Pub Date : 2025-11-24DOI: 10.1038/s41556-025-01806-7
Srivarsha Rajshekar, Omar Adame-Arana, Gaurav Bajpai, Serafin U. Colmenares, Hannah Papoi, Lucy D. Brennan, Shingo Tsukamoto, Samuel Safran, Gary H. Karpen
Nucleoli are surrounded by pericentromeric heterochromatin (PCH), reflecting a conserved spatial association between the two largest biomolecular condensates in eukaryotic nuclei. Nucleoli are the sites of ribosome synthesis, whereas the repeat-rich PCH is essential for chromosome segregation, genome stability and transcriptional silencing, yet the mechanisms for their co-assembly are unclear. Here we use high-resolution live imaging during Drosophila embryogenesis and reveal that de novo establishment of PCH–nucleolar associations is highly dynamic, as PCH transitions from extending along the nuclear edge to surrounding the nucleolus. Elimination of the nucleolus by removing the ribosomal RNA genes disrupted this process causing increased PCH compaction, followed by its reorganization into a toroidal structure. Furthermore, in embryos lacking ribosomal RNA genes, nucleolar proteins were redistributed into new bodies or ‘neocondensates’, including enrichment in the PCH toroidal hole. Combining these in vivo observations with molecular dynamics simulations based on multiphase wetting theory revealed that nucleolar–PCH associations can be mediated by a hierarchy of interaction strengths between PCH, nucleoli and proteins with dual affinities for both compartments. We validate this model by identifying such a protein, a DEAD-box RNA helicase called Pitchoune, and show that modulation of its affinity for either nucleolar or PCH components alters nucleolar–PCH organization. Together, this study unveils a dynamic programme for establishing nucleolar–PCH associations during animal development and demonstrates how interaction hierarchies and dual-affinity molecular linkers co-organize compositionally distinct condensates. Rajshekar et al. show that a hierarchy of affinities layers pericentromeric heterochromatin around nucleoli, with the RNA helicase Pitchoune (DDX18) acting as a key dual-affinity linker in Drosophila melanogaster.
{"title":"Hierarchical interactions between nucleolar and heterochromatin condensates are mediated by a dual-affinity protein","authors":"Srivarsha Rajshekar, Omar Adame-Arana, Gaurav Bajpai, Serafin U. Colmenares, Hannah Papoi, Lucy D. Brennan, Shingo Tsukamoto, Samuel Safran, Gary H. Karpen","doi":"10.1038/s41556-025-01806-7","DOIUrl":"10.1038/s41556-025-01806-7","url":null,"abstract":"Nucleoli are surrounded by pericentromeric heterochromatin (PCH), reflecting a conserved spatial association between the two largest biomolecular condensates in eukaryotic nuclei. Nucleoli are the sites of ribosome synthesis, whereas the repeat-rich PCH is essential for chromosome segregation, genome stability and transcriptional silencing, yet the mechanisms for their co-assembly are unclear. Here we use high-resolution live imaging during Drosophila embryogenesis and reveal that de novo establishment of PCH–nucleolar associations is highly dynamic, as PCH transitions from extending along the nuclear edge to surrounding the nucleolus. Elimination of the nucleolus by removing the ribosomal RNA genes disrupted this process causing increased PCH compaction, followed by its reorganization into a toroidal structure. Furthermore, in embryos lacking ribosomal RNA genes, nucleolar proteins were redistributed into new bodies or ‘neocondensates’, including enrichment in the PCH toroidal hole. Combining these in vivo observations with molecular dynamics simulations based on multiphase wetting theory revealed that nucleolar–PCH associations can be mediated by a hierarchy of interaction strengths between PCH, nucleoli and proteins with dual affinities for both compartments. We validate this model by identifying such a protein, a DEAD-box RNA helicase called Pitchoune, and show that modulation of its affinity for either nucleolar or PCH components alters nucleolar–PCH organization. Together, this study unveils a dynamic programme for establishing nucleolar–PCH associations during animal development and demonstrates how interaction hierarchies and dual-affinity molecular linkers co-organize compositionally distinct condensates. Rajshekar et al. show that a hierarchy of affinities layers pericentromeric heterochromatin around nucleoli, with the RNA helicase Pitchoune (DDX18) acting as a key dual-affinity linker in Drosophila melanogaster.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2102-2115"},"PeriodicalIF":19.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01806-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583021","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 : 2025-11-21DOI: 10.1038/s41556-025-01808-5
Guanghui Xu, Yuhan Chen, Laura M. Martins, En Li, Fuxi Wang, Tulio Magana, Junlin Ruan, Julie A. Law
