Jim Zoladek, Marion Cannac, Maël Seite, Emma Davies, Jordan Quellec, Jonathan Barthelemy, Kamila Gorna, Sophie Desgraupes, Ines Bribes, Sara Salinas, Muriel Coulpier, Nathalie J. Arhel, Massimo Palmarini, Yannick Simonin, Sam J. Wilson, Sébastien Nisole
West Nile virus (WNV) and Usutu virus (USUV) are closely related mosquito-borne neurotropic flaviviruses that share common transmission cycle and can infect humans. However, while human infections by WNV are widespread, infections by USUV are comparatively less frequent, less severe, and currently limited to Africa and Europe. To identify human host factors that contribute to the pathogenic signatures of these two flaviviruses, we carried out an arrayed expression screen of over 1,300 interferon-stimulated genes (ISGs). Several ISGs known to target flaviviruses, including IFI6, SHFL, and RTP4 were among the strongest hits. Interestingly, we also found MITD1, an ISG with no previously reported antiviral activity, among the strongest hits. We demonstrated that the antiviral activity of MITD1 was not limited to USUV and WNV, since it also inhibited Zika and dengue virus replication. We found MITD1 to interfere with viral RNA replication by sequestering specific endosomal sorting complexes required for transport-III (ESCRT-III) proteins involved in the formation of viral replication factories. MITD1 expression was not increased by type I interferon (IFN-I) in most human cells and mouse tissues that we examined, although WNV and USUV replication was strongly inhibited by IFN-I. Strikingly, MITD1 was induced in the brain of USUV-infected mice and importantly, in human monocyte-derived microglia. Using human microglial-like cells, we confirmed that MITD1 is an essential mediator of the anti-flavivirus activity of IFN-I in these cells. We conclude that MITD1 plays a key role in the cellular defenses against neurotropic flaviviruses.
{"title":"MITD1 is a brain-specific interferon-inducible factor that inhibits flavivirus replication","authors":"Jim Zoladek, Marion Cannac, Maël Seite, Emma Davies, Jordan Quellec, Jonathan Barthelemy, Kamila Gorna, Sophie Desgraupes, Ines Bribes, Sara Salinas, Muriel Coulpier, Nathalie J. Arhel, Massimo Palmarini, Yannick Simonin, Sam J. Wilson, Sébastien Nisole","doi":"10.1073/pnas.2502064122","DOIUrl":"https://doi.org/10.1073/pnas.2502064122","url":null,"abstract":"West Nile virus (WNV) and Usutu virus (USUV) are closely related mosquito-borne neurotropic flaviviruses that share common transmission cycle and can infect humans. However, while human infections by WNV are widespread, infections by USUV are comparatively less frequent, less severe, and currently limited to Africa and Europe. To identify human host factors that contribute to the pathogenic signatures of these two flaviviruses, we carried out an arrayed expression screen of over 1,300 interferon-stimulated genes (ISGs). Several ISGs known to target flaviviruses, including IFI6, SHFL, and RTP4 were among the strongest hits. Interestingly, we also found MITD1, an ISG with no previously reported antiviral activity, among the strongest hits. We demonstrated that the antiviral activity of MITD1 was not limited to USUV and WNV, since it also inhibited Zika and dengue virus replication. We found MITD1 to interfere with viral RNA replication by sequestering specific endosomal sorting complexes required for transport-III (ESCRT-III) proteins involved in the formation of viral replication factories. MITD1 expression was not increased by type I interferon (IFN-I) in most human cells and mouse tissues that we examined, although WNV and USUV replication was strongly inhibited by IFN-I. Strikingly, MITD1 was induced in the brain of USUV-infected mice and importantly, in human monocyte-derived microglia. Using human microglial-like cells, we confirmed that MITD1 is an essential mediator of the anti-flavivirus activity of IFN-I in these cells. We conclude that MITD1 plays a key role in the cellular defenses against neurotropic flaviviruses.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"9 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefano Zucca, Gloria Brunori, Henry A. Dunn, Colten K. Lankford, Laurie P. Sutton, Beatriz Algibez Flores, Nycole A. Maza, Omar Sial, Gogce Crynen, Rafael Luján, Kirill A. Martemyanov
Opioids trigger structural and functional neural adaptations of the reward circuit that lead to dependence. Synaptic cell adhesion molecules (CAMs) play a pivotal role in circuit organization and present prime candidates for orchestrating remodeling of neural connections in response to drug exposure. However, the contribution of CAMs to opioid-induced rewiring of the reward circuit has not been explored. Here, we used unbiased molecular profiling to identify CAMs in the nucleus accumbens (NAc) modulated by morphine administration. We found that opioid exposure induces the expression of ELFN1, a CAM selectively expressed in cholinergic interneurons in the NAc. We determined that ELFN1 acts trans-synaptically to modulate the strength and plasticity of the glutamatergic inputs onto cholinergic neurons via the recruitment of presynaptic metabotropic glutamate receptor 4 (mGlu4). Disruption of Elfn1 diminished morphine reward and intake in self-administering mice. Together, our findings identify a key molecular factor responsible for adjusting the strength of opioid effects by modulating the configuration of striatal circuitry in an experience-dependent fashion and unveil potential therapeutic target for combating opioid abuse.
