Pub Date : 2024-10-08DOI: 10.1016/j.cell.2024.09.023
Shukun Wang, Romana Siddique, Mark C. Hall, Phoebe A. Rice, Leifu Chang
Tn7-like transposons are characterized by their ability to insert specifically into host chromosomes. Recognition of the attachment (att) site by TnsD recruits the TnsABC proteins to form the transpososome and facilitate transposition. Although this pathway is well established, atomic-level structural insights of this process remain largely elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of the TnsC-TnsD-att DNA complex and the TnsABCD transpososome from the Tn7-like transposon in Peltigera membranacea cyanobiont 210A, a type I-B CRISPR-associated transposon. Our structures reveal a striking bending of the att DNA, featured by the intercalation of an arginine side chain of TnsD into a CC/GG dinucleotide step. The TnsABCD transpososome structure reveals TnsA-TnsB interactions and demonstrates that TnsC not only recruits TnsAB but also directly participates in the transpososome assembly. These findings provide mechanistic insights into targeted DNA insertion by Tn7-like transposons, with implications for improving the precision and efficiency of their genome-editing applications.
Tn7 类转座子的特点是能够特异性地插入宿主染色体。TnsD 识别附着（att）位点后，会招募 TnsABC 蛋白形成转座子并促进转座。虽然这一途径已被充分证实，但对这一过程的原子级结构研究在很大程度上仍是空白。在这里，我们展示了 TnsC-TnsD-att DNA 复合物和 TnsABCD 转座子的冷冻电子显微镜（cryo-EM）结构，这些复合物和转座子来自 Peltigera membranacea cyanobiont 210A 中的 Tn7 样转座子，这是一种 I-B 型 CRISPR 相关转座子。我们的结构显示，TnsD 的精氨酸侧链插入了 CC/GG 二核苷酸阶梯，从而使 att DNA 发生了明显的弯曲。TnsABCD 转座子结构揭示了 TnsA-TnsB 的相互作用，并证明 TnsC 不仅能招募 TnsAB，还能直接参与转座子的组装。这些发现从机理上揭示了 Tn7 类转座子的定向 DNA 插入，对提高基因组编辑应用的精确性和效率具有重要意义。
{"title":"Structure of TnsABCD transpososome reveals mechanisms of targeted DNA transposition","authors":"Shukun Wang, Romana Siddique, Mark C. Hall, Phoebe A. Rice, Leifu Chang","doi":"10.1016/j.cell.2024.09.023","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.023","url":null,"abstract":"Tn7-like transposons are characterized by their ability to insert specifically into host chromosomes. Recognition of the attachment (<em>att</em>) site by TnsD recruits the TnsABC proteins to form the transpososome and facilitate transposition. Although this pathway is well established, atomic-level structural insights of this process remain largely elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of the TnsC-TnsD-<em>att</em> DNA complex and the TnsABCD transpososome from the Tn7-like transposon in <em>Peltigera membranacea cyanobiont</em> 210A, a type I-B CRISPR-associated transposon. Our structures reveal a striking bending of the <em>att</em> DNA, featured by the intercalation of an arginine side chain of TnsD into a CC/GG dinucleotide step. The TnsABCD transpososome structure reveals TnsA-TnsB interactions and demonstrates that TnsC not only recruits TnsAB but also directly participates in the transpososome assembly. These findings provide mechanistic insights into targeted DNA insertion by Tn7-like transposons, with implications for improving the precision and efficiency of their genome-editing applications.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384342","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 : 2024-10-08DOI: 10.1016/j.cell.2024.09.024
Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E. Phillips, Alexandra S. Rojas, Natalie I. Ho, Yuhui Song, Michael J. Raabe, Katherine H. Xu, Peter M. Richieri, Hao Li, Natalie Aston, Rebecca L. Porter, Bidish K. Patel, Linda T. Nieman, Nathan Schurman, Briana M. Hudson, Khrystyna North, David T. Ting
Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.
{"title":"Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer","authors":"Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E. Phillips, Alexandra S. Rojas, Natalie I. Ho, Yuhui Song, Michael J. Raabe, Katherine H. Xu, Peter M. Richieri, Hao Li, Natalie Aston, Rebecca L. Porter, Bidish K. Patel, Linda T. Nieman, Nathan Schurman, Briana M. Hudson, Khrystyna North, David T. Ting","doi":"10.1016/j.cell.2024.09.024","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.024","url":null,"abstract":"Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384347","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 : 2024-10-08DOI: 10.1016/j.cell.2024.09.026
Laura E. Rosen, M. Alejandra Tortorici, Anna De Marco, Dora Pinto, William B. Foreman, Ashley L. Taylor, Young-Jun Park, Dana Bohan, Tyson Rietz, John M. Errico, Kevin Hauser, Ha V. Dang, Justin W. Chartron, Martina Giurdanella, Giuseppe Cusumano, Christian Saliba, Fabrizia Zatta, Kaitlin R. Sprouse, Amin Addetia, Samantha K. Zepeda, Tyler N. Starr
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.
