Pub Date : 2024-08-27Epub Date: 2024-08-17DOI: 10.1016/j.celrep.2024.114635
Mohd Wasif Khan, Vivianne Cruz de Jesus, Betty-Anne Mittermuller, Shaan Sareen, Victor Lee, Robert J Schroth, Pingzhao Hu, Prashen Chelikani
Early childhood caries (ECC) is influenced by microbial and host factors, including social, behavioral, and oral health. In this cross-sectional study, we analyze interkingdom dynamics in the dental plaque microbiome and its association with host variables. We use 16S rRNA and ITS1 amplicon sequencing on samples collected from preschool children and analyze questionnaire data to examine the social determinants of oral health. The results indicate a significant enrichment of Streptococcus mutans and Candida dubliniensis in ECC samples, in contrast to Neisseria oralis in caries-free children. Our interkingdom correlation analysis reveals that Candida dubliniensis is strongly correlated with both Neisseria bacilliformis and Prevotella veroralis in ECC. Additionally, ECC shows significant associations with host variables, including oral health status, age, place of residence, and mode of childbirth. This study provides empirical evidence associating the oral microbiome with socioeconomic and behavioral factors in relation to ECC, offering insights for developing targeted prevention strategies.
{"title":"Role of socioeconomic factors and interkingdom crosstalk in the dental plaque microbiome in early childhood caries.","authors":"Mohd Wasif Khan, Vivianne Cruz de Jesus, Betty-Anne Mittermuller, Shaan Sareen, Victor Lee, Robert J Schroth, Pingzhao Hu, Prashen Chelikani","doi":"10.1016/j.celrep.2024.114635","DOIUrl":"10.1016/j.celrep.2024.114635","url":null,"abstract":"<p><p>Early childhood caries (ECC) is influenced by microbial and host factors, including social, behavioral, and oral health. In this cross-sectional study, we analyze interkingdom dynamics in the dental plaque microbiome and its association with host variables. We use 16S rRNA and ITS1 amplicon sequencing on samples collected from preschool children and analyze questionnaire data to examine the social determinants of oral health. The results indicate a significant enrichment of Streptococcus mutans and Candida dubliniensis in ECC samples, in contrast to Neisseria oralis in caries-free children. Our interkingdom correlation analysis reveals that Candida dubliniensis is strongly correlated with both Neisseria bacilliformis and Prevotella veroralis in ECC. Additionally, ECC shows significant associations with host variables, including oral health status, age, place of residence, and mode of childbirth. This study provides empirical evidence associating the oral microbiome with socioeconomic and behavioral factors in relation to ECC, offering insights for developing targeted prevention strategies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999451","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 : 2024-08-27Epub Date: 2024-08-17DOI: 10.1016/j.celrep.2024.114631
Jesse D Pyle, Sean R Lund, Katherine H O'Toole, Lana Saleh
Enzymatic modification of DNA nucleobases can coordinate gene expression, nuclease protection, or mutagenesis. We recently discovered a clade of phage-specific cytosine methyltransferase (MT) and 5-methylpyrimidine dioxygenase (5mYOX) enzymes that produce 5-hydroxymethylcytosine (5hmC) as a precursor for enzymatic hypermodifications on viral genomes. Here, we identify phage MT- and 5mYOX-associated glycosyltransferases (GTs) that catalyze linkage of diverse sugars to 5hmC nucleobase substrates. Metavirome mining revealed thousands of biosynthetic gene clusters containing enzymes with predicted roles in cytosine sugar hypermodification. We developed a platform for high-throughput screening of GT-containing pathways, relying on the Escherichia coli metabolome as a substrate pool. We successfully reconstituted several pathways and isolated diverse sugar modifications appended to cytosine, including mono-, di-, or tri-saccharides comprised of hexoses, N-acetylhexosamines, or heptose. These findings expand our knowledge of hypermodifications on nucleic acids and the origins of corresponding sugar-installing enzymes.