{"title":"Trans-synaptic modulation of cholinergic circuits tunes opioid reinforcement","authors":"Stefano Zucca, Gloria Brunori, Henry A. Dunn, Colten K. Lankford, Laurie P. Sutton, Beatriz Algibez Flores, Nycole A. Maza, Omar Sial, Gogce Crynen, Rafael Luján, Kirill A. Martemyanov","doi":"10.1073/pnas.2409325122","DOIUrl":"https://doi.org/10.1073/pnas.2409325122","url":null,"abstract":"Opioids trigger structural and functional neural adaptations of the reward circuit that lead to dependence. Synaptic cell adhesion molecules (CAMs) play a pivotal role in circuit organization and present prime candidates for orchestrating remodeling of neural connections in response to drug exposure. However, the contribution of CAMs to opioid-induced rewiring of the reward circuit has not been explored. Here, we used unbiased molecular profiling to identify CAMs in the nucleus accumbens (NAc) modulated by morphine administration. We found that opioid exposure induces the expression of ELFN1, a CAM selectively expressed in cholinergic interneurons in the NAc. We determined that ELFN1 acts trans-synaptically to modulate the strength and plasticity of the glutamatergic inputs onto cholinergic neurons via the recruitment of presynaptic metabotropic glutamate receptor 4 (mGlu4). Disruption of <jats:italic>Elfn1</jats:italic> diminished morphine reward and intake in self-administering mice. Together, our findings identify a key molecular factor responsible for adjusting the strength of opioid effects by modulating the configuration of striatal circuitry in an experience-dependent fashion and unveil potential therapeutic target for combating opioid abuse.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"16 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin Larue, Fanie Pelletier, Marco Festa-Bianchet, Sandra Hamel
Individual heterogeneity shapes ecoevolutionary processes at multiple scales. Yet, the scarcity of long-term life-history data and limitations in classic statistical tools hinder our capacity to uncover and understand individual heterogeneity in wildlife populations. Here, we apply an underused multivariate statistical method to uncover four heterogenous life-history trajectories in wild female bighorn sheep ( Ovis canadensis ). Remarkably, these trajectories had remained unobserved in the population despite nearly five decades of monitoring. Our results indicate substantial among-trajectory heterogeneity in growth, senescence, life history trade-offs, fitness, and contributions to population growth. Some trajectories suggest the presence of life history trade-offs while others include silver spoon effects, leading to heterogenous life-history outputs. Then, we show that mother identity and year of birth are relatively good predictors of heterogeneity, indicating that individual trajectories could be largely set during early life. Critically, our results demonstrate that heterogeneity in life-history trajectories can be inconspicuous, yet substantial and structured across multiple traits within a population. Uncovering and understanding this heterogeneity in other wild populations will be key to advancing our knowledge of ecoevolutionary processes across populations and species.
