The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.
{"title":"Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation","authors":"Janneke G.C. Peeters, Stephanie Silveria, Merve Ozdemir, Srinivas Ramachandran, Michel DuPage","doi":"10.1016/j.celrep.2024.114724","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114724","url":null,"abstract":"<p>The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and <em>Ezh2</em> deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an <em>Ezh2</em><sup><em>Y641F</em></sup> gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing <em>Ezh2</em><sup><em>Y641F</em></sup> display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive <em>Ezh2</em><sup><em>Y641F</em></sup> Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated <em>Ezh2</em><sup><em>WT</em></sup> Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222212","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 : 2024-09-11DOI: 10.1016/j.celrep.2024.114758
Zhengyao Shao, Yanan Bai, Enamul Huq, Hong Qiao
Ethylene signaling has been indicated as a potential positive regulator of plant warm ambient temperature response, but its underlying molecular mechanisms are largely unknown. Here, we show that LHP1 and INO80 cooperate with ethylene signaling for warm ambient temperature response by activating specific bivalent genes. We found that the presence of warm ambient temperature activates ethylene signaling through EIN2 and EIN3, leading to an interaction between LHP1 and accumulated EIN2-C to co-regulate a subset of LHP1-bound genes marked by H3K27me3 and H3K4me3 bivalency. Furthermore, we demonstrate that INO80 is recruited to bivalent genes by interacting with EIN2-C and EIN3, promoting H3K4me3 enrichment and facilitating transcriptional activation in response to a warm ambient temperature. Together, our findings illustrate a mechanism wherein ethylene signaling orchestrates LHP1 and INO80 to regulate warm ambient temperature response by activating specific bivalent genes in Arabidopsis.
{"title":"LHP1 and INO80 cooperate with ethylene signaling for warm ambient temperature response by activating specific bivalent genes","authors":"Zhengyao Shao, Yanan Bai, Enamul Huq, Hong Qiao","doi":"10.1016/j.celrep.2024.114758","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114758","url":null,"abstract":"<p>Ethylene signaling has been indicated as a potential positive regulator of plant warm ambient temperature response, but its underlying molecular mechanisms are largely unknown. Here, we show that LHP1 and INO80 cooperate with ethylene signaling for warm ambient temperature response by activating specific bivalent genes. We found that the presence of warm ambient temperature activates ethylene signaling through EIN2 and EIN3, leading to an interaction between LHP1 and accumulated EIN2-C to co-regulate a subset of LHP1-bound genes marked by H3K27me3 and H3K4me3 bivalency. Furthermore, we demonstrate that INO80 is recruited to bivalent genes by interacting with EIN2-C and EIN3, promoting H3K4me3 enrichment and facilitating transcriptional activation in response to a warm ambient temperature. Together, our findings illustrate a mechanism wherein ethylene signaling orchestrates LHP1 and INO80 to regulate warm ambient temperature response by activating specific bivalent genes in <em>Arabidopsis</em>.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222216","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 : 2024-09-11DOI: 10.1016/j.celrep.2024.114729
David Boverhoff, Jolanda Kool, Roan Pijnacker, Quinten R. Ducarmon, Georg Zeller, Sudarshan Shetty, Stephan Sie, Annemieke Christine Mulder, Fiona van der Klis, Eelco Franz, Lapo Mughini-Gras, Debbie van Baarle, Susana Fuentes
Defining what constitutes a healthy microbiome throughout our lives remains an ongoing challenge. Understanding to what extent host and environmental factors can influence it has been the primary motivation for large population studies worldwide. Here, we describe the fecal microbiome of 3,746 individuals (0–87 years of age) in a nationwide study in the Netherlands, in association with extensive questionnaires. We validate previous findings, such as infant-adult trajectories, and explore the collective impact of our variables, which explain over 40% of the variation in microbiome composition. We identify associations with less explored factors, particularly those ethnic related, which show the largest impact on the adult microbiome composition, diversity, metabolic profiles, and CAZy (carbohydrate-active enzyme) repertoires. Understanding the sources of microbiome variability is crucial, given its potential as a modifiable target with therapeutic possibilities. With this work, we aim to serve as a foundational element for the design of health interventions and fundamental research.
