Pub Date : 2024-10-03DOI: 10.1038/s41580-024-00775-3
Zeming Wu, Jing Qu, Guang-Hui Liu
Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation. We also discuss how emerging therapeutic strategies could restore heterochromatin stability, maintain telomere integrity and boost the DNA repair capacity, and thus counteract cellular senescence and ageing-associated pathologies. Finally, we outline current research challenges and future directions aimed at better comprehending and delaying ageing. Heterochromatin loss, telomere attrition and DNA damage induce cellular senescence by eliciting genome instability and innate immunity responses, thereby promoting ageing and age-related diseases. This Review discusses the underlying mechanisms of these processes and emerging cell-senescence therapeutics that target them.
衰老是一个复杂的生物过程，在这个过程中，生理机能的逐渐衰退增加了对神经退行性疾病和癌症等疾病的易感性。细胞衰老是一种不可逆的细胞生长停滞状态，伴随着功能退化，已成为老化的关键驱动因素。在这篇综述中，我们将讨论异染色质丢失、端粒损耗和 DNA 损伤如何通过引发基因组不稳定性、先天免疫和炎症而导致细胞衰老、老化和与年龄相关的疾病。我们还讨论了新出现的治疗策略如何能够恢复异染色质的稳定性、维持端粒的完整性和提高DNA修复能力，从而对抗细胞衰老和与衰老相关的病症。最后，我们概述了当前的研究挑战和未来的研究方向，旨在更好地理解和延缓衰老。
{"title":"Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases","authors":"Zeming Wu, Jing Qu, Guang-Hui Liu","doi":"10.1038/s41580-024-00775-3","DOIUrl":"10.1038/s41580-024-00775-3","url":null,"abstract":"Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation. We also discuss how emerging therapeutic strategies could restore heterochromatin stability, maintain telomere integrity and boost the DNA repair capacity, and thus counteract cellular senescence and ageing-associated pathologies. Finally, we outline current research challenges and future directions aimed at better comprehending and delaying ageing. Heterochromatin loss, telomere attrition and DNA damage induce cellular senescence by eliciting genome instability and innate immunity responses, thereby promoting ageing and age-related diseases. This Review discusses the underlying mechanisms of these processes and emerging cell-senescence therapeutics that target them.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 12","pages":"979-1000"},"PeriodicalIF":81.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368831","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 : 2024-10-02DOI: 10.1038/s41580-024-00772-6
Pavel Kravchenko, Kikuë Tachibana
In sexually reproducing organisms, life begins with the fusion of transcriptionally silent gametes, the oocyte and sperm. Although initiation of transcription in the embryo, known as zygotic genome activation (ZGA), is universally required for development, the transcription factors regulating this process are poorly conserved. In this Perspective, we discuss recent insights into the mechanisms of ZGA in totipotent mammalian embryos, namely ZGA regulation by several transcription factors, including by orphan nuclear receptors (OrphNRs) such as the pioneer transcription factor NR5A2, and by factors of the DUX, TPRX and OBOX families. We performed a meta-analysis and compiled a list of pan-ZGA genes, and found that most of these genes are indeed targets of the above transcription factors. Remarkably, more than a third of these ZGA genes appear to be regulated both by OrphNRs such as NR5A2 and by OBOX proteins, whose motifs co-occur in SINE B1 retrotransposable elements, which are enriched near ZGA genes. We propose that ZGA in mice is activated by recruitment of multiple transcription factors to SINE B1 elements that function as enhancers, and discuss a potential relevance of this mechanism to Alu retrotransposable elements in human ZGA. Although zygotic genome activation (ZGA) is universally required for development, the responsible transcription factors are poorly conserved. In mammalian totipotent embryos, (pioneer) transcription factors of two families co-regulate many ZGA genes by binding to nearby SINE retrotransposons, which thus function as their enhancers.
