Pub Date : 2024-09-05DOI: 10.1016/j.cell.2024.07.056
Daniel J. Baker, Carl H. June
Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.
{"title":"Off-the-shelf CAR-T cells could prove paradigm shifting for autoimmune diseases","authors":"Daniel J. Baker, Carl H. June","doi":"10.1016/j.cell.2024.07.056","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.056","url":null,"abstract":"<p>Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of <em>Cell</em>, Wang et al.<span><span><sup>1</sup></span></span> report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138413","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: 10.1016/j.cell.2024.07.055
Hiten D. Madhani
Epigenetic inheritance of heterochromatin requires transfer of parental H3-H4 tetramers to both daughter duplexes during replication. Three recent papers exploit yeast genetics coupled to inheritance assays and AlphaFold2-multimer predictions coupled to biochemistry to reveal that a replisome component (Mrc1/CLASPIN) is an H3-H4 tetramer chaperone important for parental histone transfer to daughters.
{"title":"Deep learning meets histones at the replication fork","authors":"Hiten D. Madhani","doi":"10.1016/j.cell.2024.07.055","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.055","url":null,"abstract":"<p>Epigenetic inheritance of heterochromatin requires transfer of parental H3-H4 tetramers to both daughter duplexes during replication. Three recent papers exploit yeast genetics coupled to inheritance assays and AlphaFold2-multimer predictions coupled to biochemistry to reveal that a replisome component (Mrc1/CLASPIN) is an H3-H4 tetramer chaperone important for parental histone transfer to daughters.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138411","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 : 2024-09-05Epub Date: 2024-07-05DOI: 10.1016/j.cell.2024.06.013
Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Ding Ma, Yong Fang, Han Liang, Qinglei Gao
Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
{"title":"Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.","authors":"Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Ding Ma, Yong Fang, Han Liang, Qinglei Gao","doi":"10.1016/j.cell.2024.06.013","DOIUrl":"10.1016/j.cell.2024.06.013","url":null,"abstract":"<p><p>Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8<sup>+</sup> T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":45.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544558","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: 10.1016/j.cell.2024.07.012
Hellmut G. Augustin, Gou Young Koh
The dysfunction of blood-vessel-lining endothelial cells is a major cause of mortality. Although endothelial cells, being present in all organs as a single-cell layer, are often conceived as a rather inert cell population, the vascular endothelium as a whole should be considered a highly dynamic and interactive systemically disseminated organ. We present here a holistic view of the field of vascular research and review the diverse functions of blood-vessel-lining endothelial cells during the life cycle of the vasculature, namely responsive and relaying functions of the vascular endothelium and the responsive roles as instructive gatekeepers of organ function. Emerging translational perspectives in regenerative medicine, preventive medicine, and aging research are developed. Collectively, this review is aimed at promoting disciplinary coherence in the field of angioscience for a broader appreciation of the importance of the vasculature for organ function, systemic health, and healthy aging.
{"title":"A systems view of the vascular endothelium in health and disease","authors":"Hellmut G. Augustin, Gou Young Koh","doi":"10.1016/j.cell.2024.07.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.012","url":null,"abstract":"<p>The dysfunction of blood-vessel-lining endothelial cells is a major cause of mortality. Although endothelial cells, being present in all organs as a single-cell layer, are often conceived as a rather inert cell population, the vascular endothelium as a whole should be considered a highly dynamic and interactive systemically disseminated organ. We present here a holistic view of the field of vascular research and review the diverse functions of blood-vessel-lining endothelial cells during the life cycle of the vasculature, namely responsive and relaying functions of the vascular endothelium and the responsive roles as instructive gatekeepers of organ function. Emerging translational perspectives in regenerative medicine, preventive medicine, and aging research are developed. Collectively, this review is aimed at promoting disciplinary coherence in the field of angioscience for a broader appreciation of the importance of the vasculature for organ function, systemic health, and healthy aging.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138173","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: 10.1016/j.cell.2024.07.058
Tian-Li Wang, Ie-Ming Shih
Homologous-recombination deficiency in DNA repair characterizes a unique group of cancers that are vulnerable to PARP inhibitors and cytotoxic chemotherapy. In this issue of Cell, Luo et al., demonstrated that this genetic attribute in cancer cells may reprogram tumor immune microenvironment and show promise of targeting effector-Treg cells.
