{"title":"Spatial transcriptomic characterization of a Carnegie stage 7 human embryo","authors":"Lina Cui, Sirui Lin, Xiaolong Yang, Xinwei Xie, Xiaoyan Wang, Nannan He, Jingyu Yang, Xin Zhang, Xiaojian Lu, Xiaodi Yan, Yifei Guo, Bailing Zhang, Ran Li, Hefan Miao, Mei Ji, Runzhao Zhang, Leqian Yu, Zhenyu Xiao, Yulei Wei, Jingtao Guo","doi":"10.1038/s41556-024-01597-3","DOIUrl":"https://doi.org/10.1038/s41556-024-01597-3","url":null,"abstract":"<p>Gastrulation marks a pivotal stage in mammalian embryonic development, establishing the three germ layers and body axis through lineage diversification and morphogenetic movements. However, studying human gastrulating embryos is challenging due to limited access to early tissues. Here we show the use of spatial transcriptomics to analyse a fully intact Carnegie stage 7 human embryo at single-cell resolution, along with immunofluorescence validations in a second embryo. Employing 82 serial cryosections and Stereo-seq technology, we reconstructed a three-dimensional model of the embryo. Our findings reveal early specification of distinct mesoderm subtypes and the presence of the anterior visceral endoderm. Notably, primordial germ cells were located in the connecting stalk, and haematopoietic stem cell-independent haematopoiesis was observed in the yolk sac. This study advances our understanding of human gastrulation and provides a valuable dataset for future research in early human development.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"40 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961337","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":"Boosting cargo turnover with receptor mobility","authors":"Yi Lu, Chunmei Chang","doi":"10.1038/s41556-024-01576-8","DOIUrl":"https://doi.org/10.1038/s41556-024-01576-8","url":null,"abstract":"The clearance of biomacromolecules through selective autophagy is crucial for cellular homeostasis. A study now identifies receptor mobility as a key factor influencing cargo degradability. A dynamic cargo–receptor surface enables phase separation of essential autophagy initiation proteins, which drives phagophore formation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"15 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937082","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}
Luke J. Fulcher, Tomoaki Sobajima, Caleb Batley, Ian Gibbs-Seymour, Francis A. Barr
{"title":"MDM2 functions as a timer reporting the length of mitosis","authors":"Luke J. Fulcher, Tomoaki Sobajima, Caleb Batley, Ian Gibbs-Seymour, Francis A. Barr","doi":"10.1038/s41556-024-01592-8","DOIUrl":"https://doi.org/10.1038/s41556-024-01592-8","url":null,"abstract":"<p>Delays in mitosis trigger p53-dependent arrest in G1 of the next cell cycle, thus preventing repeated cycles of chromosome instability and aneuploidy. Here we show that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises due to the attenuation of protein synthesis in mitosis. Because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration, the amount of MDM2 gradually falls during mitosis but normally remains above a critical threshold for p53 regulation at the onset of G1. When mitosis is extended by prolonged spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, stabilizing p53. Subsequent p53-dependent p21 accumulation then channels G1 cells into a sustained cell-cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"35 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937084","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}
Gang Ma, Xiuling Fu, Lulu Zhou, Isaac A. Babarinde, Liyang Shi, Wenting Yang, Jiao Chen, Zhen Xiao, Yu Qiao, Lisha Ma, Yuhao Ou, Yuhao Li, Chen Chang, Boping Deng, Ran Zhang, Li Sun, Guoqing Tong, Dongwei Li, Yiming Li, Andrew P. Hutchins