{"title":"Virus-encoded glycosyltransferases hypermodify DNA with diverse glycans.","authors":"Jesse D Pyle, Sean R Lund, Katherine H O'Toole, Lana Saleh","doi":"10.1016/j.celrep.2024.114631","DOIUrl":"10.1016/j.celrep.2024.114631","url":null,"abstract":"<p><p>Enzymatic modification of DNA nucleobases can coordinate gene expression, nuclease protection, or mutagenesis. We recently discovered a clade of phage-specific cytosine methyltransferase (MT) and 5-methylpyrimidine dioxygenase (5mYOX) enzymes that produce 5-hydroxymethylcytosine (5hmC) as a precursor for enzymatic hypermodifications on viral genomes. Here, we identify phage MT- and 5mYOX-associated glycosyltransferases (GTs) that catalyze linkage of diverse sugars to 5hmC nucleobase substrates. Metavirome mining revealed thousands of biosynthetic gene clusters containing enzymes with predicted roles in cytosine sugar hypermodification. We developed a platform for high-throughput screening of GT-containing pathways, relying on the Escherichia coli metabolome as a substrate pool. We successfully reconstituted several pathways and isolated diverse sugar modifications appended to cytosine, including mono-, di-, or tri-saccharides comprised of hexoses, N-acetylhexosamines, or heptose. These findings expand our knowledge of hypermodifications on nucleic acids and the origins of corresponding sugar-installing enzymes.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999454","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 : 2024-08-27Epub Date: 2024-08-14DOI: 10.1016/j.celrep.2024.114618
Ketty Sinigaglia, Anna Cherian, Qiupei Du, Valentina Lacovich, Dragana Vukić, Janka Melicherová, Pavla Linhartova, Lisa Zerad, Stanislav Stejskal, Radek Malik, Jan Prochazka, Nadège Bondurand, Radislav Sedláček, Mary A O'Connell, Liam P Keegan
Adar null mutant mouse embryos die with aberrant double-stranded RNA (dsRNA)-driven interferon induction, and Adar Mavs double mutants, in which interferon induction is prevented, die soon after birth. Protein kinase R (Pkr) is aberrantly activated in Adar Mavs mouse pup intestines before death, intestinal crypt cells die, and intestinal villi are lost. Adar Mavs Eifak2 (Pkr) triple mutant mice rescue all defects and have long-term survival. Adenosine deaminase acting on RNA 1 (ADAR1) and PKR co-immunoprecipitate from cells, suggesting PKR inhibition by direct interaction. AlphaFold studies on an inhibitory PKR dsRNA binding domain (dsRBD)-kinase domain interaction before dsRNA binding and on an inhibitory ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA provide a testable model of the inhibition. Wild-type or editing-inactive human ADAR1 expressed in A549 cells inhibits activation of endogenous PKR. ADAR1 dsRNA binding is required for, but is not sufficient for, PKR inhibition. Mutating the ADAR1 dsRBD3-PKR contact prevents co-immunoprecipitation, ADAR1 inhibition of PKR activity, and co-localization of ADAR1 and PKR in cells.
Adar null 突变体小鼠胚胎在双链 RNA(dsRNA)驱动的干扰素诱导下异常死亡,而 Adar Mavs 双突变体(干扰素诱导被阻止)则在出生后不久死亡。Adar Mavs幼鼠肠道中的蛋白激酶R(Pkr)在死亡前被异常激活,肠隐窝细胞死亡,肠绒毛消失。Adar Mavs Eifak2(Pkr)三重突变小鼠能挽救所有缺陷并长期存活。作用于 RNA 1 的腺苷脱氨酶(ADAR1)和 PKR 从细胞中共同免疫沉淀,表明 PKR 通过直接相互作用而受到抑制。对抑制性 PKR dsRNA 结合结构域(dsRBD)-激酶结构域在 dsRNA 结合前的相互作用以及抑制性 ADAR1 dsRBD3-PKR 激酶结构域在 dsRNA 上的相互作用的 AlphaFold 研究提供了一个可检验的抑制模型。在 A549 细胞中表达的野生型或编辑活性人 ADAR1 可抑制内源性 PKR 的活化。ADAR1 dsRNA 的结合是 PKR 抑制所必需的,但还不够。突变 ADAR1 dsRBD3-PKR 接触可防止共免疫沉淀、ADAR1 对 PKR 活性的抑制以及 ADAR1 和 PKR 在细胞中的共定位。