{"title":"A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification","authors":"Laura E. Rosen, M. Alejandra Tortorici, Anna De Marco, Dora Pinto, William B. Foreman, Ashley L. Taylor, Young-Jun Park, Dana Bohan, Tyson Rietz, John M. Errico, Kevin Hauser, Ha V. Dang, Justin W. Chartron, Martina Giurdanella, Giuseppe Cusumano, Christian Saliba, Fabrizia Zatta, Kaitlin R. Sprouse, Amin Addetia, Samantha K. Zepeda, Tyler N. Starr","doi":"10.1016/j.cell.2024.09.026","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.026","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384348","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 : 2024-10-07DOI: 10.1016/j.cell.2024.09.016
Erica Dalla, Michael Papanicolaou, Matthew D. Park, Nicole Barth, Rui Hou, Deisy Segura-Villalobos, Luis Valencia Salazar, Dan Sun, Alistair R.R. Forrest, Maria Casanova-Acebes, David Entenberg, Miriam Merad, Julio A. Aguirre-Ghiso
Breast disseminated cancer cells (DCCs) can remain dormant in the lungs for extended periods, but the mechanisms limiting their expansion are not well understood. Research indicates that tissue-resident alveolar macrophages suppress breast cancer metastasis in lung alveoli by inducing dormancy. Through ligand-receptor mapping and intravital imaging, it was found that alveolar macrophages express transforming growth factor (TGF)-β2. This expression, along with persistent macrophage-cancer cell interactions via the TGF-βRIII receptor, maintains cancer cells in a dormant state. Depleting alveolar macrophages or losing the TGF-β2 receptor in cancer cells triggers metastatic awakening. Aggressive breast cancer cells are either suppressed by alveolar macrophages or evade this suppression by avoiding interaction and downregulating the TGF-β2 receptor. Restoring TGF-βRIII in aggressive cells reinstates TGF-β2-mediated macrophage growth suppression. Thus, alveolar macrophages act as a metastasis immune barrier, and downregulation of TGF-β2 signaling allows cancer cells to overcome macrophage-mediated growth suppression.
{"title":"Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis","authors":"Erica Dalla, Michael Papanicolaou, Matthew D. Park, Nicole Barth, Rui Hou, Deisy Segura-Villalobos, Luis Valencia Salazar, Dan Sun, Alistair R.R. Forrest, Maria Casanova-Acebes, David Entenberg, Miriam Merad, Julio A. Aguirre-Ghiso","doi":"10.1016/j.cell.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.016","url":null,"abstract":"Breast disseminated cancer cells (DCCs) can remain dormant in the lungs for extended periods, but the mechanisms limiting their expansion are not well understood. Research indicates that tissue-resident alveolar macrophages suppress breast cancer metastasis in lung alveoli by inducing dormancy. Through ligand-receptor mapping and intravital imaging, it was found that alveolar macrophages express transforming growth factor (TGF)-β2. This expression, along with persistent macrophage-cancer cell interactions via the TGF-βRIII receptor, maintains cancer cells in a dormant state. Depleting alveolar macrophages or losing the TGF-β2 receptor in cancer cells triggers metastatic awakening. Aggressive breast cancer cells are either suppressed by alveolar macrophages or evade this suppression by avoiding interaction and downregulating the TGF-β2 receptor. Restoring TGF-βRIII in aggressive cells reinstates TGF-β2-mediated macrophage growth suppression. Thus, alveolar macrophages act as a metastasis immune barrier, and downregulation of TGF-β2 signaling allows cancer cells to overcome macrophage-mediated growth suppression.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383812","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 : 2024-10-07DOI: 10.1016/j.cell.2024.09.019
Guojun Wu, Ting Xu, Naisi Zhao, Yan Y. Lam, Xiaoying Ding, Dongqin Wei, Jian Fan, Yajuan Shi, Xiaofeng Li, Mi Li, Shenjie Ji, Xuejiao Wang, Huaqing Fu, Feng Zhang, Yu Shi, Chenhong Zhang, Yongde Peng, Liping Zhao
The gut microbiota is crucial for human health, functioning as a complex adaptive system akin to a vital organ. To identify core health-relevant gut microbes, we followed the systems biology tenet that stable relationships signify core components. By analyzing metagenomic datasets from a high-fiber dietary intervention in type 2 diabetes and 26 case-control studies across 15 diseases, we identified a set of stably correlated genome pairs within co-abundance networks perturbed by dietary interventions and diseases. These genomes formed a “two competing guilds” (TCGs) model, with one guild specialized in fiber fermentation and butyrate production and the other characterized by virulence and antibiotic resistance. Our random forest models successfully distinguished cases from controls across multiple diseases and predicted immunotherapy outcomes through the use of these genomes. Our guild-based approach, which is genome specific, database independent, and interaction focused, identifies a core microbiome signature that serves as a holistic health indicator and a potential common target for health enhancement.