{"title":"Harnessing immune cells to leverage PARP inhibitors","authors":"Tian-Li Wang, Ie-Ming Shih","doi":"10.1016/j.cell.2024.07.058","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.058","url":null,"abstract":"<p>Homologous-recombination deficiency in DNA repair characterizes a unique group of cancers that are vulnerable to PARP inhibitors and cytotoxic chemotherapy. In this issue of <em>Cell</em>, Luo et al., demonstrated that this genetic attribute in cancer cells may reprogram tumor immune microenvironment and show promise of targeting effector-Treg cells.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138412","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: 10.1016/j.cell.2024.08.005
Carlise Sorenson, Katarzyna P. Adamala
Building biological computers is one of the most intensively pursued goals of modern synthetic biology. The new TriLoS tristate-based logic synthesis platform, published in this issue of Cell, offers a long-awaited solution to scale up the complexity of biocomputing, opening a path to move this field beyond proof-of-principle demonstrations.
{"title":"Laws of thought in living cells","authors":"Carlise Sorenson, Katarzyna P. Adamala","doi":"10.1016/j.cell.2024.08.005","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.005","url":null,"abstract":"<p>Building biological computers is one of the most intensively pursued goals of modern synthetic biology. The new TriLoS tristate-based logic synthesis platform, published in this issue of <em>Cell</em>, offers a long-awaited solution to scale up the complexity of biocomputing, opening a path to move this field beyond proof-of-principle demonstrations.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138172","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 : 2024-09-04DOI: 10.1016/j.cell.2024.08.043
Eric M. Mucker, Alec W. Freyn, Sandra L. Bixler, Deniz Cizmeci, Caroline Atyeo, Patricia L. Earl, Harini Natarajan, Genesis Santos, Tiffany R. Frey, Rafael H. Levin, Anusha Meni, Guha A. Arunkumar, Daniel Stadlbauer, Patricia A. Jorquera, Hamilton Bennett, Joshua C. Johnson, Kath Hardcastle, Jeffrey L. Americo, Catherine A. Cotter, Jeff W. Koehler, Jay W. Hooper
In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.
{"title":"Comparison of protection against mpox following mRNA or modified vaccinia Ankara vaccination in nonhuman primates","authors":"Eric M. Mucker, Alec W. Freyn, Sandra L. Bixler, Deniz Cizmeci, Caroline Atyeo, Patricia L. Earl, Harini Natarajan, Genesis Santos, Tiffany R. Frey, Rafael H. Levin, Anusha Meni, Guha A. Arunkumar, Daniel Stadlbauer, Patricia A. Jorquera, Hamilton Bennett, Joshua C. Johnson, Kath Hardcastle, Jeffrey L. Americo, Catherine A. Cotter, Jeff W. Koehler, Jay W. Hooper","doi":"10.1016/j.cell.2024.08.043","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.043","url":null,"abstract":"<p>In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130830","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 : 2024-08-29DOI: 10.1016/j.cell.2024.07.039
Niccolò Carlino, Aitor Blanco-Míguez, Michal Punčochář, Claudia Mengoni, Federica Pinto, Alessia Tatti, Paolo Manghi, Federica Armanini, Michele Avagliano, Coral Barcenilla, Samuel Breselge, Raul Cabrera-Rubio, Inés Calvete-Torre, Mairéad Coakley, José F. Cobo-Díaz, Francesca De Filippis, Hrituraj Dey, John Leech, Eline S. Klaassens, Stephen Knobloch, Edoardo Pasolli
Complex microbiomes are part of the food we eat and influence our own microbiome, but their diversity remains largely unexplored. Here, we generated the open access curatedFoodMetagenomicData (cFMD) resource by integrating 1,950 newly sequenced and 583 public food metagenomes. We produced 10,899 metagenome-assembled genomes spanning 1,036 prokaryotic and 108 eukaryotic species-level genome bins (SGBs), including 320 previously undescribed taxa. Food SGBs displayed significant microbial diversity within and between food categories. Extension to >20,000 human metagenomes revealed that food SGBs accounted on average for 3% of the adult gut microbiome. Strain-level analysis highlighted potential instances of food-to-gut transmission and intestinal colonization (e.g., Lacticaseibacillus paracasei) as well as SGBs with divergent genomic structures in food and humans (e.g., Streptococcus gallolyticus and Limosilactobabillus mucosae). The cFMD expands our knowledge on food microbiomes, their role in shaping the human microbiome, and supports future uses of metagenomics for food quality, safety, and authentication.
