Pub Date : 2024-09-16DOI: 10.1038/s42003-024-06778-2
Terumasa Tokunaga, Noriko Sato, Mary Arai, Takumi Nakamura, Takeshi Ishihara
Measuring neuronal activity is important for understanding neuronal function. Ca2+ imaging by genetically encoded calcium indicators (GECIs) is a powerful way to measure neuronal activity. Although it revealed important aspects of neuronal function, measuring the neuronal membrane voltage is important to understand neuronal function as it triggers neuronal activation. Recent progress of genetically encoded voltage indicators (GEVIs) enabled us fast and precise measurements of neuronal membrane voltage. To clarify the relation of the membrane voltage and intracellular Ca2+, we analyzed neuronal activities of olfactory neuron AWA in Caenorhabditis elegans by GCaMP6f (GECI) and paQuasAr3 (GEVI) responding to odorants. We found that the membrane voltage encodes the stimuli change by the timing and the duration by the weak semi-stable depolarization. However, the change of the intracellular Ca2+ encodes the strength of the stimuli. Furthermore, ODR-3, a G-protein alpha subunit, was shown to be important for stabilizing the membrane voltage. These results suggest that the combination of calcium and voltage imaging provides a deeper understanding of the information in neural circuits. Simultaneous imaging of intracellular Ca2+ and membrane voltage in olfactory neurons in C. elegans revealed that the membrane voltage encoded the presence of stimuli and the onset of an appropriate concentration of odor stimulus.
{"title":"Mechanism of sensory perception unveiled by simultaneous measurement of membrane voltage and intracellular calcium","authors":"Terumasa Tokunaga, Noriko Sato, Mary Arai, Takumi Nakamura, Takeshi Ishihara","doi":"10.1038/s42003-024-06778-2","DOIUrl":"10.1038/s42003-024-06778-2","url":null,"abstract":"Measuring neuronal activity is important for understanding neuronal function. Ca2+ imaging by genetically encoded calcium indicators (GECIs) is a powerful way to measure neuronal activity. Although it revealed important aspects of neuronal function, measuring the neuronal membrane voltage is important to understand neuronal function as it triggers neuronal activation. Recent progress of genetically encoded voltage indicators (GEVIs) enabled us fast and precise measurements of neuronal membrane voltage. To clarify the relation of the membrane voltage and intracellular Ca2+, we analyzed neuronal activities of olfactory neuron AWA in Caenorhabditis elegans by GCaMP6f (GECI) and paQuasAr3 (GEVI) responding to odorants. We found that the membrane voltage encodes the stimuli change by the timing and the duration by the weak semi-stable depolarization. However, the change of the intracellular Ca2+ encodes the strength of the stimuli. Furthermore, ODR-3, a G-protein alpha subunit, was shown to be important for stabilizing the membrane voltage. These results suggest that the combination of calcium and voltage imaging provides a deeper understanding of the information in neural circuits. Simultaneous imaging of intracellular Ca2+ and membrane voltage in olfactory neurons in C. elegans revealed that the membrane voltage encoded the presence of stimuli and the onset of an appropriate concentration of odor stimulus.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06778-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s42003-024-06837-8
Héctor Botella, Richard A. Fariña, Francisco Huera-Huarte
The colonization of the pelagic realm by the vertebrates represents one of the major transitions in the evolutionary success of the group and in the establishment of modern complex marine ecosystem. It has been traditionally related with the Devonian rise of jawed vertebrates, but new evidences indicate that first active swimmers, invading the water column, occurred within earlier armoured jawless fishes (“ostracoderms”). These “primitive” fishes lacked conventional fish control surfaces and the precise mechanism used to generate lift and stabilizing forces still remains unclear. We show that, because of their shape, the rigid cephalic shield of Pteraspidiformes, a group of Silurian-Devonian “ostracoderms”, generate significant forces for hydrodynamic lift. Particle Image Velocimetry and force measurements in a water channel shows that the flow over real-sized Pteraspidiformes models is similar to that over delta wings, dominated by the formation of leading-edge vortices resulting in enhanced vortex lift forces and delayed stall angles of attack. Additionally, experiments simulating ground effect show that Pteraspidiformes present better hydrodynamic performance under fully pelagic conditions than in a benthic scenario. This suggests that, lacking movable appendages other than the caudal fin, leading-edge vortices were exploited by earliest vertebrates to colonize the water column more than 400 Mya. Digital particle image velocimetry and force measurements in a water channel provide evidence that leading-edge vortices could be exploited by earliest vertebrates to colonize the water column more than 400 Mya.
