a more complete understanding of the regulation of cell signalling and heralds a new era of drug development opportunities to combat important human diseases. Protein tyrosine phosphatases (PTPs) regulate cell signalling and contribute to a wide range of human diseases. This Review discusses mechanistic insights into PTP function and regulation, their physiological roles and the development of PTP-targeted therapeutics.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 2","pages":"129-152"},"PeriodicalIF":90.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194782","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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