在有性生殖的生物体中，生命始于转录沉默配子（卵细胞和精子）的融合。虽然胚胎中转录的启动（称为子代基因组激活（ZGA））是发育的普遍需要，但调控这一过程的转录因子的保守性很差。在本《视角》中，我们讨论了最近对全能哺乳动物胚胎中 ZGA 机制的见解，即 ZGA 受多种转录因子调控，包括孤儿核受体（OrphNRs）（如先驱转录因子 NR5A2）以及 DUX、TPRX 和 OBOX 家族因子。我们进行了一项荟萃分析，编制了一份泛 ZGA 基因列表，发现其中大多数基因确实是上述转录因子的靶标。值得注意的是，在这些 ZGA 基因中，有三分之一以上的基因似乎同时受到 OrphNRs（如 NR5A2）和 OBOX 蛋白的调控，OBOX 蛋白的基序共同出现在 SINE B1 可逆转录元件中，而 SINE B1 可逆转录元件富集在 ZGA 基因附近。我们提出，小鼠的 ZGA 是通过将多种转录因子招募到起增强子作用的 SINE B1 元件而激活的，并讨论了这一机制与人类 ZGA 中的 Alu 可逆转录元件的潜在相关性。
{"title":"Rise and SINE: roles of transcription factors and retrotransposons in zygotic genome activation","authors":"Pavel Kravchenko, Kikuë Tachibana","doi":"10.1038/s41580-024-00772-6","DOIUrl":"10.1038/s41580-024-00772-6","url":null,"abstract":"In sexually reproducing organisms, life begins with the fusion of transcriptionally silent gametes, the oocyte and sperm. Although initiation of transcription in the embryo, known as zygotic genome activation (ZGA), is universally required for development, the transcription factors regulating this process are poorly conserved. In this Perspective, we discuss recent insights into the mechanisms of ZGA in totipotent mammalian embryos, namely ZGA regulation by several transcription factors, including by orphan nuclear receptors (OrphNRs) such as the pioneer transcription factor NR5A2, and by factors of the DUX, TPRX and OBOX families. We performed a meta-analysis and compiled a list of pan-ZGA genes, and found that most of these genes are indeed targets of the above transcription factors. Remarkably, more than a third of these ZGA genes appear to be regulated both by OrphNRs such as NR5A2 and by OBOX proteins, whose motifs co-occur in SINE B1 retrotransposable elements, which are enriched near ZGA genes. We propose that ZGA in mice is activated by recruitment of multiple transcription factors to SINE B1 elements that function as enhancers, and discuss a potential relevance of this mechanism to Alu retrotransposable elements in human ZGA. Although zygotic genome activation (ZGA) is universally required for development, the responsible transcription factors are poorly conserved. In mammalian totipotent embryos, (pioneer) transcription factors of two families co-regulate many ZGA genes by binding to nearby SINE retrotransposons, which thus function as their enhancers.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 1","pages":"68-79"},"PeriodicalIF":81.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362743","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 : 2024-10-01DOI: 10.1038/s41580-024-00788-y
Eytan Zlotorynski
mRNAs with alternative in-frame translation initiation sites can yield proteoforms with distinct localization and functions.
具有替代框架内翻译起始位点的 mRNA 可产生具有不同定位和功能的蛋白形式。
{"title":"Proteoforms: a tale of two (initiation) sites","authors":"Eytan Zlotorynski","doi":"10.1038/s41580-024-00788-y","DOIUrl":"10.1038/s41580-024-00788-y","url":null,"abstract":"mRNAs with alternative in-frame translation initiation sites can yield proteoforms with distinct localization and functions.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 11","pages":"843-843"},"PeriodicalIF":81.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362742","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 : 2024-09-30DOI: 10.1038/s41580-024-00777-1
Megan R. Chastney, Jasmin Kaivola, Veli-Matti Leppänen, Johanna Ivaska
Integrin receptors are the main molecular link between cells and the extracellular matrix (ECM) as well as mediating cell–cell interactions. Integrin–ECM binding triggers the formation of heterogeneous multi-protein assemblies termed integrin adhesion complexes (IACs) that enable integrins to transform extracellular cues into intracellular signals that affect many cellular processes, especially cell motility. Cell migration is essential for diverse physiological and pathological processes and is dysregulated in cancer to favour cell invasion and metastasis. Here, we discuss recent findings on the role of integrins in cell migration with a focus on cancer cell dissemination. We review how integrins regulate the spatial distribution and dynamics of different IACs, covering classical focal adhesions, emerging adhesion types and adhesion regulation. We discuss the diverse roles integrins have during cancer progression from cell migration across varied ECM landscapes to breaching barriers such as the basement membrane, and eventual colonization of distant organs.