DNA methylation is maintained by forming self-reinforcing connections with other repressive chromatin modifications, resulting in stably silenced genes and transposons. However, these mechanisms fail to explain how new methylation patterns are generated. In Arabidopsis, CLASSY3 targets the RNA-directed DNA methylation machinery to different loci in reproductive tissues, generating distinct epigenomes via unknown mechanism(s). Here we discovered that several different REPRODUCTIVE MERISTEM (REM) transcription factors are required for methylation at CLASSY3 targets specific to anther or ovule tissues. We designate these factors as REM INSTRUCTS METHYLATION (RIMs) and demonstrate that disruption of their DNA-binding domains, or the motifs they recognize, blocks RNA-directed DNA methylation. Furthermore, we demonstrate that mis-expression of RIM12 is sufficient to initiate siRNA production at ovule targets in anthers. These findings reveal a critical role for genetic information in targeting DNA methylation in reproductive tissues, expanding our understanding of how methylation is regulated to include inputs from both genetic and epigenetic information. Xu et al. identify REPRODUCTIVE MERISTEM transcription factors that are required for RNA-directed DNA methylation at CLASSY3 target loci in male and female reproductive tissues of Arabidopsis.
{"title":"Transcription factors instruct DNA methylation patterns in plant reproductive tissues","authors":"Guanghui Xu, Yuhan Chen, Laura M. Martins, En Li, Fuxi Wang, Tulio Magana, Junlin Ruan, Julie A. Law","doi":"10.1038/s41556-025-01808-5","DOIUrl":"10.1038/s41556-025-01808-5","url":null,"abstract":"DNA methylation is maintained by forming self-reinforcing connections with other repressive chromatin modifications, resulting in stably silenced genes and transposons. However, these mechanisms fail to explain how new methylation patterns are generated. In Arabidopsis, CLASSY3 targets the RNA-directed DNA methylation machinery to different loci in reproductive tissues, generating distinct epigenomes via unknown mechanism(s). Here we discovered that several different REPRODUCTIVE MERISTEM (REM) transcription factors are required for methylation at CLASSY3 targets specific to anther or ovule tissues. We designate these factors as REM INSTRUCTS METHYLATION (RIMs) and demonstrate that disruption of their DNA-binding domains, or the motifs they recognize, blocks RNA-directed DNA methylation. Furthermore, we demonstrate that mis-expression of RIM12 is sufficient to initiate siRNA production at ovule targets in anthers. These findings reveal a critical role for genetic information in targeting DNA methylation in reproductive tissues, expanding our understanding of how methylation is regulated to include inputs from both genetic and epigenetic information. Xu et al. identify REPRODUCTIVE MERISTEM transcription factors that are required for RNA-directed DNA methylation at CLASSY3 target loci in male and female reproductive tissues of Arabidopsis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2116-2127"},"PeriodicalIF":19.1,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01808-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559951","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 : 2025-11-18DOI: 10.1038/s41556-025-01814-7
Lucrezia della Volpe, Andrew J. Lee, Mateusz Antoszewski, Amy A. Deik, Ksenia R. Safina, Teng Gao, Chun-Jie Guo, Tianyi Ye, Peng Lyu, Jorge D. Martin-Rufino, Nicole Castano, Jonathan Good, Yaniris Molina-Aponte, Jiawei Zhao, Clary B. Clish, Peter van Galen, Vijay G. Sankaran
Improved ex vivo expansion of human haematopoietic stem cells (HSCs) would considerably advance transplantation and genome-engineered therapies, yet existing culture methods still allow substantial HSC loss. Here we show that this attrition is driven largely by ferroptosis, a metabolically regulated, iron-dependent cell-death pathway, and that it can be blocked to augment HSC expansion. Inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1 markedly increases the expansion of cord blood and adult HSCs consistently across donors in both widely used serum-free cultures and recently reported chemically defined conditions. The expanded cells retain phenotypic and molecular stem cell identity and mediate improved durable, multilineage engraftment in xenotransplanted mice without genotoxicity or aberrant haematopoiesis. Mechanistically, ferroptosis blockade is accompanied by upregulated ribosome biogenesis and cholesterol synthesis, increasing levels of 7-dehydrocholesterol—a potent endogenous ferroptosis inhibitor that itself promotes HSC expansion. Crucially, this approach enhances yields of therapeutically genome-modified HSCs, paving a path for clinical applications. della Volpe et al. augment the ex vivo expansion potential of human haematopoietic stem cells (HSCs) by inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1. Treated HSCs have enhanced in vivo repopulation capacity.