{"title":"A core microbiome signature as an indicator of health","authors":"Guojun Wu, Ting Xu, Naisi Zhao, Yan Y. Lam, Xiaoying Ding, Dongqin Wei, Jian Fan, Yajuan Shi, Xiaofeng Li, Mi Li, Shenjie Ji, Xuejiao Wang, Huaqing Fu, Feng Zhang, Yu Shi, Chenhong Zhang, Yongde Peng, Liping Zhao","doi":"10.1016/j.cell.2024.09.019","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.019","url":null,"abstract":"The gut microbiota is crucial for human health, functioning as a complex adaptive system akin to a vital organ. To identify core health-relevant gut microbes, we followed the systems biology tenet that stable relationships signify core components. By analyzing metagenomic datasets from a high-fiber dietary intervention in type 2 diabetes and 26 case-control studies across 15 diseases, we identified a set of stably correlated genome pairs within co-abundance networks perturbed by dietary interventions and diseases. These genomes formed a “two competing guilds” (TCGs) model, with one guild specialized in fiber fermentation and butyrate production and the other characterized by virulence and antibiotic resistance. Our random forest models successfully distinguished cases from controls across multiple diseases and predicted immunotherapy outcomes through the use of these genomes. Our guild-based approach, which is genome specific, database independent, and interaction focused, identifies a core microbiome signature that serves as a holistic health indicator and a potential common target for health enhancement.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383810","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 : 2024-10-04DOI: 10.1016/j.cell.2024.09.025
Onyou Nam, Sabina Musiał, Manon Demulder, Caroline McKenzie, Adam Dowle, Matthew Dowson, James Barrett, James N. Blaza, Benjamin D. Engel, Luke C.M. Mackinder
Diatoms are central to the global carbon cycle. At the heart of diatom carbon fixation is an overlooked organelle called the pyrenoid, where concentrated CO2 is delivered to densely packed Rubisco. Diatom pyrenoids fix approximately one-fifth of global CO2, but the protein composition of this organelle is largely unknown. Using fluorescence protein tagging and affinity purification-mass spectrometry, we generate a high-confidence spatially defined protein-protein interaction network for the diatom pyrenoid. Within our pyrenoid interaction network are 10 proteins with previously unknown functions. We show that six of these form a shell that encapsulates the Rubisco matrix and is critical for pyrenoid structural integrity, shape, and function. Although not conserved at a sequence or structural level, the diatom pyrenoid shares some architectural similarities to prokaryotic carboxysomes. Collectively, our results support the convergent evolution of pyrenoids across the two main plastid lineages and uncover a major structural and functional component of global CO2 fixation.
{"title":"A protein blueprint of the diatom CO2-fixing organelle","authors":"Onyou Nam, Sabina Musiał, Manon Demulder, Caroline McKenzie, Adam Dowle, Matthew Dowson, James Barrett, James N. Blaza, Benjamin D. Engel, Luke C.M. Mackinder","doi":"10.1016/j.cell.2024.09.025","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.025","url":null,"abstract":"Diatoms are central to the global carbon cycle. At the heart of diatom carbon fixation is an overlooked organelle called the pyrenoid, where concentrated CO<sub>2</sub> is delivered to densely packed Rubisco. Diatom pyrenoids fix approximately one-fifth of global CO<sub>2</sub>, but the protein composition of this organelle is largely unknown. Using fluorescence protein tagging and affinity purification-mass spectrometry, we generate a high-confidence spatially defined protein-protein interaction network for the diatom pyrenoid. Within our pyrenoid interaction network are 10 proteins with previously unknown functions. We show that six of these form a shell that encapsulates the Rubisco matrix and is critical for pyrenoid structural integrity, shape, and function. Although not conserved at a sequence or structural level, the diatom pyrenoid shares some architectural similarities to prokaryotic carboxysomes. Collectively, our results support the convergent evolution of pyrenoids across the two main plastid lineages and uncover a major structural and functional component of global CO<sub>2</sub> fixation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374134","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 : 2024-10-04DOI: 10.1016/j.cell.2024.09.045
Ya Cui, Wenbin Ye, Jason Sheng Li, Jingyi Jessica Li, Eric Vilain, Tamer Sallam, Wei Li
(Cell 187, 2336–2341.e1–e5; April 25, 2024)
(细胞》187 期，2336-2341.e1-e5；2024 年 4 月 25 日）
{"title":"A genome-wide spectrum of tandem repeat expansions in 338,963 humans","authors":"Ya Cui, Wenbin Ye, Jason Sheng Li, Jingyi Jessica Li, Eric Vilain, Tamer Sallam, Wei Li","doi":"10.1016/j.cell.2024.09.045","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.045","url":null,"abstract":"(Cell <em>187</em>, 2336–2341.e1–e5; April 25, 2024)","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374516","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 : 2024-10-04DOI: 10.1016/j.cell.2024.09.021
Huan Zhao, Zixin Liu, Hui Chen, Maoying Han, Mingjun Zhang, Kuo Liu, Hengwei Jin, Xiuxiu Liu, Mengyang Shi, Wenjuan Pu, Markus Werner, Michael Meister, Stefan G. Kauschke, Ruilin Sun, Jinjin Wang, Ruling Shen, Qing-Dong Wang, Xin Ma, Jan S. Tchorz, Bin Zhou
Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox consisting of three p16Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.