{"title":"The role and regulation of integrins in cell migration and invasion","authors":"Megan R. Chastney, Jasmin Kaivola, Veli-Matti Leppänen, Johanna Ivaska","doi":"10.1038/s41580-024-00777-1","DOIUrl":"https://doi.org/10.1038/s41580-024-00777-1","url":null,"abstract":"<p>Integrin receptors are the main molecular link between cells and the extracellular matrix (ECM) as well as mediating cell–cell interactions. Integrin–ECM binding triggers the formation of heterogeneous multi-protein assemblies termed integrin adhesion complexes (IACs) that enable integrins to transform extracellular cues into intracellular signals that affect many cellular processes, especially cell motility. Cell migration is essential for diverse physiological and pathological processes and is dysregulated in cancer to favour cell invasion and metastasis. Here, we discuss recent findings on the role of integrins in cell migration with a focus on cancer cell dissemination. We review how integrins regulate the spatial distribution and dynamics of different IACs, covering classical focal adhesions, emerging adhesion types and adhesion regulation. We discuss the diverse roles integrins have during cancer progression from cell migration across varied ECM landscapes to breaching barriers such as the basement membrane, and eventual colonization of distant organs.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"37 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330230","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 : 2024-09-26DOI: 10.1038/s41580-024-00787-z
Terri L. Cain, Marta Derecka, Shannon McKinney-Freeman
{"title":"Author Correction: The role of the haematopoietic stem cell niche in development and ageing","authors":"Terri L. Cain, Marta Derecka, Shannon McKinney-Freeman","doi":"10.1038/s41580-024-00787-z","DOIUrl":"10.1038/s41580-024-00787-z","url":null,"abstract":"","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 1","pages":"80-80"},"PeriodicalIF":81.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41580-024-00787-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321127","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 : 2024-09-23DOI: 10.1038/s41580-024-00782-4
Michael M. Kozlov, Justin W. Taraska
{"title":"Publisher Correction: Generation of nanoscopic membrane curvature for membrane trafficking","authors":"Michael M. Kozlov, Justin W. Taraska","doi":"10.1038/s41580-024-00782-4","DOIUrl":"10.1038/s41580-024-00782-4","url":null,"abstract":"","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 11","pages":"947-947"},"PeriodicalIF":81.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41580-024-00782-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308181","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 : 2024-09-10DOI: 10.1038/s41580-024-00770-8
Terri L. Cain, Marta Derecka, Shannon McKinney-Freeman
Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored. Blood production depends on haematopoietic stem cells (HSCs) and progenitor cells, which are regulated by their microenvironment or niche. New lineage-tracing models and microscopy tools are increasing the understanding of HSC specification and function, and how stem cell–niche interactions are perturbed during ageing.