{"title":"Delta wing design in earliest nektonic vertebrates","authors":"Héctor Botella, Richard A. Fariña, Francisco Huera-Huarte","doi":"10.1038/s42003-024-06837-8","DOIUrl":"10.1038/s42003-024-06837-8","url":null,"abstract":"The colonization of the pelagic realm by the vertebrates represents one of the major transitions in the evolutionary success of the group and in the establishment of modern complex marine ecosystem. It has been traditionally related with the Devonian rise of jawed vertebrates, but new evidences indicate that first active swimmers, invading the water column, occurred within earlier armoured jawless fishes (“ostracoderms”). These “primitive” fishes lacked conventional fish control surfaces and the precise mechanism used to generate lift and stabilizing forces still remains unclear. We show that, because of their shape, the rigid cephalic shield of Pteraspidiformes, a group of Silurian-Devonian “ostracoderms”, generate significant forces for hydrodynamic lift. Particle Image Velocimetry and force measurements in a water channel shows that the flow over real-sized Pteraspidiformes models is similar to that over delta wings, dominated by the formation of leading-edge vortices resulting in enhanced vortex lift forces and delayed stall angles of attack. Additionally, experiments simulating ground effect show that Pteraspidiformes present better hydrodynamic performance under fully pelagic conditions than in a benthic scenario. This suggests that, lacking movable appendages other than the caudal fin, leading-edge vortices were exploited by earliest vertebrates to colonize the water column more than 400 Mya. Digital particle image velocimetry and force measurements in a water channel provide evidence that leading-edge vortices could be exploited by earliest vertebrates to colonize the water column more than 400 Mya.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06837-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s42003-024-06853-8
Hesheng Xiao, Leihui Wang, Shuo Yan, He Ma, Zhen Xu, Feilong Wang, Jingrong Wang, Wenjing Tao, Deshou Wang
Fish sex is largely influenced by steroid hormones, especially sex hormones. Here, we established a steroid hormone-free genetic model by mutation of cyp11a1 in Nile tilapia, which was confirmed by EIA assay. Gonadal phenotype and transcriptome analyses showed that the XX mutants displayed sex reversal from female to male but with defective spermatogenesis. Despite the sex reversal, the aromatase encoding gene cyp19a1a was continuously expressed in the gonads of the XX mutants, which might be caused by androgen deficiency. Whole-mount fluorescence in situ hybridization and transcriptome analysis showed that the gonads of the XX mutants firstly developed towards ovary but shifted to testis between 10 to 15 days after hatching. Detailed expression analysis of key sex differentiation pathway genes foxl3 and dmrt1 combined with apoptosis analysis revealed transdifferentiation of germ cells from female to male during sex reversal. Rescue experiments showed that both P5 and E2 treatment rescued the sex reversal of cyp11a1 mutant XX fish. Overall, our results revealed a transient ovary-like stage and transdifferentiation of germ cells from female to male in the early gonads of the steroid hormone-deprived cyp11a1 mutant XX fish. Revealing of a transient ovary-like stage and transdifferentiation of germ cells from female to male in the early gonads of the XX fish after steroid hormone-deprivation.