{"title":"Uncovering bighorn sheep life-history trajectories in multidimensional trait space","authors":"Benjamin Larue, Fanie Pelletier, Marco Festa-Bianchet, Sandra Hamel","doi":"10.1073/pnas.2417158122","DOIUrl":"https://doi.org/10.1073/pnas.2417158122","url":null,"abstract":"Individual heterogeneity shapes ecoevolutionary processes at multiple scales. Yet, the scarcity of long-term life-history data and limitations in classic statistical tools hinder our capacity to uncover and understand individual heterogeneity in wildlife populations. Here, we apply an underused multivariate statistical method to uncover four heterogenous life-history trajectories in wild female bighorn sheep ( <jats:italic>Ovis canadensis</jats:italic> ). Remarkably, these trajectories had remained unobserved in the population despite nearly five decades of monitoring. Our results indicate substantial among-trajectory heterogeneity in growth, senescence, life history trade-offs, fitness, and contributions to population growth. Some trajectories suggest the presence of life history trade-offs while others include silver spoon effects, leading to heterogenous life-history outputs. Then, we show that mother identity and year of birth are relatively good predictors of heterogeneity, indicating that individual trajectories could be largely set during early life. Critically, our results demonstrate that heterogeneity in life-history trajectories can be inconspicuous, yet substantial and structured across multiple traits within a population. Uncovering and understanding this heterogeneity in other wild populations will be key to advancing our knowledge of ecoevolutionary processes across populations and species.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"70 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kang Liu, Lina Wu, Yuanyuan Ma, Desheng Chen, Rujia Liu, Xiaobo Zhang, Dechen Jiang, Rongrong Pan
Simultaneous profiling of multiple molecules trafficking at a single organelle and the surrounding cytosol within a living cell is crucial for elucidating their functions, necessitating advanced techniques that provide high spatial–temporal resolution and molecule specificity. In this study, we present an electrochemical nanodevice based on a θ-nanopipette designed to coanalyze calcium ions (Ca 2+ ) and reactive oxygen species (ROS) at a single mitochondrion and its surrounding cytosol, thereby enhancing our understanding of their trafficking within the signaling pathways of cellular autophagy. Two independent nanosensors integrated within the channels of the θ-nanopipette spatially isolate a single target mitochondrion from the cytosol and simultaneously measure the release of Ca 2+ and ROS with high spatial–temporal resolution. Dynamic tracking reveals the direct trafficking of lysosomal Ca 2+ to the mitochondrion rather than to the cytosol, which triggers ROS-induced ROS release within the mitochondria. Furthermore, highly temporal and concurrent observations revealed a second burst of Ca 2+ in both the mitochondrion and the cytosol, which is not consistent with the change in ROS. These dynamic data elucidate the potential role of a beneficial feedback loop between the Ca 2+ signaling pathway and the subsequent generation of mitochondrial ROS in ML-SA-induced autophagy. More importantly, this innovative platform facilitates detailed profiling of the molecular interactions between trafficking molecules within the mitochondria and the adjacent cytosolic environment, which is hardly realized using the current superresolution optical microscopy.