{"title":"An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation.","authors":"Ketty Sinigaglia, Anna Cherian, Qiupei Du, Valentina Lacovich, Dragana Vukić, Janka Melicherová, Pavla Linhartova, Lisa Zerad, Stanislav Stejskal, Radek Malik, Jan Prochazka, Nadège Bondurand, Radislav Sedláček, Mary A O'Connell, Liam P Keegan","doi":"10.1016/j.celrep.2024.114618","DOIUrl":"10.1016/j.celrep.2024.114618","url":null,"abstract":"<p><p>Adar null mutant mouse embryos die with aberrant double-stranded RNA (dsRNA)-driven interferon induction, and Adar Mavs double mutants, in which interferon induction is prevented, die soon after birth. Protein kinase R (Pkr) is aberrantly activated in Adar Mavs mouse pup intestines before death, intestinal crypt cells die, and intestinal villi are lost. Adar Mavs Eifak2 (Pkr) triple mutant mice rescue all defects and have long-term survival. Adenosine deaminase acting on RNA 1 (ADAR1) and PKR co-immunoprecipitate from cells, suggesting PKR inhibition by direct interaction. AlphaFold studies on an inhibitory PKR dsRNA binding domain (dsRBD)-kinase domain interaction before dsRNA binding and on an inhibitory ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA provide a testable model of the inhibition. Wild-type or editing-inactive human ADAR1 expressed in A549 cells inhibits activation of endogenous PKR. ADAR1 dsRNA binding is required for, but is not sufficient for, PKR inhibition. Mutating the ADAR1 dsRBD3-PKR contact prevents co-immunoprecipitation, ADAR1 inhibition of PKR activity, and co-localization of ADAR1 and PKR in cells.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987489","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 : 2024-08-27Epub Date: 2024-08-14DOI: 10.1016/j.celrep.2024.114622
Hannah N W Weinstein, Kevin Hu, Lisa Fish, Yih-An Chen, Paul Allegakoen, Julia H Pham, Keliana S F Hui, Chih-Hao Chang, Meltem Tutar, Lorena Benitez-Rivera, Maria B Baco, Hanbing Song, Andrew O Giacomelli, Francisca Vazquez, Mahmoud Ghandi, Hani Goodarzi, Franklin W Huang
Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
{"title":"RPL22 is a tumor suppressor in MSI-high cancers and a splicing regulator of MDM4.","authors":"Hannah N W Weinstein, Kevin Hu, Lisa Fish, Yih-An Chen, Paul Allegakoen, Julia H Pham, Keliana S F Hui, Chih-Hao Chang, Meltem Tutar, Lorena Benitez-Rivera, Maria B Baco, Hanbing Song, Andrew O Giacomelli, Francisca Vazquez, Mahmoud Ghandi, Hani Goodarzi, Franklin W Huang","doi":"10.1016/j.celrep.2024.114622","DOIUrl":"10.1016/j.celrep.2024.114622","url":null,"abstract":"<p><p>Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987492","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 : 2024-08-27Epub Date: 2024-08-09DOI: 10.1016/j.celrep.2024.114607
Mack B Reynolds, Benjamin Klein, Michael J McFadden, Norah K Judge, Hannah E Navarrete, Britton C Michmerhuizen, Dominik Awad, Tracey L Schultz, Paul W Harms, Li Zhang, Teresa R O'Meara, Jonathan Z Sexton, Costas A Lyssiotis, J Michelle Kahlenberg, Mary X O'Riordan
Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.