{"title":"Inhibiting ferroptosis enhances ex vivo expansion of human haematopoietic stem cells","authors":"Lucrezia della Volpe, Andrew J. Lee, Mateusz Antoszewski, Amy A. Deik, Ksenia R. Safina, Teng Gao, Chun-Jie Guo, Tianyi Ye, Peng Lyu, Jorge D. Martin-Rufino, Nicole Castano, Jonathan Good, Yaniris Molina-Aponte, Jiawei Zhao, Clary B. Clish, Peter van Galen, Vijay G. Sankaran","doi":"10.1038/s41556-025-01814-7","DOIUrl":"10.1038/s41556-025-01814-7","url":null,"abstract":"Improved ex vivo expansion of human haematopoietic stem cells (HSCs) would considerably advance transplantation and genome-engineered therapies, yet existing culture methods still allow substantial HSC loss. Here we show that this attrition is driven largely by ferroptosis, a metabolically regulated, iron-dependent cell-death pathway, and that it can be blocked to augment HSC expansion. Inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1 markedly increases the expansion of cord blood and adult HSCs consistently across donors in both widely used serum-free cultures and recently reported chemically defined conditions. The expanded cells retain phenotypic and molecular stem cell identity and mediate improved durable, multilineage engraftment in xenotransplanted mice without genotoxicity or aberrant haematopoiesis. Mechanistically, ferroptosis blockade is accompanied by upregulated ribosome biogenesis and cholesterol synthesis, increasing levels of 7-dehydrocholesterol—a potent endogenous ferroptosis inhibitor that itself promotes HSC expansion. Crucially, this approach enhances yields of therapeutically genome-modified HSCs, paving a path for clinical applications. della Volpe et al. augment the ex vivo expansion potential of human haematopoietic stem cells (HSCs) by inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1. Treated HSCs have enhanced in vivo repopulation capacity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2214-2224"},"PeriodicalIF":19.1,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01814-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536152","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 : 2025-11-17DOI: 10.1038/s41556-025-01810-x
August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer
Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.
{"title":"DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth","authors":"August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer","doi":"10.1038/s41556-025-01810-x","DOIUrl":"10.1038/s41556-025-01810-x","url":null,"abstract":"Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2143-2151"},"PeriodicalIF":19.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01810-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531628","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 : 2025-11-17DOI: 10.1038/s41556-025-01836-1
Dario F. De Jesus, Zijie Zhang, Natalie K. Brown, Xiaolu Li, Ling Xiao, Jiang Hu, Matthew J. Gaffrey, Garrett Fogarty, Sevim Kahraman, Jiangbo Wei, Giorgio Basile, Tariq M. Rana, Clayton Mathews, Alvin C. Powers, Audrey V. Parent, Mark A. Atkinson, Sirano Dhe-Paganon, Decio L. Eizirik, Wei-Jun Qian, Chuan He, Rohit N. Kulkarni
{"title":"Author Correction: Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes","authors":"Dario F. De Jesus, Zijie Zhang, Natalie K. Brown, Xiaolu Li, Ling Xiao, Jiang Hu, Matthew J. Gaffrey, Garrett Fogarty, Sevim Kahraman, Jiangbo Wei, Giorgio Basile, Tariq M. Rana, Clayton Mathews, Alvin C. Powers, Audrey V. Parent, Mark A. Atkinson, Sirano Dhe-Paganon, Decio L. Eizirik, Wei-Jun Qian, Chuan He, Rohit N. Kulkarni","doi":"10.1038/s41556-025-01836-1","DOIUrl":"10.1038/s41556-025-01836-1","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"208-208"},"PeriodicalIF":19.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01836-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536156","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 : 2025-11-11DOI: 10.1038/s41556-025-01800-z
Deborah Fass, Carolyn S. Sevier
Phase separation is a mechanism for non-organellar macromolecule segregation typical in the cell cytosol and nucleus. Two recent studies revealed functional phase separation within the endoplasmic reticulum, where calcium-mediated condensates co-ordinate chaperones and disulfide catalysts to enhance secretory protein production.