{"title":"The nuclear matrix stabilizes primed-specific genes in human pluripotent stem cells","authors":"Gang Ma, Xiuling Fu, Lulu Zhou, Isaac A. Babarinde, Liyang Shi, Wenting Yang, Jiao Chen, Zhen Xiao, Yu Qiao, Lisha Ma, Yuhao Ou, Yuhao Li, Chen Chang, Boping Deng, Ran Zhang, Li Sun, Guoqing Tong, Dongwei Li, Yiming Li, Andrew P. Hutchins","doi":"10.1038/s41556-024-01595-5","DOIUrl":"https://doi.org/10.1038/s41556-024-01595-5","url":null,"abstract":"<p>The nuclear matrix, a proteinaceous gel composed of proteins and RNA, is an important nuclear structure that supports chromatin architecture, but its role in human pluripotent stem cells (hPSCs) has not been described. Here we show that by disrupting heterogeneous nuclear ribonucleoprotein U (HNRNPU) or the nuclear matrix protein, Matrin-3, primed hPSCs adopted features of the naive pluripotent state, including morphology and upregulation of naive-specific marker genes. We demonstrate that <i>HNRNPU</i> depletion leads to increased chromatin accessibility, reduced DNA contacts and increased nuclear size. Mechanistically, HNRNPU acts as a transcriptional co-factor that anchors promoters of primed-specific genes to the nuclear matrix with POLII to promote their expression and their RNA stability. Overall, HNRNPU promotes cell-type stability and when reduced promotes conversion to earlier embryonic states.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"5 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937086","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":"Transcription factor networks in cellular quiescence","authors":"Mithun Mitra, Sandra L. Batista, Hilary A. Coller","doi":"10.1038/s41556-024-01582-w","DOIUrl":"10.1038/s41556-024-01582-w","url":null,"abstract":"Many of the cells in mammalian tissues are in a reversible quiescent state; they are not dividing, but retain the ability to proliferate in response to extracellular signals. Quiescence relies on the activities of transcription factors (TFs) that orchestrate the repression of genes that promote proliferation and establish a quiescence-specific gene expression program. Here we discuss how the coordinated activities of TFs in different quiescent stem cells and differentiated cells maintain reversible cell cycle arrest and establish cell-protective signalling pathways. We further cover the emerging mechanisms governing the dysregulation of quiescence TF networks with age. We explore how recent developments in single-cell technologies have enhanced our understanding of quiescence heterogeneity and gene regulatory networks. We further discuss how TFs and their activities are themselves regulated at the RNA, protein and chromatin levels. Finally, we summarize the challenges associated with defining TF networks in quiescent cells. Recent developments in single-cell technologies have increased our understanding of how the coordinated activities of transcription factors in different quiescent cells and differentiated cells maintain reversible cell cycle arrest.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"14-27"},"PeriodicalIF":17.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937087","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":"Precursor occupancy controls mitochondrial import channel via proteolysis","authors":"","doi":"10.1038/s41556-024-01575-9","DOIUrl":"https://doi.org/10.1038/s41556-024-01575-9","url":null,"abstract":"Blocking the translocase of the outer membrane (TOM) channel induces elimination of unoccupied protein import channels in the inner membrane by an ATP-dependent protease. Precursor-dependent adjustment of the number of translocator channels provides new insights into mitochondrial quality control upon protein import stress.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"36 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936057","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}
Zakery N. Baker, Yunyun Zhu, Rachel M. Guerra, Andrew J. Smith, Aline Arra, Lia R. Serrano, Katherine A. Overmyer, Shankar Mukherji, Elizabeth A. Craig, Joshua J. Coon, David J. Pagliarini
{"title":"Triacylglycerol mobilization underpins mitochondrial stress recovery","authors":"Zakery N. Baker, Yunyun Zhu, Rachel M. Guerra, Andrew J. Smith, Aline Arra, Lia R. Serrano, Katherine A. Overmyer, Shankar Mukherji, Elizabeth A. Craig, Joshua J. Coon, David J. Pagliarini","doi":"10.1038/s41556-024-01586-6","DOIUrl":"https://doi.org/10.1038/s41556-024-01586-6","url":null,"abstract":"<p>Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to <i>Saccharomyces cerevisiae</i> and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936280","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}
Joana C. Macedo, Maria M. da Silva, Elsa Logarinho