{"title":"Identifying specific functional roles for senescence across cell types","authors":"Huan Zhao, Zixin Liu, Hui Chen, Maoying Han, Mingjun Zhang, Kuo Liu, Hengwei Jin, Xiuxiu Liu, Mengyang Shi, Wenjuan Pu, Markus Werner, Michael Meister, Stefan G. Kauschke, Ruilin Sun, Jinjin Wang, Ruling Shen, Qing-Dong Wang, Xin Ma, Jan S. Tchorz, Bin Zhou","doi":"10.1016/j.cell.2024.09.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.021","url":null,"abstract":"Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an <em>in vivo</em> genetic toolbox consisting of three <em>p16</em><sup><em>Ink4a</em></sup>-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined <em>p16</em><sup><em>Ink4a</em>+</sup> cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of <em>p16</em><sup><em>Ink4a</em>+</sup> macrophages significantly mitigates hepatocellular damage, whereas eliminating <em>p16</em><sup><em>Ink4a</em>+</sup> ECs aggravates liver injury. Additionally, targeted reprogramming of <em>p16</em><sup><em>Ink4a</em>+</sup> ECs through <em>Kdr</em> overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of <em>p16</em><sup><em>Ink4a</em>+</sup> cells and offers insights for developing cell-type-specific senolytic therapies in the future.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374133","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 : 2024-10-03Epub Date: 2024-08-20DOI: 10.1016/j.cell.2024.07.038
Mingkee Achom, Ananthan Sadagopan, Chunyang Bao, Fiona McBride, Jiao Li, Prathyusha Konda, Richard W Tourdot, Qingru Xu, Maria Nakhoul, Daniel S Gallant, Usman Ali Ahmed, Jillian O'Toole, Dory Freeman, Gwo-Shu Mary Lee, Jonathan L Hecht, Eric C Kauffman, David J Einstein, Toni K Choueiri, Cheng-Zhong Zhang, Srinivas R Viswanathan
Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.
{"title":"A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.","authors":"Mingkee Achom, Ananthan Sadagopan, Chunyang Bao, Fiona McBride, Jiao Li, Prathyusha Konda, Richard W Tourdot, Qingru Xu, Maria Nakhoul, Daniel S Gallant, Usman Ali Ahmed, Jillian O'Toole, Dory Freeman, Gwo-Shu Mary Lee, Jonathan L Hecht, Eric C Kauffman, David J Einstein, Toni K Choueiri, Cheng-Zhong Zhang, Srinivas R Viswanathan","doi":"10.1016/j.cell.2024.07.038","DOIUrl":"10.1016/j.cell.2024.07.038","url":null,"abstract":"<p><p>Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":45.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016441","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 : 2024-10-03DOI: 10.1016/j.cell.2024.09.002
Fasséli Coulibaly
In this issue of Cell, Penzes et al. describe the use of cryo-EM to identify the cause of a mysterious disease affecting farmed superworms across the US. The study illustrates the power of ex vivo cryo-EM, which uses amplification-free samples to advance at once diagnostic, DNA packaging mechanism, and preventative measures.
{"title":"Cryo-EM vs. Disease X","authors":"Fasséli Coulibaly","doi":"10.1016/j.cell.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.002","url":null,"abstract":"In this issue of <em>Cell</em>, Penzes et al. describe the use of cryo-EM to identify the cause of a mysterious disease affecting farmed superworms across the US. The study illustrates the power of <em>ex vivo</em> cryo-EM, which uses amplification-free samples to advance at once diagnostic, DNA packaging mechanism, and preventative measures.","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369677","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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