{"title":"Expanding the genetic code for site-specific lysine lactylation","authors":"Zhi Zong","doi":"10.1038/s41580-025-00832-5","DOIUrl":"https://doi.org/10.1038/s41580-025-00832-5","url":null,"abstract":"In this Tools of the Trade article, Zong (Zhou lab) describes how using genetic code expansion enabled the precise incorporation of post-translational modifications such as lysine lactylation into proteins, allowing the authors to investigate their role in cellular processes.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"132 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083415","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":"Unravelling the complexity of gene regulation through multiplexed protein mapping","authors":"Isabel Nadine Goronzy","doi":"10.1038/s41580-025-00830-7","DOIUrl":"https://doi.org/10.1038/s41580-025-00830-7","url":null,"abstract":"In this Tools of the Trade article, Goronzy (Guttman lab) describes the development of ChIP-DIP, a high-throughput, split-pool barcoding method that enables genome-wide profiling of hundreds of regulatory proteins, transforming our ability to study the regulation of gene activity across cell types and biological contexts.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"11 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124317","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":"Silencing centromeres with age","authors":"Katharine H. Wrighton","doi":"10.1038/s41580-025-00829-0","DOIUrl":"https://doi.org/10.1038/s41580-025-00829-0","url":null,"abstract":"Centromeres are silenced in aged cells by the epigenetic downregulation of centromere transcription.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"39 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072634","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":"Shaping epithelial tissues by stem cell mechanics in development and cancer","authors":"Vincent F. Fiore, Jorge Almagro, Elaine Fuchs","doi":"10.1038/s41580-024-00821-0","DOIUrl":"https://doi.org/10.1038/s41580-024-00821-0","url":null,"abstract":"<p>Adult stem cells balance self-renewal and differentiation to build, maintain and repair tissues. The role of signalling pathways and transcriptional networks in controlling stem cell function has been extensively studied, but there is increasing appreciation that mechanical forces also have a crucial regulatory role. Mechanical forces, signalling pathways and transcriptional networks must be coordinated across diverse length and timescales to maintain tissue homeostasis and function. Such coordination between stem cells and neighbouring cells dictates when cells divide, migrate and differentiate. Recent advances in measuring and manipulating the mechanical forces that act upon and are produced by stem cells are providing new insights into development and disease. In this Review, we discuss the mechanical forces involved when epithelial stem cells construct their microenvironment and what happens in cancer when stem cell niche mechanics are disrupted or dysregulated. As the skin has evolved to withstand the harsh mechanical pressures from the outside environment, we often use the stem cells of mammalian skin epithelium as a paradigm for adult stem cells shaping their surrounding tissues.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"14 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055052","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":"The centromere as a tag of self-DNA","authors":"Ruth Kroschewski","doi":"10.1038/s41580-025-00827-2","DOIUrl":"https://doi.org/10.1038/s41580-025-00827-2","url":null,"abstract":"Intriguing findings in yeast suggested that centromeres ‘tag’ DNA as self and allow its condensation during mitosis; vice versa, if a certain DNA is condensed during mitosis, it harbours a centromere.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"29 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055051","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}
Jesus M. Gomez-Salinero, David Redmond, Shahin Rafii
{"title":"Microenvironmental determinants of endothelial cell heterogeneity","authors":"Jesus M. Gomez-Salinero, David Redmond, Shahin Rafii","doi":"10.1038/s41580-024-00825-w","DOIUrl":"https://doi.org/10.1038/s41580-024-00825-w","url":null,"abstract":"<p>During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specific signalling activated by vasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures, contributing to the pathogenesis of disease processes. We also describe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"35 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049942","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}
Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky
{"title":"The roles of mitochondria in global and local intracellular calcium signalling","authors":"Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky","doi":"10.1038/s41580-024-00820-1","DOIUrl":"https://doi.org/10.1038/s41580-024-00820-1","url":null,"abstract":"<p>Activation of Ca<sup>2+</sup> channels in Ca<sup>2+</sup> stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca<sup>2+</sup>]<sub>c</sub>) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca<sup>2+</sup> uptake and chelation, alongside efficient Ca<sup>2+</sup> release mechanisms. Still, mitochondria do not store Ca<sup>2+</sup> in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca<sup>2+</sup>]<sub>c</sub> signals. However, mitochondria take up Ca<sup>2+</sup> at high local [Ca<sup>2+</sup>]<sub>c</sub> signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca<sup>2+</sup>]<sub>c</sub>. Accumulated Ca<sup>2+</sup> in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca<sup>2+</sup>]<sub>c</sub> to exert control over processes that are sensitive to Ca<sup>2+</sup>. Thus, the mitochondrial handling of [Ca<sup>2+</sup>]<sub>c</sub> is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca<sup>2+</sup> handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"20 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044165","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":"Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction","authors":"Madelon M. Maurice, Stephane Angers","doi":"10.1038/s41580-024-00823-y","DOIUrl":"https://doi.org/10.1038/s41580-024-00823-y","url":null,"abstract":"<p>In multicellular organisms, Wnt proteins govern stem and progenitor cell renewal and differentiation to regulate embryonic development, adult tissue homeostasis and tissue regeneration. Defects in canonical Wnt signalling, which is transduced intracellularly by β-catenin, have been associated with developmental disorders, degenerative diseases and cancers. Although a simple model describing Wnt–β-catenin signalling is widely used to introduce this pathway and has largely remained unchanged over the past 30 years, in this Review we discuss recent studies that have provided important new insights into the mechanisms of Wnt production, receptor activation and intracellular signalling that advance our understanding of the molecular mechanisms that underlie this important cell–cell communication system. In addition, we review the recent development of molecules capable of activating the Wnt–β-catenin pathway with selectivity in vitro and in vivo that is enabling new lines of study to pave the way for the development of Wnt therapies for the treatment of human diseases.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"13 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A guide to the biogenesis and functions of endogenous small non-coding RNAs in animals","authors":"Karina Jouravleva, Phillip D. Zamore","doi":"10.1038/s41580-024-00818-9","DOIUrl":"https://doi.org/10.1038/s41580-024-00818-9","url":null,"abstract":"<p>Small non-coding RNAs can be categorized into two main classes: structural RNAs and regulatory RNAs. Structural RNAs, which are abundant and ubiquitously expressed, have essential roles in the maturation of pre-mRNAs, modification of rRNAs and the translation of coding transcripts. By contrast, regulatory RNAs are often expressed in a developmental-specific, tissue-specific or cell-type-specific manner and exert precise control over gene expression. Reductions in cost and improvements in the accuracy of high-throughput RNA sequencing have led to the identification of many new small RNA species. In this Review, we provide a broad discussion of the genomic origins, biogenesis and functions of structural small RNAs, including tRNAs, small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), vault RNAs (vtRNAs) and Y RNAs as well as their derived RNA fragments, and of regulatory small RNAs, such as microRNAs (miRNAs), endogenous small interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs), in animals.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"35 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030728","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}