{"title":"Steroid hormone-deprived sex reversal in cyp11a1 mutant XX tilapia experiences an ovary-like stage at molecular level","authors":"Hesheng Xiao, Leihui Wang, Shuo Yan, He Ma, Zhen Xu, Feilong Wang, Jingrong Wang, Wenjing Tao, Deshou Wang","doi":"10.1038/s42003-024-06853-8","DOIUrl":"10.1038/s42003-024-06853-8","url":null,"abstract":"Fish sex is largely influenced by steroid hormones, especially sex hormones. Here, we established a steroid hormone-free genetic model by mutation of cyp11a1 in Nile tilapia, which was confirmed by EIA assay. Gonadal phenotype and transcriptome analyses showed that the XX mutants displayed sex reversal from female to male but with defective spermatogenesis. Despite the sex reversal, the aromatase encoding gene cyp19a1a was continuously expressed in the gonads of the XX mutants, which might be caused by androgen deficiency. Whole-mount fluorescence in situ hybridization and transcriptome analysis showed that the gonads of the XX mutants firstly developed towards ovary but shifted to testis between 10 to 15 days after hatching. Detailed expression analysis of key sex differentiation pathway genes foxl3 and dmrt1 combined with apoptosis analysis revealed transdifferentiation of germ cells from female to male during sex reversal. Rescue experiments showed that both P5 and E2 treatment rescued the sex reversal of cyp11a1 mutant XX fish. Overall, our results revealed a transient ovary-like stage and transdifferentiation of germ cells from female to male in the early gonads of the steroid hormone-deprived cyp11a1 mutant XX fish. Revealing of a transient ovary-like stage and transdifferentiation of germ cells from female to male in the early gonads of the XX fish after steroid hormone-deprivation.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06853-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s42003-024-06870-7
Marc A. Mapalo, Joanna M. Wolfe, Javier Ortega-Hernández
{"title":"Author Correction: Cretaceous amber inclusions illuminate the evolutionary origin of tardigrades","authors":"Marc A. Mapalo, Joanna M. Wolfe, Javier Ortega-Hernández","doi":"10.1038/s42003-024-06870-7","DOIUrl":"10.1038/s42003-024-06870-7","url":null,"abstract":"","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06870-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s42003-024-06866-3
Xuan Fang, Changyu Liu, Kang Wei, Zixing Shu, Yi Zou, Zihao Zhang, Qing Ding, Shaoze Jing, Weigang Li, Tianqi Wang, Hao Li, Hua Wu, Chaoxu Liu, Tian Ma
Electromagnetic fields (EMFs) have emerged as an effective treatment for osteoporosis. However, the specific mechanism underlying their therapeutic efficacy remains controversial. Herein, we confirm the pro-osteogenic effects of 15 Hz and 0.4-1 mT low-frequency sinusoidal EMFs (SEMFs) on rat bone marrow mesenchymal stem cells (BMSCs). Subsequent miRNA sequencing reveal that miR-34b-5p is downregulated in both the 0.4 mT and 1 mT SEMFs-stimulated groups. To clarify the role of miR-34b-5p in osteogenesis, BMSCs are transfected separately with miR-34b-5p mimic and inhibitor. The results indicate that miR-34b-5p mimic transfection suppress osteogenic differentiation, whereas inhibition of miR-34b-5p promote osteogenic differentiation of BMSCs. In vivo assessments using microcomputed tomography, H&E staining, and Masson staining show that miR-34b-5p inhibitor injections alleviate bone mass loss and trabecular microstructure deterioration in ovariectomy (OVX) rats. Further validation demonstrates that miR-34b-5p exerts its effects by regulating STAC2 expression. Modulating the miR-34b-5p/STAC2 axis attenuate the pro-osteogenic effects of low-frequency SEMFs on BMSCs. These studies indicate that the pro-osteogenic effect of SEMFs is partly due to the regulation of the miR-34b-5p/STAC2 pathway, which provides a potential therapeutic candidate for osteoporosis. Low-frequency sinusoidal electromagnetic fields enhance osteogenesis in mice by regulating the miR34b-5p/STAC2 axis, providing insights into potential osteoporosis treatments.