巨噬细胞的代谢可塑性是炎症程序的核心,然而在感染过程中协调代谢和炎症程序的机制却鲜为人知。在这里,我们发现 I 型干扰素(IFN)能在耐甲氧西林金黄色葡萄球菌(MRSA)感染期间暂时引导炎症的代谢控制。我们发现,巨噬细胞中交错的 Toll 样受体和 I 型干扰素信号传递允许氧化磷酸化(OXPHOS)和有氧糖酵解相结合的短暂能量状态,随后是诱导型一氧化氮合酶(iNOS)介导的 OXPHOS 破坏。这种破坏会促进 I 型 IFN,抑制其他促炎细胞因子,特别是白细胞介素-1β。感染后,iNOS 的表达在 24 小时内达到峰值,随后乳酸通过组蛋白乳酰化驱动 Nos2 抑制。I 型 IFN 预处理可延长感染诱导的 iNOS 表达,扩大 I 型 IFN 的作用。表皮 I 型 IFN 组成型表达的小鼠皮肤 MRSA 感染会导致 iNOS 水平升高、伤口愈合受损、血管病变和肺部感染。因此,动态调节的 I 型 IFN 信号可协调控制感染诱发炎症的免疫代谢检查点。
{"title":"Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.","authors":"Mack B Reynolds, Benjamin Klein, Michael J McFadden, Norah K Judge, Hannah E Navarrete, Britton C Michmerhuizen, Dominik Awad, Tracey L Schultz, Paul W Harms, Li Zhang, Teresa R O'Meara, Jonathan Z Sexton, Costas A Lyssiotis, J Michelle Kahlenberg, Mary X O'Riordan","doi":"10.1016/j.celrep.2024.114607","DOIUrl":"10.1016/j.celrep.2024.114607","url":null,"abstract":"<p><p>Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912014","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 : 2024-08-27Epub Date: 2024-08-08DOI: 10.1016/j.celrep.2024.114617
Zhiying Yao, Yi Liu, Qi Chen, Xiaoxin Chen, Zhenshuo Zhu, Sha Song, Xianjue Ma, Peiguo Yang
Liquid-liquid phase separation (LLPS) mediated by G3BP1/2 proteins and non-translating mRNAs mediates stress granule (SG) assembly. We investigated the phylogenetic evolution of G3BP orthologs from unicellular yeast to mammals and identified both conserved and divergent features. The modular domain organization of G3BP orthologs is generally conserved. However, invertebrate orthologs displayed reduced capacity for SG assembly in human cells compared to vertebrate orthologs. We demonstrated that the protein-interaction network facilitated by the NTF2L domain is a crucial determinant of this specificity. The evolution of the G3BP1 network coincided with its exploitation by certain viruses, as evident from the interaction between viral proteins and G3BP orthologs in insects and vertebrates. We revealed the importance and divergence of the G3BP interaction network in human SG formation. Leveraging this network, we established a 7-component in vitro SG reconstitution system for quantitative studies. These findings highlight the significance of G3BP network divergence in the evolution of biological processes.
{"title":"The divergent effects of G3BP orthologs on human stress granule assembly imply a centric role for the core protein interaction network.","authors":"Zhiying Yao, Yi Liu, Qi Chen, Xiaoxin Chen, Zhenshuo Zhu, Sha Song, Xianjue Ma, Peiguo Yang","doi":"10.1016/j.celrep.2024.114617","DOIUrl":"10.1016/j.celrep.2024.114617","url":null,"abstract":"<p><p>Liquid-liquid phase separation (LLPS) mediated by G3BP1/2 proteins and non-translating mRNAs mediates stress granule (SG) assembly. We investigated the phylogenetic evolution of G3BP orthologs from unicellular yeast to mammals and identified both conserved and divergent features. The modular domain organization of G3BP orthologs is generally conserved. However, invertebrate orthologs displayed reduced capacity for SG assembly in human cells compared to vertebrate orthologs. We demonstrated that the protein-interaction network facilitated by the NTF2L domain is a crucial determinant of this specificity. The evolution of the G3BP1 network coincided with its exploitation by certain viruses, as evident from the interaction between viral proteins and G3BP orthologs in insects and vertebrates. We revealed the importance and divergence of the G3BP interaction network in human SG formation. Leveraging this network, we established a 7-component in vitro SG reconstitution system for quantitative studies. These findings highlight the significance of G3BP network divergence in the evolution of biological processes.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909764","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 : 2024-08-27Epub Date: 2024-07-23DOI: 10.1016/j.celrep.2024.114542
Helen C Wang, Ran Chen, Wei Yang, Yanan Li, Rohini Muthukumar, Riddhi M Patel, Emily B Casey, Elisabeth Denby, Jeffrey A Magee
Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2c attenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.