{"title":"Unexplored microbial diversity from 2,500 food metagenomes and links with the human microbiome","authors":"Niccolò Carlino, Aitor Blanco-Míguez, Michal Punčochář, Claudia Mengoni, Federica Pinto, Alessia Tatti, Paolo Manghi, Federica Armanini, Michele Avagliano, Coral Barcenilla, Samuel Breselge, Raul Cabrera-Rubio, Inés Calvete-Torre, Mairéad Coakley, José F. Cobo-Díaz, Francesca De Filippis, Hrituraj Dey, John Leech, Eline S. Klaassens, Stephen Knobloch, Edoardo Pasolli","doi":"10.1016/j.cell.2024.07.039","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.039","url":null,"abstract":"<p>Complex microbiomes are part of the food we eat and influence our own microbiome, but their diversity remains largely unexplored. Here, we generated the open access curatedFoodMetagenomicData (cFMD) resource by integrating 1,950 newly sequenced and 583 public food metagenomes. We produced 10,899 metagenome-assembled genomes spanning 1,036 prokaryotic and 108 eukaryotic species-level genome bins (SGBs), including 320 previously undescribed taxa. Food SGBs displayed significant microbial diversity within and between food categories. Extension to >20,000 human metagenomes revealed that food SGBs accounted on average for 3% of the adult gut microbiome. Strain-level analysis highlighted potential instances of food-to-gut transmission and intestinal colonization (e.g., <em>Lacticaseibacillus paracasei</em>) as well as SGBs with divergent genomic structures in food and humans (e.g., <em>Streptococcus gallolyticus</em> and <em>Limosilactobabillus mucosae</em>). The cFMD expands our knowledge on food microbiomes, their role in shaping the human microbiome, and supports future uses of metagenomics for food quality, safety, and authentication.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090518","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 : 2024-08-29DOI: 10.1016/j.cell.2024.08.011
Eleftheria Parasyraki, Medhavi Mallick, Victoria Hatch, Viviana Vastolo, Michael U. Musheev, Emil Karaulanov, Alexandr Gopanenko, Simon Moxon, Maria Méndez-Lago, Dandan Han, Lars Schomacher, Debasish Mukherjee, Christof Niehrs
5-Methylcytosine (5mC) is an established epigenetic mark in vertebrate genomic DNA, but whether its oxidation intermediates formed during TET-mediated DNA demethylation possess an instructive role of their own that is also physiologically relevant remains unresolved. Here, we reveal a 5-formylcytosine (5fC) nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in Xenopus and mouse embryos. We identify this chromocenter as the perinucleolar compartment, a structure associated with RNA Pol III transcription. In Xenopus embryos, 5fC is highly enriched on Pol III target genes activated at ZGA, notably at oocyte-type tandem arrayed tRNA genes. By manipulating Tet and Tdg enzymes, we show that 5fC is required as a regulatory mark to promote Pol III recruitment as well as tRNA expression. Concordantly, 5fC modification of a tRNA transgene enhances its expression in vivo. The results establish 5fC as an activating epigenetic mark during zygotic reprogramming of Pol III gene expression.
5-甲基胞嘧啶(5mC)是脊椎动物基因组 DNA 中一个公认的表观遗传标记,但其在 TET 介导的 DNA 去甲基化过程中形成的氧化中间产物是否具有与生理相关的指导作用仍未解决。在这里,我们发现了一个 5-甲酰基胞嘧啶(5fC)核染色中心,它在章鱼和小鼠胚胎的子代基因组激活(ZGA)过程中瞬时形成。我们确定该染色中心为核周区室,这是一种与 RNA Pol III 转录相关的结构。在章鱼胚胎中,5fC 在 ZGA 激活的 Pol III 目标基因上高度富集,尤其是在卵母细胞型串联排列 tRNA 基因上。通过操纵 Tet 和 Tdg 酶,我们发现 5fC 是促进 Pol III 招募和 tRNA 表达所必需的调控标记。同时,对 tRNA 转基因进行 5fC 修饰可增强其在体内的表达。这些结果确立了 5fC 在 Pol III 基因表达的合子重编程过程中是一个激活的表观遗传标记。