{"title":"Highly spatial–temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell","authors":"Kang Liu, Lina Wu, Yuanyuan Ma, Desheng Chen, Rujia Liu, Xiaobo Zhang, Dechen Jiang, Rongrong Pan","doi":"10.1073/pnas.2424591122","DOIUrl":"https://doi.org/10.1073/pnas.2424591122","url":null,"abstract":"Simultaneous profiling of multiple molecules trafficking at a single organelle and the surrounding cytosol within a living cell is crucial for elucidating their functions, necessitating advanced techniques that provide high spatial–temporal resolution and molecule specificity. In this study, we present an electrochemical nanodevice based on a θ-nanopipette designed to coanalyze calcium ions (Ca <jats:sup>2+</jats:sup> ) and reactive oxygen species (ROS) at a single mitochondrion and its surrounding cytosol, thereby enhancing our understanding of their trafficking within the signaling pathways of cellular autophagy. Two independent nanosensors integrated within the channels of the θ-nanopipette spatially isolate a single target mitochondrion from the cytosol and simultaneously measure the release of Ca <jats:sup>2+</jats:sup> and ROS with high spatial–temporal resolution. Dynamic tracking reveals the direct trafficking of lysosomal Ca <jats:sup>2+</jats:sup> to the mitochondrion rather than to the cytosol, which triggers ROS-induced ROS release within the mitochondria. Furthermore, highly temporal and concurrent observations revealed a second burst of Ca <jats:sup>2+</jats:sup> in both the mitochondrion and the cytosol, which is not consistent with the change in ROS. These dynamic data elucidate the potential role of a beneficial feedback loop between the Ca <jats:sup>2+</jats:sup> signaling pathway and the subsequent generation of mitochondrial ROS in ML-SA-induced autophagy. More importantly, this innovative platform facilitates detailed profiling of the molecular interactions between trafficking molecules within the mitochondria and the adjacent cytosolic environment, which is hardly realized using the current superresolution optical microscopy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"45 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shoichi Nishitani, Kevin Ao, Amad Jalil, Octavio I. Arias-Soto, Ava Moudi, Feiyang Chen, Ankita Biyani, Padma N. Muppirala, Markita P. Landry
Single-walled carbon nanotubes (SWCNTs) exhibit nonphotobleaching, near-infrared (NIR) fluorescence suitable for bioimaging applications. In particular, SWCNT fluorescence quenching induced by biopolymer dispersants facilitates flexible design of molecular nanosensors, yet challenges remain in analyte selectivity and lack of rational design strategies. A sought-after alternative to haphazard molecular modulation of SWCNT-based fluorescence is to couple the movement of a quencher to the SWCNT surface, enabling fluorescence energy transfer to modulate molecular recognition with high selectivity. This study presents the rational design of SWCNT-based nanosensors with fluorescence energy transfer, leveraging the unique properties of methylene blue (MB) proximity–mediated fluorescence quenching. MB-SWCNT-based nanosensors exhibit 1- stability in redox environments and 2- analyte-specific displacement-driven fluorescence modulation. By designing hybridization-induced displacement of MB-conjugated ssDNA from the SWCNT surface, we calculate that SWCNT fluorescence modulation can occur within a 6.8 nm fluorescence resonance energy transfer distance from the SWCNT surface and develop a robust and versatile platform to synthesize oligonucleotide nanosensors with tunable Δ F / F0 of up to 150%. Building upon this strategy, we developed four distinct nanosensors capable of selectively detecting tobacco mosaic virus (TMV) viral RNA fragments, which successfully differentiated TMV-infected plants from mock controls. Finally, we demonstrate the potential expansion of our design to target a wider scope of biomolecules using the biotin-avidin system as a model. Taken together, our study presents a generalizable platform that enables rational engineering of SWCNT NIR fluorescence intensity through MB distance-dependent fluorescence energy transfer, overcoming the intrinsic selectivity challenges of current SWCNT nanosensors.