{"title":"Low frequency sinusoidal electromagnetic fields promote the osteogenic differentiation of rat bone marrow mesenchymal stem cells by modulating miR-34b-5p/STAC2","authors":"Xuan Fang, Changyu Liu, Kang Wei, Zixing Shu, Yi Zou, Zihao Zhang, Qing Ding, Shaoze Jing, Weigang Li, Tianqi Wang, Hao Li, Hua Wu, Chaoxu Liu, Tian Ma","doi":"10.1038/s42003-024-06866-3","DOIUrl":"10.1038/s42003-024-06866-3","url":null,"abstract":"Electromagnetic fields (EMFs) have emerged as an effective treatment for osteoporosis. However, the specific mechanism underlying their therapeutic efficacy remains controversial. Herein, we confirm the pro-osteogenic effects of 15 Hz and 0.4-1 mT low-frequency sinusoidal EMFs (SEMFs) on rat bone marrow mesenchymal stem cells (BMSCs). Subsequent miRNA sequencing reveal that miR-34b-5p is downregulated in both the 0.4 mT and 1 mT SEMFs-stimulated groups. To clarify the role of miR-34b-5p in osteogenesis, BMSCs are transfected separately with miR-34b-5p mimic and inhibitor. The results indicate that miR-34b-5p mimic transfection suppress osteogenic differentiation, whereas inhibition of miR-34b-5p promote osteogenic differentiation of BMSCs. In vivo assessments using microcomputed tomography, H&E staining, and Masson staining show that miR-34b-5p inhibitor injections alleviate bone mass loss and trabecular microstructure deterioration in ovariectomy (OVX) rats. Further validation demonstrates that miR-34b-5p exerts its effects by regulating STAC2 expression. Modulating the miR-34b-5p/STAC2 axis attenuate the pro-osteogenic effects of low-frequency SEMFs on BMSCs. These studies indicate that the pro-osteogenic effect of SEMFs is partly due to the regulation of the miR-34b-5p/STAC2 pathway, which provides a potential therapeutic candidate for osteoporosis. Low-frequency sinusoidal electromagnetic fields enhance osteogenesis in mice by regulating the miR34b-5p/STAC2 axis, providing insights into potential osteoporosis treatments.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06866-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1038/s42003-024-06865-4
William Connell, Kristle Garcia, Hani Goodarzi, Michael J. Keiser
Chemical probes interrogate disease mechanisms at the molecular level by linking genetic changes to observable traits. However, comprehensive chemical screens in diverse biological models are impractical. To address this challenge, we develop ChemProbe, a model that predicts cellular sensitivity to hundreds of molecular probes and drugs by learning to combine transcriptomes and chemical structures. Using ChemProbe, we infer the chemical sensitivity of cancer cell lines and tumor samples and analyze how the model makes predictions. We retrospectively evaluate drug response predictions for precision breast cancer treatment and prospectively validate chemical sensitivity predictions in new cellular models, including a genetically modified cell line. Our model interpretation analysis identifies transcriptome features reflecting compound targets and protein network modules, identifying genes that drive ferroptosis. ChemProbe is an interpretable in silico screening tool that allows researchers to measure cellular response to diverse compounds, facilitating research into molecular mechanisms of chemical sensitivity. Predictive modeling of chemical sensitivity relates transcriptomic features and compound structures to cellular responses, revealing mechanisms of drug action and facilitating precision treatment strategies in cancer.