{"title":"5-Formylcytosine is an activating epigenetic mark for RNA Pol III during zygotic reprogramming","authors":"Eleftheria Parasyraki, Medhavi Mallick, Victoria Hatch, Viviana Vastolo, Michael U. Musheev, Emil Karaulanov, Alexandr Gopanenko, Simon Moxon, Maria Méndez-Lago, Dandan Han, Lars Schomacher, Debasish Mukherjee, Christof Niehrs","doi":"10.1016/j.cell.2024.08.011","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.011","url":null,"abstract":"<p>5-Methylcytosine (5mC) is an established epigenetic mark in vertebrate genomic DNA, but whether its oxidation intermediates formed during TET-mediated DNA demethylation possess an instructive role of their own that is also physiologically relevant remains unresolved. Here, we reveal a 5-formylcytosine (5fC) nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in <em>Xenopus</em> and mouse embryos. We identify this chromocenter as the perinucleolar compartment, a structure associated with RNA Pol III transcription. In <em>Xenopus</em> embryos, 5fC is highly enriched on Pol III target genes activated at ZGA, notably at oocyte-type tandem arrayed <em>tRNA</em> genes. By manipulating Tet and Tdg enzymes, we show that 5fC is required as a regulatory mark to promote Pol III recruitment as well as <em>tRNA</em> expression. Concordantly, 5fC modification of a <em>tRNA</em> transgene enhances its expression <em>in vivo</em>. The results establish 5fC as an activating epigenetic mark during zygotic reprogramming of Pol III gene expression.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090521","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 : 2024-08-28DOI: 10.1016/j.cell.2024.07.050
Peiyu Xu, Makoto Saito, Guilhem Faure, Samantha Maguire, Samuel Chau-Duy-Tam Vo, Max E. Wilkinson, Huihui Kuang, Bing Wang, William J. Rice, Rhiannon K. Macrae, Feng Zhang
Fanzor (Fz) is an ωRNA-guided endonuclease extensively found throughout the eukaryotic domain with unique gene editing potential. Here, we describe the structures of Fzs from three different organisms. We find that Fzs share a common ωRNA interaction interface, regardless of the length of the ωRNA, which varies considerably across species. The analysis also reveals Fz’s mode of DNA recognition and unwinding capabilities as well as the presence of a non-canonical catalytic site. The structures demonstrate how protein conformations of Fz shift to allow the binding of double-stranded DNA to the active site within the R-loop. Mechanistically, examination of structures in different states shows that the conformation of the lid loop on the RuvC domain is controlled by the formation of the guide/DNA heteroduplex, regulating the activation of nuclease and DNA double-stranded displacement at the single cleavage site. Our findings clarify the mechanism of Fz, establishing a foundation for engineering efforts.
Fanzor(Fz)是一种ωRNA引导的内切酶,广泛存在于真核生物领域,具有独特的基因编辑潜力。在这里,我们描述了三种不同生物的 Fzs 结构。我们发现,无论ωRNA的长度如何,Fzs都有一个共同的ωRNA相互作用界面。分析还揭示了 Fz 的 DNA 识别模式和解旋能力,以及非经典催化位点的存在。这些结构展示了 Fz 蛋白构象如何转变,从而使双链 DNA 与 R 环内的活性位点结合。从机理上讲,对不同状态下结构的研究表明,RuvC结构域上的睑环构象受向导/DNA异质双链的形成控制,从而调节核酸酶的激活和DNA双链在单个裂解位点的位移。我们的发现阐明了 Fz 的机制,为工程学研究奠定了基础。
{"title":"Structural insights into the diversity and DNA cleavage mechanism of Fanzor","authors":"Peiyu Xu, Makoto Saito, Guilhem Faure, Samantha Maguire, Samuel Chau-Duy-Tam Vo, Max E. Wilkinson, Huihui Kuang, Bing Wang, William J. Rice, Rhiannon K. Macrae, Feng Zhang","doi":"10.1016/j.cell.2024.07.050","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.050","url":null,"abstract":"<p>Fanzor (Fz) is an ωRNA-guided endonuclease extensively found throughout the eukaryotic domain with unique gene editing potential. Here, we describe the structures of Fzs from three different organisms. We find that Fzs share a common ωRNA interaction interface, regardless of the length of the ωRNA, which varies considerably across species. The analysis also reveals Fz’s mode of DNA recognition and unwinding capabilities as well as the presence of a non-canonical catalytic site. The structures demonstrate how protein conformations of Fz shift to allow the binding of double-stranded DNA to the active site within the R-loop. Mechanistically, examination of structures in different states shows that the conformation of the lid loop on the RuvC domain is controlled by the formation of the guide/DNA heteroduplex, regulating the activation of nuclease and DNA double-stranded displacement at the single cleavage site. Our findings clarify the mechanism of Fz, establishing a foundation for engineering efforts.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085759","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}