{"title":"Redox dye–mediated fluorescence energy transfer of carbon nanotube–based nanosensors","authors":"Shoichi Nishitani, Kevin Ao, Amad Jalil, Octavio I. Arias-Soto, Ava Moudi, Feiyang Chen, Ankita Biyani, Padma N. Muppirala, Markita P. Landry","doi":"10.1073/pnas.2419666122","DOIUrl":"https://doi.org/10.1073/pnas.2419666122","url":null,"abstract":"Single-walled carbon nanotubes (SWCNTs) exhibit nonphotobleaching, near-infrared (NIR) fluorescence suitable for bioimaging applications. In particular, SWCNT fluorescence quenching induced by biopolymer dispersants facilitates flexible design of molecular nanosensors, yet challenges remain in analyte selectivity and lack of rational design strategies. A sought-after alternative to haphazard molecular modulation of SWCNT-based fluorescence is to couple the movement of a quencher to the SWCNT surface, enabling fluorescence energy transfer to modulate molecular recognition with high selectivity. This study presents the rational design of SWCNT-based nanosensors with fluorescence energy transfer, leveraging the unique properties of methylene blue (MB) proximity–mediated fluorescence quenching. MB-SWCNT-based nanosensors exhibit 1- stability in redox environments and 2- analyte-specific displacement-driven fluorescence modulation. By designing hybridization-induced displacement of MB-conjugated ssDNA from the SWCNT surface, we calculate that SWCNT fluorescence modulation can occur within a 6.8 nm fluorescence resonance energy transfer distance from the SWCNT surface and develop a robust and versatile platform to synthesize oligonucleotide nanosensors with tunable Δ <jats:italic>F</jats:italic> / <jats:italic>F</jats:italic> <jats:sub>0</jats:sub> of up to 150%. Building upon this strategy, we developed four distinct nanosensors capable of selectively detecting tobacco mosaic virus (TMV) viral RNA fragments, which successfully differentiated TMV-infected plants from mock controls. Finally, we demonstrate the potential expansion of our design to target a wider scope of biomolecules using the biotin-avidin system as a model. Taken together, our study presents a generalizable platform that enables rational engineering of SWCNT NIR fluorescence intensity through MB distance-dependent fluorescence energy transfer, overcoming the intrinsic selectivity challenges of current SWCNT nanosensors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"183 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Romain Gailleton, Nimitha R. Mathew, Laura Reusch, Karin Schön, Lydia Scharf, Anneli Strömberg, Andrea Cvjetkovic, Luaay Aziz, Johan Hellgren, Ka-Wei Tang, Mats Bemark, Davide Angeletti
The nasal mucosa is the first immunologically active site that respiratory viruses encounter and establishing immunity at the initial point of pathogen contact is essential for preventing viral spread. Influenza A virus (IAV) in humans preferentially replicates in the upper respiratory tract (URT) but mouse models of infection result in lower respiratory tract infection. Here, we optimize IAV inoculation to enhance replication in the nasal turbinate (NT) and study local B cell immunity. We demonstrate that URT-targeted IAV infection stimulates robust local B cell responses, including germinal center (GC) B cell formation in the NT, outside of classical nasal-associated lymphoid tissues. NT GC contributes to local tissue-resident B cell generation and enhances local antibody production. Furthermore, URT-focused immunization also induces significant GC formation in the NT. Finally, we detect steady-state GC in the NT of both mice and healthy humans, suggesting continuous immune surveillance triggered by environmental stimuli. These findings highlight the pivotal role of the NT in local and systemic immunity, with important implications for future mucosal vaccines targeting the upper airways.
{"title":"Ectopic germinal centers in the nasal turbinates contribute to B cell immunity to intranasal viral infection and vaccination","authors":"Romain Gailleton, Nimitha R. Mathew, Laura Reusch, Karin Schön, Lydia Scharf, Anneli Strömberg, Andrea Cvjetkovic, Luaay Aziz, Johan Hellgren, Ka-Wei Tang, Mats Bemark, Davide Angeletti","doi":"10.1073/pnas.2421724122","DOIUrl":"https://doi.org/10.1073/pnas.2421724122","url":null,"abstract":"The nasal mucosa is the first immunologically active site that respiratory viruses encounter and establishing immunity at the initial point of pathogen contact is essential for preventing viral spread. Influenza A virus (IAV) in humans preferentially replicates in the upper respiratory tract (URT) but mouse models of infection result in lower respiratory tract infection. Here, we optimize IAV inoculation to enhance replication in the nasal turbinate (NT) and study local B cell immunity. We demonstrate that URT-targeted IAV infection stimulates robust local B cell responses, including germinal center (GC) B cell formation in the NT, outside of classical nasal-associated lymphoid tissues. NT GC contributes to local tissue-resident B cell generation and enhances local antibody production. Furthermore, URT-focused immunization also induces significant GC formation in the NT. Finally, we detect steady-state GC in the NT of both mice and healthy humans, suggesting continuous immune surveillance triggered by environmental stimuli. These findings highlight the pivotal role of the NT in local and systemic immunity, with important implications for future mucosal vaccines targeting the upper airways.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaohan Wang, Mengyao Liu, Yifan Zhang, Dongyuan Ma, Lu Wang, Feng Liu
