Nature Cell Biology最新文献

{"title":"Speckle signatures dictate cancer prognosis","authors":"Hiro Takakuwa, Tetsuro Hirose","doi":"10.1038/s41556-024-01569-7","DOIUrl":"10.1038/s41556-024-01569-7","url":null,"abstract":"Nuclear speckles are dynamic structures enriched in RNA and RNA regulators, with varying compositions. A study now reports two distinct signatures of nuclear speckles that are linked to the prognosis of clear cell renal cell carcinoma. The signatures influence the expression of genes regulated by the transcription factor HIF2α.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 2","pages":"180-181"},"PeriodicalIF":17.3,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917015","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":"Nuclear speckles regulate functional programs in cancer","authors":"Katherine A. Alexander, Ruofan Yu, Nicolas Skuli, Nathan J. Coffey, Son Nguyen, Christine L. Faunce, Hua Huang, Ian P. Dardani, Austin L. Good, Joan Lim, Catherine Y. Li, Nicholas Biddle, Eric F. Joyce, Arjun Raj, Daniel Lee, Brian Keith, M. Celeste Simon, Shelley L. Berger","doi":"10.1038/s41556-024-01570-0","DOIUrl":"10.1038/s41556-024-01570-0","url":null,"abstract":"Nuclear speckles are dynamic nuclear bodies characterized by high concentrations of factors involved in RNA production. Although the contents of speckles suggest multifaceted roles in gene regulation, their biological functions are unclear. Here we investigate speckle variation in human cancer, finding two main signatures. One speckle signature was similar to healthy adjacent tissues, whereas the other was dissimilar, and considered an aberrant cancer speckle state. Aberrant speckles show altered positioning within the nucleus, higher levels of the TREX RNA export complex and correlate with poorer patient outcomes in clear cell renal cell carcinoma (ccRCC), a cancer typified by hyperactivation of the HIF-2α transcription factor. We demonstrate that HIF-2α promotes physical association of certain target genes with speckles depending on HIF-2α protein speckle-targeting motifs, defined in this study. We identify homologous speckle-targeting motifs within many transcription factors, suggesting that DNA-speckle targeting may be a general gene regulatory mechanism. Integrating functional, genomic and imaging studies, we show that HIF-2α gene regulatory programs are impacted by speckle state and by abrogation of HIF-2α-driven speckle targeting. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of select HIF-2α-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumour speckle states broadly correlate with altered functional pathways and expression of speckle-associated gene neighbourhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer. This study reports that nuclear speckle constituents have two expression states in cancer correlating with patient survival and HIF-2α functional programs. HIF-2α mediates nuclear speckle association of key genes activated in renal cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 2","pages":"322-335"},"PeriodicalIF":17.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911691","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 transcription factor GABPA is a master regulator of naive pluripotency","authors":"Chengjie Zhou, Meng Wang, Chunxia Zhang, Yi Zhang","doi":"10.1038/s41556-024-01554-0","DOIUrl":"10.1038/s41556-024-01554-0","url":null,"abstract":"The establishment of naive pluripotency is a continuous process starting with the generation of inner cell mass (ICM) that then differentiates into epiblast (EPI). Recent studies have revealed key transcription factors (TFs) for ICM formation, but which TFs initiate EPI specification remains unknown. Here, using a targeted rapid protein degradation system, we show that GABPA is not only a regulator of major ZGA, but also a master EPI specifier required for naive pluripotency establishment by regulating 47% of EPI genes during E3.5 to E4.5 transition. Chromatin binding dynamics analysis suggests that GABPA controls EPI formation at least partly by binding to the ICM gene promoters occupied by the pluripotency regulators TFAP2C and SOX2 at E3.5 to establish naive pluripotency at E4.5. Our study not only uncovers GABPA as a master pluripotency regulator, but also supports the notion that mammalian pluripotency establishment requires a dynamic and stepwise multi-TF regulatory network. Zhang and colleagues identify the transcription factor GABPA as a regulator of zygotic genome activation, epiblast formation and naive pluripotency establishment.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"48-58"},"PeriodicalIF":17.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01554-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911692","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}