{"title":"Profiling the fecal microbiome and its modulators across the lifespan in the Netherlands","authors":"David Boverhoff, Jolanda Kool, Roan Pijnacker, Quinten R. Ducarmon, Georg Zeller, Sudarshan Shetty, Stephan Sie, Annemieke Christine Mulder, Fiona van der Klis, Eelco Franz, Lapo Mughini-Gras, Debbie van Baarle, Susana Fuentes","doi":"10.1016/j.celrep.2024.114729","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114729","url":null,"abstract":"<p>Defining what constitutes a healthy microbiome throughout our lives remains an ongoing challenge. Understanding to what extent host and environmental factors can influence it has been the primary motivation for large population studies worldwide. Here, we describe the fecal microbiome of 3,746 individuals (0–87 years of age) in a nationwide study in the Netherlands, in association with extensive questionnaires. We validate previous findings, such as infant-adult trajectories, and explore the collective impact of our variables, which explain over 40% of the variation in microbiome composition. We identify associations with less explored factors, particularly those ethnic related, which show the largest impact on the adult microbiome composition, diversity, metabolic profiles, and CAZy (carbohydrate-active enzyme) repertoires. Understanding the sources of microbiome variability is crucial, given its potential as a modifiable target with therapeutic possibilities. With this work, we aim to serve as a foundational element for the design of health interventions and fundamental research.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222218","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 : 2024-09-10DOI: 10.1016/j.celrep.2024.114728
Xinran Li, Xiao Li, Cong Xiang, Jin Cao, Jiansheng Guo, Shilei Zhu, Jingyi Tan, Lijing Wang, Chun Gao, Shengduo Liu, Lifeng Zhao, Bo Yuan, Pinglong Xu, Bing Yang, Dali Li, Bin Zhao, Xin-Hua Feng
Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B–E (GSDMB–GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.
{"title":"Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis","authors":"Xinran Li, Xiao Li, Cong Xiang, Jin Cao, Jiansheng Guo, Shilei Zhu, Jingyi Tan, Lijing Wang, Chun Gao, Shengduo Liu, Lifeng Zhao, Bo Yuan, Pinglong Xu, Bing Yang, Dali Li, Bin Zhao, Xin-Hua Feng","doi":"10.1016/j.celrep.2024.114728","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114728","url":null,"abstract":"<p>Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B–E (GSDMB–GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222223","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}
Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei. Here, we present mice lacking dopaminergic histamine H2 receptor (H2R) in the ventral tegmental area (VTA) that exhibit a behavioral phenotype mirroring some of the symptoms of mania, including increased locomotor activity and reduced anxiety- and depression-like behavior. These behavioral deficits can be reversed by the mood stabilizers lithium and valproate. H2R deletion in dopaminergic neurons significantly enhances neuronal activity, concurrent with a decrease in the γ-aminobutyric acid (GABA) type A receptor (GABAAR) membrane presence and inhibitory transmission. Conversely, either overexpression of H2R in VTA dopaminergic neurons or treatment of H2R agonist amthamine within the VTA counteracts amphetamine-induced hyperactivity. Together, our results demonstrate the engagement of H2R in reducing VTA dopaminergic activity, shedding light on the role of H2R as a potential target for mania therapy.
{"title":"Deletion of histamine H2 receptor in VTA dopaminergic neurons of mice induces behavior reminiscent of mania","authors":"Shijia Ma, Qianyi Ma, Songhui Hu, Xinlei Mo, Chenze Zhu, Xingxian Zhang, Zetao Jia, Lingjie Tang, Lei Jiang, Yihui Cui, Zhong Chen, Weiwei Hu, Xiangnan Zhang","doi":"10.1016/j.celrep.2024.114717","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114717","url":null,"abstract":"<p>Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei. Here, we present mice lacking dopaminergic histamine H2 receptor (H2R) in the ventral tegmental area (VTA) that exhibit a behavioral phenotype mirroring some of the symptoms of mania, including increased locomotor activity and reduced anxiety- and depression-like behavior. These behavioral deficits can be reversed by the mood stabilizers lithium and valproate. H2R deletion in dopaminergic neurons significantly enhances neuronal activity, concurrent with a decrease in the γ-aminobutyric acid (GABA) type A receptor (GABA<sub>A</sub>R) membrane presence and inhibitory transmission. Conversely, either overexpression of H2R in VTA dopaminergic neurons or treatment of H2R agonist amthamine within the VTA counteracts amphetamine-induced hyperactivity. Together, our results demonstrate the engagement of H2R in reducing VTA dopaminergic activity, shedding light on the role of H2R as a potential target for mania therapy.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222228","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 : 2024-09-10DOI: 10.1016/j.celrep.2024.114705
Liyen Loh, Salomé Carcy, Harsha S. Krovi, Joanne Domenico, Andrea Spengler, Yong Lin, Joshua Torres, Rishvanth K. Prabakar, William Palmer, Paul J. Norman, Matthew Stone, Tonya Brunetti, Hannah V. Meyer, Laurent Gapin
The “innate-like” T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.