{"title":"The role of the haematopoietic stem cell niche in development and ageing","authors":"Terri L. Cain, Marta Derecka, Shannon McKinney-Freeman","doi":"10.1038/s41580-024-00770-8","DOIUrl":"10.1038/s41580-024-00770-8","url":null,"abstract":"Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored. Blood production depends on haematopoietic stem cells (HSCs) and progenitor cells, which are regulated by their microenvironment or niche. New lineage-tracing models and microscopy tools are increasing the understanding of HSC specification and function, and how stem cell–niche interactions are perturbed during ageing.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 1","pages":"32-50"},"PeriodicalIF":81.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160376","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 : 2024-09-09DOI: 10.1038/s41580-024-00773-5
Bailong Xiao
Mechanical force is an essential physical element that contributes to the formation and function of life. The discovery of the evolutionarily conserved PIEZO family, including PIEZO1 and PIEZO2 in mammals, as bona fide mechanically activated cation channels has transformed our understanding of how mechanical forces are sensed and transduced into biological activities. In this Review, I discuss recent structure–function studies that have illustrated how PIEZO1 and PIEZO2 adopt their unique structural design and curvature-based gating dynamics, enabling their function as dedicated mechanotransduction channels with high mechanosensitivity and selective cation conductivity. I also discuss our current understanding of the physiological and pathophysiological roles mediated by PIEZO channels, including PIEZO1-dependent regulation of development and functional homeostasis and PIEZO2-dominated mechanosensation of touch, tactile pain, proprioception and interoception of mechanical states of internal organs. Despite the remarkable progress in PIEZO research, this Review also highlights outstanding questions in the field. The mechanically activated cation channels PIEZO1 and PIEZO2 are crucial for mechanotransduction processes in mammals. This Review discusses the structural design and gating dynamics of PIEZO channels that enable their high mechanosensitivity, and highlights their physiological and pathological relevance.
{"title":"Mechanisms of mechanotransduction and physiological roles of PIEZO channels","authors":"Bailong Xiao","doi":"10.1038/s41580-024-00773-5","DOIUrl":"10.1038/s41580-024-00773-5","url":null,"abstract":"Mechanical force is an essential physical element that contributes to the formation and function of life. The discovery of the evolutionarily conserved PIEZO family, including PIEZO1 and PIEZO2 in mammals, as bona fide mechanically activated cation channels has transformed our understanding of how mechanical forces are sensed and transduced into biological activities. In this Review, I discuss recent structure–function studies that have illustrated how PIEZO1 and PIEZO2 adopt their unique structural design and curvature-based gating dynamics, enabling their function as dedicated mechanotransduction channels with high mechanosensitivity and selective cation conductivity. I also discuss our current understanding of the physiological and pathophysiological roles mediated by PIEZO channels, including PIEZO1-dependent regulation of development and functional homeostasis and PIEZO2-dominated mechanosensation of touch, tactile pain, proprioception and interoception of mechanical states of internal organs. Despite the remarkable progress in PIEZO research, this Review also highlights outstanding questions in the field. The mechanically activated cation channels PIEZO1 and PIEZO2 are crucial for mechanotransduction processes in mammals. This Review discusses the structural design and gating dynamics of PIEZO channels that enable their high mechanosensitivity, and highlights their physiological and pathological relevance.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 11","pages":"886-903"},"PeriodicalIF":81.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158970","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 : 2024-09-05DOI: 10.1038/s41580-024-00776-2
Jeroen van den Berg
In this Tools of the Trade article, Jeroen van den Berg (van Oudenaarden lab) presents a new method based on pulse-labelling of nascent DNA to study the dynamics of DNA replication in single cells.
在这篇贸易工具文章中，Jeroen van den Berg（van Oudenaarden 实验室）介绍了一种基于新生 DNA 脉冲标记的新方法，用于研究单细胞中 DNA 复制的动态。
{"title":"Dynamics of DNA replication speeds in single cells","authors":"Jeroen van den Berg","doi":"10.1038/s41580-024-00776-2","DOIUrl":"10.1038/s41580-024-00776-2","url":null,"abstract":"In this Tools of the Trade article, Jeroen van den Berg (van Oudenaarden lab) presents a new method based on pulse-labelling of nascent DNA to study the dynamics of DNA replication in single cells.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 11","pages":"841-841"},"PeriodicalIF":81.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137987","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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