{"title":"Learning chemical sensitivity reveals mechanisms of cellular response","authors":"William Connell, Kristle Garcia, Hani Goodarzi, Michael J. Keiser","doi":"10.1038/s42003-024-06865-4","DOIUrl":"10.1038/s42003-024-06865-4","url":null,"abstract":"Chemical probes interrogate disease mechanisms at the molecular level by linking genetic changes to observable traits. However, comprehensive chemical screens in diverse biological models are impractical. To address this challenge, we develop ChemProbe, a model that predicts cellular sensitivity to hundreds of molecular probes and drugs by learning to combine transcriptomes and chemical structures. Using ChemProbe, we infer the chemical sensitivity of cancer cell lines and tumor samples and analyze how the model makes predictions. We retrospectively evaluate drug response predictions for precision breast cancer treatment and prospectively validate chemical sensitivity predictions in new cellular models, including a genetically modified cell line. Our model interpretation analysis identifies transcriptome features reflecting compound targets and protein network modules, identifying genes that drive ferroptosis. ChemProbe is an interpretable in silico screening tool that allows researchers to measure cellular response to diverse compounds, facilitating research into molecular mechanisms of chemical sensitivity. Predictive modeling of chemical sensitivity relates transcriptomic features and compound structures to cellular responses, revealing mechanisms of drug action and facilitating precision treatment strategies in cancer.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06865-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1038/s42003-024-06800-7
Maddelyn Harden, Maxim Kovalev, Gary Molano, Christie Yorke, Robert Miller, Daniel Reed, Filipe Alberto, David S. Koos, Rusty Lansford, Sergey Nuzhdin
Kelps are vital for marine ecosystems, yet the genetic diversity underlying their capacity to adapt to climate change remains unknown. In this study, we focused on the kelp Macrocystis pyrifera a species critical to coastal habitats. We developed a protocol to evaluate heat stress response in 204 Macrocystis pyrifera genotypes subjected to heat stress treatments ranging from 21 °C to 27 °C. Here we show that haploid gametophytes exhibiting a heat-stress tolerant (HST) phenotype also produced greater biomass as genetically similar diploid sporophytes in a warm-water ocean farm. HST was measured as chlorophyll autofluorescence per genotype, presented here as fluorescent intensity values. This correlation suggests a predictive relationship between the growth performance of the early microscopic gametophyte stage HST and the later macroscopic sporophyte stage, indicating the potential for selecting resilient kelp strains under warmer ocean temperatures. However, HST kelps showed reduced genetic variation, underscoring the importance of integrating heat tolerance genes into a broader genetic pool to maintain the adaptability of kelp populations in the face of climate change. 204 Macrocystis pyrifera genotypes were screened and a panel of heat-stress tolerant (HST) gametophytes were identified. A subsequent analysis revealed a correlation between the HST strains and increased sporophyte biomass under warmer ocean conditions.
{"title":"Heat stress analysis suggests a genetic basis for tolerance in Macrocystis pyrifera across developmental stages","authors":"Maddelyn Harden, Maxim Kovalev, Gary Molano, Christie Yorke, Robert Miller, Daniel Reed, Filipe Alberto, David S. Koos, Rusty Lansford, Sergey Nuzhdin","doi":"10.1038/s42003-024-06800-7","DOIUrl":"10.1038/s42003-024-06800-7","url":null,"abstract":"Kelps are vital for marine ecosystems, yet the genetic diversity underlying their capacity to adapt to climate change remains unknown. In this study, we focused on the kelp Macrocystis pyrifera a species critical to coastal habitats. We developed a protocol to evaluate heat stress response in 204 Macrocystis pyrifera genotypes subjected to heat stress treatments ranging from 21 °C to 27 °C. Here we show that haploid gametophytes exhibiting a heat-stress tolerant (HST) phenotype also produced greater biomass as genetically similar diploid sporophytes in a warm-water ocean farm. HST was measured as chlorophyll autofluorescence per genotype, presented here as fluorescent intensity values. This correlation suggests a predictive relationship between the growth performance of the early microscopic gametophyte stage HST and the later macroscopic sporophyte stage, indicating the potential for selecting resilient kelp strains under warmer ocean temperatures. However, HST kelps showed reduced genetic variation, underscoring the importance of integrating heat tolerance genes into a broader genetic pool to maintain the adaptability of kelp populations in the face of climate change. 204 Macrocystis pyrifera genotypes were screened and a panel of heat-stress tolerant (HST) gametophytes were identified. A subsequent analysis revealed a correlation between the HST strains and increased sporophyte biomass under warmer ocean conditions.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06800-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1038/s42003-024-06811-4
Maria V. Sukhanova, Rashid O. Anarbaev, Ekaterina A. Maltseva, Mikhail M. Kutuzov, Olga I. Lavrik
The formation of nuclear biomolecular condensates is often associated with local accumulation of proteins at a site of DNA damage. The key role in the formation of DNA repair foci belongs to PARP1, which is a sensor of DNA damage and catalyzes the synthesis of poly(ADP-ribose) attracting repair factors. We show here that biogenic cations such as Mg2+, Ca2+, Mn2+, spermidine3+, or spermine4+ can induce liquid-like assembly of poly(ADP-ribosyl)ated [PARylated] PARP1 into multimolecular associates (hereafter: self-assembly). The self-assembly of PARylated PARP1 affects the level of its automodification and hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG). Furthermore, association of PARylated PARP1 with repair proteins strongly stimulates strand displacement DNA synthesis by DNA polymerase β (Pol β) but has no noticeable effect on DNA ligase III activity. Thus, liquid-like self-assembly of PARylated PARP1 may play a critical part in the regulation of i) its own activity, ii) PARG-dependent hydrolysis of poly(ADP-ribose), and iii) Pol β–mediated DNA synthesis. The latter can be considered an additional factor influencing the choice between long-patch and short-patch DNA synthesis during repair. Formation of biomolecular condensate via liquid-like assembly of PARylated PARP1 is driven by biogenic cations. This assembly regulates autoPARylation of PARP1, PARG-dependent hydrolysis of poly(ADP-ribose) and Polβ-mediated DNA synthesis.