{"title":"Unraveling the phenotypic states of human innate-like T cells: Comparative insights with conventional T cells and mouse models","authors":"Liyen Loh, Salomé Carcy, Harsha S. Krovi, Joanne Domenico, Andrea Spengler, Yong Lin, Joshua Torres, Rishvanth K. Prabakar, William Palmer, Paul J. Norman, Matthew Stone, Tonya Brunetti, Hannah V. Meyer, Laurent Gapin","doi":"10.1016/j.celrep.2024.114705","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114705","url":null,"abstract":"<p>The “innate-like” T cell compartment, known as T<sub>inn</sub>, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of T<sub>inn</sub> compared to conventional T cells (T<sub>conv</sub>) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of T<sub>inn</sub> cells share an effector program driven by specific transcription factors, distinct from those governing T<sub>conv</sub> cells. Conversely, only a fraction of thymic T<sub>inn</sub> cells displays an effector phenotype, while others share transcriptional features with developing T<sub>conv</sub> cells, indicating potential divergent developmental pathways. Unlike the mouse, human T<sub>inn</sub> cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 T<sub>inn</sub> cells in humans, which implies distinct immune regulatory mechanisms across species.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1016/j.celrep.2024.114721
Laura Hüser, Yash Chhabra, Olesia Gololobova, Vania Wang, Guanshu Liu, Agrani Dixit, Murilo Ramos Rocha, Elizabeth I. Harper, Mitchell E. Fane, Gloria E. Marino-Bravante, Daniel J. Zabransky, Kathy Q. Cai, Jochen Utikal, Barbara S. Slusher, Jeremy Walston, Evan J. Lipson, Kenneth W. Witwer, Ashani T. Weeraratna
Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.
年龄增长是皮肤黑色素瘤的一个不利预后因素。然而,细胞外囊泡(EVs)在黑色素瘤肿瘤微环境(TME)中的作用尚未被研究。虽然从年轻与衰老的成纤维细胞中分离出的EVs的大小和形态保持不变,但其中的蛋白质货物的含量却发生了变化。衰老降低了四跨蛋白 CD9 在真皮成纤维细胞和释放的 EVs 中的表达。CD9是EV货物分拣的关键调节因子。调节成纤维细胞中CD9的表达足以改变其在EVs中的水平。对CD9敲除(KD)与对照细胞释放的EV进行质谱分析发现,血管生成促进因子血管生成素样蛋白2(ANGPTL2)显著增加。对原代内皮细胞的分析证实,在 CD9 KD 条件下,血管萌发增加。总之,我们的数据表明,老化的 EV 在促进肿瘤容许的微环境中发挥着重要作用。
{"title":"Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma","authors":"Laura Hüser, Yash Chhabra, Olesia Gololobova, Vania Wang, Guanshu Liu, Agrani Dixit, Murilo Ramos Rocha, Elizabeth I. Harper, Mitchell E. Fane, Gloria E. Marino-Bravante, Daniel J. Zabransky, Kathy Q. Cai, Jochen Utikal, Barbara S. Slusher, Jeremy Walston, Evan J. Lipson, Kenneth W. Witwer, Ashani T. Weeraratna","doi":"10.1016/j.celrep.2024.114721","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114721","url":null,"abstract":"<p>Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1016/j.celrep.2024.114711
Maja C. Stöber, Rocío Chamorro González, Lotte Brückner, Thomas Conrad, Nadine Wittstruck, Annabell Szymansky, Angelika Eggert, Johannes H. Schulte, Richard P. Koche, Anton G. Henssen, Roland F. Schwarz, Kerstin Haase
Neuroblastoma exhibits significant inter- and intra-tumor genetic heterogeneity and varying clinical outcomes. Extrachromosomal DNAs (ecDNAs) may drive this heterogeneity by independently segregating during cell division, leading to rapid oncogene amplification. While ecDNA-mediated oncogene amplification is linked to poor prognosis in various cancers, the effects of ecDNA copy-number heterogeneity on intermediate phenotypes are poorly understood. Here, we leverage DNA and RNA sequencing from the same single cells in cell lines and neuroblastoma patients to investigate these effects. By analyzing ecDNA amplicon structures, we reveal extensive intercellular ecDNA copy-number heterogeneity. We also provide direct evidence of how this heterogeneity influences the expression of cargo genes, including MYCN and its downstream targets, and the overall transcriptional state of neuroblastoma cells. Our findings highlight the role of ecDNA copy number in promoting rapid adaptability of cellular states within tumors, underscoring the need for ecDNA-specific treatment strategies to address tumor formation and adaptation.