During fetal stage, hematopoietic stem and progenitor cells (HSPCs) undergo rapid proliferation with a tight control of genomic stability. Although histone H3 lysine 4 (H3K4) methylation has been reported to stabilize the genome in proliferating cells, its specific role in HSPC development remains elusive. In this study, we demonstrated that tryptophan-aspartic acid (WD) repeat protein 5 (Wdr5)-mediated H3K4 methylation is crucial for maintaining genomic stability of proliferating HSPCs in zebrafish embryos. Loss of wdr5 led to a severe reduction of HSPC pool in the caudal hematopoietic tissue, accompanied with attenuated H3K4 methylation level and evident p53 -dependent apoptosis in the HSPCs. Mechanistically, Wdr5-mediated H3K4 methylation maintains genomic stability by inhibiting the formation of abnormal R-loops in the HSPCs, whereas accumulation of R-loops exacerbates DNA damage. Moreover, the absence of H3K4 trimethylation leads to an inactivated DNA damage response (DDR) pathway, which is deleterious to DNA damage repair and genomic stability. Subsequently, we found that DDR-associated genes, mutL homolog 1 and breast and ovarian cancer interacting helicase 1 , are important to ensure HSPC survival, likely by stabilizing their genome. In summary, these findings reveal that Wdr5-mediated H3K4 methylation is essential for HSPC development through tight control of R-loop accumulation and DDR-associated program to ensure genomic stability and survival of proliferating HSPCs.
{"title":"Wdr5-mediated H3K4 methylation facilitates HSPC development via maintenance of genomic stability in zebrafish","authors":"Xiaohan Wang, Mengyao Liu, Yifan Zhang, Dongyuan Ma, Lu Wang, Feng Liu","doi":"10.1073/pnas.2420534122","DOIUrl":"https://doi.org/10.1073/pnas.2420534122","url":null,"abstract":"During fetal stage, hematopoietic stem and progenitor cells (HSPCs) undergo rapid proliferation with a tight control of genomic stability. Although histone H3 lysine 4 (H3K4) methylation has been reported to stabilize the genome in proliferating cells, its specific role in HSPC development remains elusive. In this study, we demonstrated that tryptophan-aspartic acid (WD) repeat protein 5 (Wdr5)-mediated H3K4 methylation is crucial for maintaining genomic stability of proliferating HSPCs in zebrafish embryos. Loss of <jats:italic>wdr5</jats:italic> led to a severe reduction of HSPC pool in the caudal hematopoietic tissue, accompanied with attenuated H3K4 methylation level and evident <jats:italic>p53</jats:italic> -dependent apoptosis in the HSPCs. Mechanistically, Wdr5-mediated H3K4 methylation maintains genomic stability by inhibiting the formation of abnormal R-loops in the HSPCs, whereas accumulation of R-loops exacerbates DNA damage. Moreover, the absence of H3K4 trimethylation leads to an inactivated DNA damage response (DDR) pathway, which is deleterious to DNA damage repair and genomic stability. Subsequently, we found that DDR-associated genes, <jats:italic>mutL homolog 1</jats:italic> and <jats:italic>breast and ovarian cancer interacting helicase 1</jats:italic> , are important to ensure HSPC survival, likely by stabilizing their genome. In summary, these findings reveal that Wdr5-mediated H3K4 methylation is essential for HSPC development through tight control of R-loop accumulation and DDR-associated program to ensure genomic stability and survival of proliferating HSPCs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"26 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vinícius G. Contessoto, Antonio B. Oliveira Jr., Sumitabha Brahmachari, Peter G. Wolynes, Michele Di Pierro, José N. Onuchic
During mitosis, there are significant structural changes in chromosomes. We used a maximum entropy approach to invert experimental Hi-C data to generate effective energy landscapes for chromosomal structures at different stages during the cell cycle. Modeled mitotic structures show a hierarchical organization of helices of helices. High-periodicity loops span hundreds of kilobases or less, while the other low-periodicity ones are larger in genomic separation, spanning several megabases. The structural ensembles reveal a progressive decrease in compartmentalization from interphase to mitosis, accompanied by the appearance of a second diagonal in prometaphase, indicating an organized array of loops. While there is a local tendency to form chiral helices, overall, no preferential left-handed or right-handed chirality appears to develop on the time scale of the cell cycle. Chromatin thus appears to be a liquid crystal containing numerous defects that anneal rather slowly.