核生物分子凝聚体的形成往往与 DNA 损伤部位蛋白质的局部聚集有关。在 DNA 修复灶形成过程中起关键作用的是 PARP1，它是 DNA 损伤的传感器，能催化聚（ADP-核糖）吸引修复因子的合成。我们在此表明，Mg2+、Ca2+、Mn2+、精胺3+或精胺4+等生物阳离子可诱导聚（ADP-核糖基）[PARylated] PARP1液态组装成多分子联合体（以下简称：自组装）。PARylated PARP1 的自组装会影响其自动调节和聚(ADP-核糖)糖水解酶（PARG）水解聚(ADP-核糖)的水平。此外，PARylated PARP1 与修复蛋白的结合会强烈刺激 DNA 聚合酶 β（Pol β）的链置换 DNA 合成，但对 DNA 连接酶 III 的活性没有明显影响。因此，PARylated PARP1 的液态自组装可能在以下调节过程中起着关键作用：i）自身活性；ii）PARG 依赖性水解聚（ADP-核糖）；iii）Pol β 介导的 DNA 合成。后者可被视为影响修复过程中长补丁和短补丁 DNA 合成之间选择的另一个因素。在生物阳离子的驱动下，PAR 化的 PARP1 通过液态组装形成生物分子凝聚物。这种组装调节 PARP1 的自身 PARylation 、PARG 依赖性的聚（ADP-核糖）水解和 Polβ 介导的 DNA 合成。
{"title":"Divalent and multivalent cations control liquid-like assembly of poly(ADP-ribosyl)ated PARP1 into multimolecular associates in vitro","authors":"Maria V. Sukhanova, Rashid O. Anarbaev, Ekaterina A. Maltseva, Mikhail M. Kutuzov, Olga I. Lavrik","doi":"10.1038/s42003-024-06811-4","DOIUrl":"10.1038/s42003-024-06811-4","url":null,"abstract":"The formation of nuclear biomolecular condensates is often associated with local accumulation of proteins at a site of DNA damage. The key role in the formation of DNA repair foci belongs to PARP1, which is a sensor of DNA damage and catalyzes the synthesis of poly(ADP-ribose) attracting repair factors. We show here that biogenic cations such as Mg2+, Ca2+, Mn2+, spermidine3+, or spermine4+ can induce liquid-like assembly of poly(ADP-ribosyl)ated [PARylated] PARP1 into multimolecular associates (hereafter: self-assembly). The self-assembly of PARylated PARP1 affects the level of its automodification and hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG). Furthermore, association of PARylated PARP1 with repair proteins strongly stimulates strand displacement DNA synthesis by DNA polymerase β (Pol β) but has no noticeable effect on DNA ligase III activity. Thus, liquid-like self-assembly of PARylated PARP1 may play a critical part in the regulation of i) its own activity, ii) PARG-dependent hydrolysis of poly(ADP-ribose), and iii) Pol β–mediated DNA synthesis. The latter can be considered an additional factor influencing the choice between long-patch and short-patch DNA synthesis during repair. Formation of biomolecular condensate via liquid-like assembly of PARylated PARP1 is driven by biogenic cations. This assembly regulates autoPARylation of PARP1, PARG-dependent hydrolysis of poly(ADP-ribose) and Polβ-mediated DNA synthesis.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06811-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-14DOI: 10.1038/s42003-024-06780-8
Jonas Karolis Degutis, Denis Chaimow, Daniel Haenelt, Moataz Assem, John Duncan, John-Dylan Haynes, Nikolaus Weiskopf, Romy Lorenz
The dorsolateral prefrontal cortex (dlPFC) is reliably engaged in working memory (WM) and comprises different cytoarchitectonic layers, yet their functional role in human WM is unclear. Here, participants completed a delayed-match-to-sample task while undergoing functional magnetic resonance imaging (fMRI) at ultra-high resolution. We examine layer-specific activity to manipulations in WM load and motor response. Superficial layers exhibit a preferential response to WM load during the delay and retrieval periods of a WM task, indicating a lamina-specific activation of the frontoparietal network. Multivariate patterns encoding WM load in the superficial layer dynamically change across the three periods of the task. Last, superficial and deep layers are non-differentially involved in the motor response, challenging earlier findings of a preferential deep layer activation. Taken together, our results provide new insights into the functional laminar circuitry of the dlPFC during WM and support a dynamic account of dlPFC coding. Layer-specific imaging of the human dorsolateral prefrontal cortex reveals distinct laminar responses to working memory load and dynamic coding of working memory trial phases.