{"title":"Intercellular extrachromosomal DNA copy-number heterogeneity drives neuroblastoma cell state diversity","authors":"Maja C. Stöber, Rocío Chamorro González, Lotte Brückner, Thomas Conrad, Nadine Wittstruck, Annabell Szymansky, Angelika Eggert, Johannes H. Schulte, Richard P. Koche, Anton G. Henssen, Roland F. Schwarz, Kerstin Haase","doi":"10.1016/j.celrep.2024.114711","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114711","url":null,"abstract":"<p>Neuroblastoma exhibits significant inter- and intra-tumor genetic heterogeneity and varying clinical outcomes. Extrachromosomal DNAs (ecDNAs) may drive this heterogeneity by independently segregating during cell division, leading to rapid oncogene amplification. While ecDNA-mediated oncogene amplification is linked to poor prognosis in various cancers, the effects of ecDNA copy-number heterogeneity on intermediate phenotypes are poorly understood. Here, we leverage DNA and RNA sequencing from the same single cells in cell lines and neuroblastoma patients to investigate these effects. By analyzing ecDNA amplicon structures, we reveal extensive intercellular ecDNA copy-number heterogeneity. We also provide direct evidence of how this heterogeneity influences the expression of cargo genes, including MYCN and its downstream targets, and the overall transcriptional state of neuroblastoma cells. Our findings highlight the role of ecDNA copy number in promoting rapid adaptability of cellular states within tumors, underscoring the need for ecDNA-specific treatment strategies to address tumor formation and adaptation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1016/j.celrep.2024.114709
Huakun Zhang, Bao Liu
In a recent issue of Cell Reports, Bray et al. found genetic adaptation in kinetochore components and ion transporters underlying polyploid stabilization in Cochlearia. This resurrects the issue of whether nascent polyploidy in diverse organisms establish via common biological mechanisms.
{"title":"Does nascent polyploidy employ common mechanisms to stabilize and establish?","authors":"Huakun Zhang, Bao Liu","doi":"10.1016/j.celrep.2024.114709","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114709","url":null,"abstract":"<p>In a recent issue of <em>Cell Reports</em>, Bray et al. found genetic adaptation in kinetochore components and ion transporters underlying polyploid stabilization in <em>Cochlearia</em>. This resurrects the issue of whether nascent polyploidy in diverse organisms establish via common biological mechanisms.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1016/j.celrep.2024.114719
Christine Germeys, Tijs Vandoorne, Kristofer Davie, Suresh Poovathingal, Kara Heeren, Wendy Vermeire, FatemehArefeh Nami, Matthieu Moisse, Annelies Quaegebeur, Annerieke Sierksma, Laura Rué, Adrià Sicart, Caroline Eykens, Lenja De Cock, Bart De Strooper, Peter Carmeliet, Philip Van Damme, Katrien De Bock, Ludo Van Den Bosch
Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.
{"title":"Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response","authors":"Christine Germeys, Tijs Vandoorne, Kristofer Davie, Suresh Poovathingal, Kara Heeren, Wendy Vermeire, FatemehArefeh Nami, Matthieu Moisse, Annelies Quaegebeur, Annerieke Sierksma, Laura Rué, Adrià Sicart, Caroline Eykens, Lenja De Cock, Bart De Strooper, Peter Carmeliet, Philip Van Damme, Katrien De Bock, Ludo Van Den Bosch","doi":"10.1016/j.celrep.2024.114719","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114719","url":null,"abstract":"<p>Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of <em>Egln2</em> protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of <em>EGLN2</em> restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis <em>in vivo</em>, as well as in patient-derived cells.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222226","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}