{"title":"Misshapen chromosomes in check by mechanics","authors":"Joana C. Macedo, Maria M. da Silva, Elsa Logarinho","doi":"10.1038/s41556-024-01573-x","DOIUrl":"10.1038/s41556-024-01573-x","url":null,"abstract":"Errors in chromosome segregation during cell division lead to changes in nuclear features. A study now shows that a mechanosensitive nuclear checkpoint activates the tumour suppressor p53 to halt the proliferation of aneuploid cells. These findings provide mechanistic insights to explore in both ageing and cancer pathologies.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"9-11"},"PeriodicalIF":17.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840881","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":"Gallbladder-derived retinoic acid signalling drives reconstruction of the damaged intrahepatic biliary ducts","authors":"Jianbo He, Shuang Li, Zhuolin Yang, Jianlong Ma, Chuanfang Qian, Zhuofu Huang, Linke Li, Yun Yang, Jingying Chen, Yunfan Sun, Tianyu Zhao, Lingfei Luo","doi":"10.1038/s41556-024-01568-8","DOIUrl":"10.1038/s41556-024-01568-8","url":null,"abstract":"Severe damage to the intrahepatic biliary duct (IHBD) network occurs in multiple human advanced cholangiopathies, such as primary sclerosing cholangitis, biliary atresia and end-stage primary biliary cholangitis. Whether and how a severely damaged IHBD network could reconstruct has remained unclear. Here we show that, although the gallbladder is not directly connected to the IHBD, there is a common hepatic duct (CHD) in between, and severe damage to the IHBD network induces migration of gallbladder smooth muscle cells (SMCs) to coat the CHD in mouse and zebrafish models. These gallbladder-derived, CHD-coating SMCs produce retinoic acid to activate Sox9b in the CHD, which drives proliferation and ingrowth of CHD cells into the inner liver to reconstruct the IHBD network. This study reveals a hitherto unappreciated function of the gallbladder in the recovery of injured liver, and characterizes mechanisms involved in how the gallbladder and liver communicate through inter-organ cell migration to drive tissue regeneration. Carrying out cholecystectomy will thus cause previously unexpected impairments to liver health. Luo et al. show in zebrafish and mouse that, upon intrahepatic biliary duct damage, gallbladder smooth muscle cells migrate to the common hepatic duct, where they produce retinoic acid to promote regeneration of the intrahepatic biliary duct.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"39-47"},"PeriodicalIF":17.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936061","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}
Alison R. S. Pashos, Anne R. Meyer, Cameron Bussey-Sutton, Erin S. O’Connor, Mariel Coradin, Marilyne Coulombe, Kent A. Riemondy, Sanjana Potlapelly, Brian D. Strahl, Gunnar C. Hansson, Peter J. Dempsey, Justin Brumbaugh
{"title":"H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium","authors":"Alison R. S. Pashos, Anne R. Meyer, Cameron Bussey-Sutton, Erin S. O’Connor, Mariel Coradin, Marilyne Coulombe, Kent A. Riemondy, Sanjana Potlapelly, Brian D. Strahl, Gunnar C. Hansson, Peter J. Dempsey, Justin Brumbaugh","doi":"10.1038/s41556-024-01580-y","DOIUrl":"https://doi.org/10.1038/s41556-024-01580-y","url":null,"abstract":"<p>Plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration. While precise gene expression controls these processes, the regulatory mechanisms that restrict or promote cell plasticity are poorly understood. Here we use the mouse small intestine as a model system to study cell plasticity. We find that H3K36 methylation reinforces expression of cell-type-associated genes to maintain specialized cell identity in intestinal epithelial cells. Depleting H3K36 methylation disrupts lineage commitment and activates regenerative gene expression. Correspondingly, we observe rapid and reversible remodelling of H3K36 methylation following injury-induced regeneration. These data suggest a fundamental role for H3K36 methylation in reinforcing specialized lineages and regulating cell plasticity and regeneration.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"23 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936059","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}