{"title":"Dynamic layer-specific processing in the prefrontal cortex during working memory","authors":"Jonas Karolis Degutis, Denis Chaimow, Daniel Haenelt, Moataz Assem, John Duncan, John-Dylan Haynes, Nikolaus Weiskopf, Romy Lorenz","doi":"10.1038/s42003-024-06780-8","DOIUrl":"10.1038/s42003-024-06780-8","url":null,"abstract":"The dorsolateral prefrontal cortex (dlPFC) is reliably engaged in working memory (WM) and comprises different cytoarchitectonic layers, yet their functional role in human WM is unclear. Here, participants completed a delayed-match-to-sample task while undergoing functional magnetic resonance imaging (fMRI) at ultra-high resolution. We examine layer-specific activity to manipulations in WM load and motor response. Superficial layers exhibit a preferential response to WM load during the delay and retrieval periods of a WM task, indicating a lamina-specific activation of the frontoparietal network. Multivariate patterns encoding WM load in the superficial layer dynamically change across the three periods of the task. Last, superficial and deep layers are non-differentially involved in the motor response, challenging earlier findings of a preferential deep layer activation. Taken together, our results provide new insights into the functional laminar circuitry of the dlPFC during WM and support a dynamic account of dlPFC coding. Layer-specific imaging of the human dorsolateral prefrontal cortex reveals distinct laminar responses to working memory load and dynamic coding of working memory trial phases.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06780-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The nucleosome including H2A.B, a mammalian-specific H2A variant, plays pivotal roles in spermatogenesis, embryogenesis, and oncogenesis, indicating unique involvement in transcriptional regulation distinct from canonical H2A nucleosomes. Despite its significance, the exact regulatory mechanism remains elusive. This study utilized solid-state nanopores to investigate DNA unwinding dynamics, applying local force between DNA and histones. Comparative analysis of canonical H2A and H2A.B nucleosomes demonstrated that the H2A.B variant required a lower voltage for complete DNA unwinding. Furthermore, synchronization analysis and molecular dynamics simulations indicate that the H2A.B variant rapidly unwinds DNA, causing the H2A-H2B dimer to dissociate from DNA immediately upon disassembly of the histone octamer. In contrast, canonical H2A nucleosomes unwind DNA at a slower rate, suggesting that the H2A-H2B dimer undergoes a state of stacking at the pore. These findings suggest that nucleosomal DNA in the H2A.B nucleosomes undergoes a DNA unwinding process involving histone octamer disassembly distinct from that of canonical H2A nucleosomes, enabling smoother unwinding. The integrated approach of MD simulations and nanopore measurements is expected to evolve into a versatile tool for studying molecular interactions, not only within nucleosomes but also through the forced dissociation of DNA-protein complexes. Research combining molecular dynamics simulations and solid-state nanopore measurements reveals distinct disassembly pathways that may explain the distinct properties and roles of H2A.B nucleosomes in spermatogenesis, embryogenesis, and oncogenesis.