{"title":"Energy landscape analysis of the development of the chromosome structure across the cell cycle","authors":"Vinícius G. Contessoto, Antonio B. Oliveira Jr., Sumitabha Brahmachari, Peter G. Wolynes, Michele Di Pierro, José N. Onuchic","doi":"10.1073/pnas.2425225122","DOIUrl":"https://doi.org/10.1073/pnas.2425225122","url":null,"abstract":"During mitosis, there are significant structural changes in chromosomes. We used a maximum entropy approach to invert experimental Hi-C data to generate effective energy landscapes for chromosomal structures at different stages during the cell cycle. Modeled mitotic structures show a hierarchical organization of helices of helices. High-periodicity loops span hundreds of kilobases or less, while the other low-periodicity ones are larger in genomic separation, spanning several megabases. The structural ensembles reveal a progressive decrease in compartmentalization from interphase to mitosis, accompanied by the appearance of a second diagonal in prometaphase, indicating an organized array of loops. While there is a local tendency to form chiral helices, overall, no preferential left-handed or right-handed chirality appears to develop on the time scale of the cell cycle. Chromatin thus appears to be a liquid crystal containing numerous defects that anneal rather slowly.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johanna L. Hall, Shiun-Jr Yang, David T. Limmer, Graham R. Fleming
Photosystem II (PSII) can achieve near-unity quantum efficiency of light harvesting in ideal conditions and can dissipate excess light energy as heat to prevent the formation of reactive oxygen species (ROS) under light stress. Understanding how this pigment–protein complex accomplishes these opposing goals is a topic of great interest that has so far been explored primarily through the lens of the system energetics. Despite PSII’s known flat energy landscape, a thorough consideration of the entropic effects on energy transfer in PSII is lacking. In this work, we aim to discern the free energetic design principles underlying the PSII energy transfer network. To accomplish this goal, we employ a structure-based rate matrix and compute the free energy terms in time following a specific initial excitation to discern how entropy and enthalpy drive ensemble system dynamics. We find that the interplay between the entropy and enthalpy components differ among each protein subunit, which allows each subunit to fulfill a unique role in the energy transfer network. This individuality ensures that PSII can accomplish efficient energy trapping in the reaction center (RC), effective nonphotochemical quenching (NPQ) in the periphery, and robust energy trapping in the other-monomer RC if the same-monomer RC is closed. We also show that entropy, in particular, is a dynamically tunable feature of the PSII free energy landscape accomplished through regulation of LHCII binding. These findings help rationalize natural photosynthesis and provide design principles for more efficient solar energy harvesting technologies.