{"title":"Kmt2c restricts G-CSF-driven HSC mobilization and granulocyte production in a methyltransferase-independent manner.","authors":"Helen C Wang, Ran Chen, Wei Yang, Yanan Li, Rohini Muthukumar, Riddhi M Patel, Emily B Casey, Elisabeth Denby, Jeffrey A Magee","doi":"10.1016/j.celrep.2024.114542","DOIUrl":"10.1016/j.celrep.2024.114542","url":null,"abstract":"<p><p>Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2c attenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757388","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 : 2024-08-27Epub Date: 2024-08-18DOI: 10.1016/j.celrep.2024.114649
Sahil Nagpal, Karthikeyan Swaminathan, Daniel Beaudet, Maud Verdier, Samuel Wang, Christopher L Berger, Florian Berger, Adam G Hendricks
Each cargo in a cell employs a unique set of motor proteins for its transport. To dissect the roles of each type of motor, we developed optogenetic inhibitors of endogenous kinesin-1, -2, -3 and dynein motors and examined their effect on the transport of early endosomes, late endosomes, and lysosomes. While kinesin-1, -3, and dynein transport vesicles at all stages of endocytosis, kinesin-2 primarily drives late endosomes and lysosomes. Transient optogenetic inhibition of kinesin-1 or dynein causes both early and late endosomes to move more processively by relieving competition with opposing motors. Kinesin-2 and -3 support long-range transport, and optogenetic inhibition reduces the distances that their cargoes move. These results suggest that the directionality of transport is controlled through regulating kinesin-1 and dynein activity. On vesicles transported by several kinesin and dynein motors, modulating the activity of a single type of motor on the cargo is sufficient to direct motility.
{"title":"Optogenetic control of kinesin-1, -2, -3 and dynein reveals their specific roles in vesicular transport.","authors":"Sahil Nagpal, Karthikeyan Swaminathan, Daniel Beaudet, Maud Verdier, Samuel Wang, Christopher L Berger, Florian Berger, Adam G Hendricks","doi":"10.1016/j.celrep.2024.114649","DOIUrl":"10.1016/j.celrep.2024.114649","url":null,"abstract":"<p><p>Each cargo in a cell employs a unique set of motor proteins for its transport. To dissect the roles of each type of motor, we developed optogenetic inhibitors of endogenous kinesin-1, -2, -3 and dynein motors and examined their effect on the transport of early endosomes, late endosomes, and lysosomes. While kinesin-1, -3, and dynein transport vesicles at all stages of endocytosis, kinesin-2 primarily drives late endosomes and lysosomes. Transient optogenetic inhibition of kinesin-1 or dynein causes both early and late endosomes to move more processively by relieving competition with opposing motors. Kinesin-2 and -3 support long-range transport, and optogenetic inhibition reduces the distances that their cargoes move. These results suggest that the directionality of transport is controlled through regulating kinesin-1 and dynein activity. On vesicles transported by several kinesin and dynein motors, modulating the activity of a single type of motor on the cargo is sufficient to direct motility.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003705","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 : 2024-08-27Epub Date: 2024-08-08DOI: 10.1016/j.celrep.2024.114599
Micah G Donovan, Angela L Rachubinski, Keith P Smith, Paula Araya, Katherine A Waugh, Belinda Enriquez-Estrada, Eleanor C Britton, Hannah R Lyford, Ross E Granrath, Kyndal A Schade, Kohl T Kinning, Neetha Paul Eduthan, Kelly D Sullivan, Matthew D Galbraith, Joaquin M Espinosa
Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.
{"title":"Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome.","authors":"Micah G Donovan, Angela L Rachubinski, Keith P Smith, Paula Araya, Katherine A Waugh, Belinda Enriquez-Estrada, Eleanor C Britton, Hannah R Lyford, Ross E Granrath, Kyndal A Schade, Kohl T Kinning, Neetha Paul Eduthan, Kelly D Sullivan, Matthew D Galbraith, Joaquin M Espinosa","doi":"10.1016/j.celrep.2024.114599","DOIUrl":"10.1016/j.celrep.2024.114599","url":null,"abstract":"<p><p>Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909762","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 : 2024-08-27Epub Date: 2024-08-07DOI: 10.1016/j.celrep.2024.114587
Yichi Zhang, Matthieu Dos Santos, Huocong Huang, Kenian Chen, Puneeth Iyengar, Rodney Infante, Patricio M Polanco, Rolf A Brekken, Chunyu Cai, Ambar Caijgas, Karla Cano Hernandez, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N Olson
Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.
{"title":"A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.","authors":"Yichi Zhang, Matthieu Dos Santos, Huocong Huang, Kenian Chen, Puneeth Iyengar, Rodney Infante, Patricio M Polanco, Rolf A Brekken, Chunyu Cai, Ambar Caijgas, Karla Cano Hernandez, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N Olson","doi":"10.1016/j.celrep.2024.114587","DOIUrl":"10.1016/j.celrep.2024.114587","url":null,"abstract":"<p><p>Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906079","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}