包括哺乳动物特异性 H2A 变体 H2A.B 在内的核小体在精子发生、胚胎发育和肿瘤发生中发挥着关键作用，表明它在转录调控中的独特参与有别于典型的 H2A 核小体。尽管其意义重大，但确切的调控机制仍然难以捉摸。本研究利用固态纳米孔研究 DNA 的解旋动力学，在 DNA 和组蛋白之间施加局部作用力。对典型 H2A 和 H2A.B 核糖体的比较分析表明，H2A.B 变体需要较低的电压才能完全解开 DNA。此外，同步分析和分子动力学模拟表明，H2A.B 变体能迅速解开 DNA，使 H2A-H2B 二聚体在组蛋白八聚体解体后立即与 DNA 分离。与此相反，典型的 H2A 核小体解开 DNA 的速度较慢，这表明 H2A-H2B 二聚体在孔中处于堆积状态。这些研究结果表明，H2A.B核小体中的核糖体DNA经历了与典型H2A核小体不同的DNA解旋过程，其中涉及组蛋白八聚体的解体，从而使解旋过程更加顺畅。分子动力学模拟和纳米孔测量的综合方法有望发展成为研究分子相互作用的多功能工具，不仅可以研究核小体内部的相互作用，还可以通过强制解离 DNA 蛋白复合物进行研究。将分子动力学模拟和固态纳米孔测量相结合的研究揭示了不同的解体途径，这些途径可以解释 H2A.B 核小体在精子发生、胚胎发育和肿瘤发生过程中的不同特性和作用。
{"title":"Nucleosomal DNA unwinding pathway through canonical and non-canonical histone disassembly","authors":"Hikaru Nozawa, Fritz Nagae, Satoshi Ogihara, Rina Hirano, Hirohito Yamazaki, Ryo Iizuka, Munetaka Akatsu, Tomoya Kujirai, Shoji Takada, Hitoshi Kurumizaka, Sotaro Uemura","doi":"10.1038/s42003-024-06856-5","DOIUrl":"10.1038/s42003-024-06856-5","url":null,"abstract":"The nucleosome including H2A.B, a mammalian-specific H2A variant, plays pivotal roles in spermatogenesis, embryogenesis, and oncogenesis, indicating unique involvement in transcriptional regulation distinct from canonical H2A nucleosomes. Despite its significance, the exact regulatory mechanism remains elusive. This study utilized solid-state nanopores to investigate DNA unwinding dynamics, applying local force between DNA and histones. Comparative analysis of canonical H2A and H2A.B nucleosomes demonstrated that the H2A.B variant required a lower voltage for complete DNA unwinding. Furthermore, synchronization analysis and molecular dynamics simulations indicate that the H2A.B variant rapidly unwinds DNA, causing the H2A-H2B dimer to dissociate from DNA immediately upon disassembly of the histone octamer. In contrast, canonical H2A nucleosomes unwind DNA at a slower rate, suggesting that the H2A-H2B dimer undergoes a state of stacking at the pore. These findings suggest that nucleosomal DNA in the H2A.B nucleosomes undergoes a DNA unwinding process involving histone octamer disassembly distinct from that of canonical H2A nucleosomes, enabling smoother unwinding. The integrated approach of MD simulations and nanopore measurements is expected to evolve into a versatile tool for studying molecular interactions, not only within nucleosomes but also through the forced dissociation of DNA-protein complexes. Research combining molecular dynamics simulations and solid-state nanopore measurements reveals distinct disassembly pathways that may explain the distinct properties and roles of H2A.B nucleosomes in spermatogenesis, embryogenesis, and oncogenesis.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06856-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：