{"title":"AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress","authors":"Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li","doi":"10.1038/s41556-024-01549-x","DOIUrl":"10.1038/s41556-024-01549-x","url":null,"abstract":"Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment. Zhai, Yang et al. report a central role for AMPK in regulating aldolase B-mediated glycerol synthesis and excretion under hypoxia as a mechanism to balance the trade-off between reductive and energy stress during tumour growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"141-153"},"PeriodicalIF":17.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911644","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":"TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling","authors":"Wei-Ting Lu, Lykourgos-Panagiotis Zalmas, Chris Bailey, James R. M. Black, Carlos Martinez-Ruiz, Oriol Pich, Francisco Gimeno-Valiente, Ieva Usaite, Alastair Magness, Kerstin Thol, Thomas A. Webber, Ming Jiang, Rebecca E. Saunders, Yun-Hsin Liu, Dhruva Biswas, Esther O. Ige, Birgit Aerne, Eva Grönroos, Subramanian Venkatesan, Georgia Stavrou, Takahiro Karasaki, Maise Al Bakir, Matthew Renshaw, Hang Xu, Deborah Schneider-Luftman, Natasha Sharma, Laura Tovini, TRACERx Consortium, Mariam Jamal-Hanjani, Sarah E. McClelland, Kevin Litchfield, Nicolai J. Birkbak, Michael Howell, Nicolas Tapon, Kasper Fugger, Nicholas McGranahan, Jiri Bartek, Nnennaya Kanu, Charles Swanton","doi":"10.1038/s41556-024-01558-w","DOIUrl":"10.1038/s41556-024-01558-w","url":null,"abstract":"Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency. FAT1 ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. FAT1 loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of YAP1 partially rescues numerical CIN caused by FAT1 loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP15SA is sufficient to induce numerical CIN. Taken together, we show that FAT1 loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity. Lu et al. perform systematic functional analyses using data from the TRACERx cohort of patients with non-small-cell lung cancer and delineate how FAT1 regulates homologous recombination repair, chromosomal instability and whole-genome doubling with distinct mechanisms.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"154-168"},"PeriodicalIF":17.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01558-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904746","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}

{"title":"Bridging art and science","authors":"Sabrya Carim","doi":"10.1038/s41556-024-01587-5","DOIUrl":"10.1038/s41556-024-01587-5","url":null,"abstract":"Ahna Skop is a geneticist and artist at the University of Wisconsin–Madison, USA. Ahna’s lab studies the assembly and function of mammalian midbody and midbody remnant, which are assembled at the end of mitosis. Ahna also leans into her passion for scientific art to engage the public. We were fascinated to hear Ahna’s thoughts on open questions and challenges in the field and to learn about her passion of marrying science and art.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"2-3"},"PeriodicalIF":17.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858397","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":"Worrying through the ECM","authors":"Daryl J. V. David","doi":"10.1038/s41556-024-01579-5","DOIUrl":"10.1038/s41556-024-01579-5","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2013-2013"},"PeriodicalIF":17.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798571","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":"Cu in cancer metabolism","authors":"Zhe Wang","doi":"10.1038/s41556-024-01578-6","DOIUrl":"10.1038/s41556-024-01578-6","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2013-2013"},"PeriodicalIF":17.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798553","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":"Regulating chromatin assembly","authors":"Sabrya Carim","doi":"10.1038/s41556-024-01581-x","DOIUrl":"10.1038/s41556-024-01581-x","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2013-2013"},"PeriodicalIF":17.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798588","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":"Making stronger T cells","authors":"Stylianos Lefkopoulos","doi":"10.1038/s41556-024-01577-7","DOIUrl":"10.1038/s41556-024-01577-7","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2013-2013"},"PeriodicalIF":17.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798600","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}