{"title":"Entropy is an important design principle in the photosystem II supercomplex","authors":"Johanna L. Hall, Shiun-Jr Yang, David T. Limmer, Graham R. Fleming","doi":"10.1073/pnas.2426331122","DOIUrl":"https://doi.org/10.1073/pnas.2426331122","url":null,"abstract":"Photosystem II (PSII) can achieve near-unity quantum efficiency of light harvesting in ideal conditions and can dissipate excess light energy as heat to prevent the formation of reactive oxygen species (ROS) under light stress. Understanding how this pigment–protein complex accomplishes these opposing goals is a topic of great interest that has so far been explored primarily through the lens of the system energetics. Despite PSII’s known flat energy landscape, a thorough consideration of the entropic effects on energy transfer in PSII is lacking. In this work, we aim to discern the free energetic design principles underlying the PSII energy transfer network. To accomplish this goal, we employ a structure-based rate matrix and compute the free energy terms in time following a specific initial excitation to discern how entropy and enthalpy drive ensemble system dynamics. We find that the interplay between the entropy and enthalpy components differ among each protein subunit, which allows each subunit to fulfill a unique role in the energy transfer network. This individuality ensures that PSII can accomplish efficient energy trapping in the reaction center (RC), effective nonphotochemical quenching (NPQ) in the periphery, and robust energy trapping in the other-monomer RC if the same-monomer RC is closed. We also show that entropy, in particular, is a dynamically tunable feature of the PSII free energy landscape accomplished through regulation of LHCII binding. These findings help rationalize natural photosynthesis and provide design principles for more efficient solar energy harvesting technologies.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"201 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei Zhang, Wenming Li, Jun Du, Chen Yang, Lei Yu, Peng Yang, Haifeng Zhang, Zebin Wu, Gaoran Ge, Huilin Yang, Dechun Geng
Redox imbalance contributes to aberrant osteoclastogenesis and osteoporotic bone loss. In this study, we observed lower Forkhead box protein O3 (FoxO3), a transcription factor associated with cellular oxidative stress, enhanced osteoclastogenesis in osteoporosis (OP). Single-cell RNA sequencing (scRNA-seq) analysis on the human femoral head indicated that FoxO3 is widely expressed in macrophages. Furthermore, Lysm-Cre;FoxO3 f/f OVX mice showed increased reactive oxygen species (ROS), enhanced osteoclastogenesis, and more bone loss than normal OVX mice. Mechanistically, we identified FoxO3 promoter methylation as a crucial factor contributing to decreased FoxO3, thereby influencing osteoclastogenesis and OC function. Intriguingly, we observed that Dnmt3a, highly expressed during osteoclastogenesis, played a pivotal role in regulating the methylation of the FoxO3 promoter. Knockdown of Dnmt3a promoted FoxO3 expression, inhibiting osteoclastogenesis and mitigating OP. Interestingly, we observed that Dnmt3a alleviated osteoclastogenesis by suppressing ROS via upregulating FoxO3 rather than inducing the dissociation of RANK and TRAF6. Collectively, this study elucidates the role and mechanism of FoxO3 in osteoclastogenesis and OP, providing a epigenetic target for the treatment of OP.
{"title":"Dnmt3a-mediated hypermethylation of FoxO3 promotes redox imbalance during osteoclastogenesis","authors":"Wei Zhang, Wenming Li, Jun Du, Chen Yang, Lei Yu, Peng Yang, Haifeng Zhang, Zebin Wu, Gaoran Ge, Huilin Yang, Dechun Geng","doi":"10.1073/pnas.2418023122","DOIUrl":"https://doi.org/10.1073/pnas.2418023122","url":null,"abstract":"Redox imbalance contributes to aberrant osteoclastogenesis and osteoporotic bone loss. In this study, we observed lower Forkhead box protein O3 (FoxO3), a transcription factor associated with cellular oxidative stress, enhanced osteoclastogenesis in osteoporosis (OP). Single-cell RNA sequencing (scRNA-seq) analysis on the human femoral head indicated that FoxO3 is widely expressed in macrophages. Furthermore, Lysm-Cre;FoxO3 <jats:sup>f/f</jats:sup> OVX mice showed increased reactive oxygen species (ROS), enhanced osteoclastogenesis, and more bone loss than normal OVX mice. Mechanistically, we identified FoxO3 promoter methylation as a crucial factor contributing to decreased FoxO3, thereby influencing osteoclastogenesis and OC function. Intriguingly, we observed that Dnmt3a, highly expressed during osteoclastogenesis, played a pivotal role in regulating the methylation of the FoxO3 promoter. Knockdown of Dnmt3a promoted FoxO3 expression, inhibiting osteoclastogenesis and mitigating OP. Interestingly, we observed that Dnmt3a alleviated osteoclastogenesis by suppressing ROS via upregulating FoxO3 rather than inducing the dissociation of RANK and TRAF6. Collectively, this study elucidates the role and mechanism of FoxO3 in osteoclastogenesis and OP, providing a epigenetic target for the treatment of OP.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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