{"title":"Young secretory proteins go through a phase","authors":"Deborah Fass, Carolyn S. Sevier","doi":"10.1038/s41556-025-01800-z","DOIUrl":"10.1038/s41556-025-01800-z","url":null,"abstract":"Phase separation is a mechanism for non-organellar macromolecule segregation typical in the cell cytosol and nucleus. Two recent studies revealed functional phase separation within the endoplasmic reticulum, where calcium-mediated condensates co-ordinate chaperones and disulfide catalysts to enhance secretory protein production.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1887-1888"},"PeriodicalIF":19.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487115","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}
In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a ‘leaky’ H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment. Lu, Wang et al. profile H3K36me2 throughout oocyte-to-embryo transition, pre-implantation and early post-implantation development and report a role for H3K36me2 in post-implantation embryos to re-establish lineage-specific DNA methylation.
{"title":"Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation","authors":"Xukun Lu, Lijuan Wang, Bofeng Liu, Xiaoyu Hu, Zhengmao Wang, Ling Liu, Guang Yu, Lijun Dong, Feng Kong, Qiang Fan, Yu Zhang, Wei Xie","doi":"10.1038/s41556-025-01805-8","DOIUrl":"10.1038/s41556-025-01805-8","url":null,"abstract":"In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a ‘leaky’ H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment. Lu, Wang et al. profile H3K36me2 throughout oocyte-to-embryo transition, pre-implantation and early post-implantation development and report a role for H3K36me2 in post-implantation embryos to re-establish lineage-specific DNA methylation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2128-2142"},"PeriodicalIF":19.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484917","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}
The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca2+ storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca2+ triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin. Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of proinsulin.
{"title":"Ca2+-driven PDIA6 biomolecular condensation ensures proinsulin folding","authors":"Young-Ho Lee, Tomohide Saio, Mai Watabe, Motonori Matsusaki, Shingo Kanemura, Yuxi Lin, Taro Mannen, Tsubura Kuramochi, Yuka Kamada, Katsuya Iuchi, Michiko Tajiri, Kotono Suzuki, Yan Li, Yunseok Heo, Kotone Ishii, Kenta Arai, Kazunori Ban, Mayuko Hashimoto, Shuichiro Oshita, Satoshi Ninagawa, Yoshikazu Hattori, Hiroyuki Kumeta, Airu Takeuchi, Shinji Kajimoto, Hiroya Abe, Eiichiro Mori, Takahiro Muraoka, Takakazu Nakabayashi, Satoko Akashi, Tsukasa Okiyoneda, Michele Vendruscolo, Kenji Inaba, Masaki Okumura","doi":"10.1038/s41556-025-01794-8","DOIUrl":"10.1038/s41556-025-01794-8","url":null,"abstract":"The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca2+ storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca2+ triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin. Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of proinsulin.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1952-1964"},"PeriodicalIF":19.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01794-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484919","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 : 2025-11-10DOI: 10.1038/s41556-025-01825-4
Sangbum Park, David G. Gonzalez, Boris Guirao, Jonathan D. Boucher, Katie Cockburn, Edward D. Marsh, Kailin R. Mesa, Samara Brown, Panteleimon Rompolas, Ann M. Haberman, Yohanns Bellaïche, Valentina Greco
{"title":"Author Correction: Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice","authors":"Sangbum Park, David G. Gonzalez, Boris Guirao, Jonathan D. Boucher, Katie Cockburn, Edward D. Marsh, Kailin R. Mesa, Samara Brown, Panteleimon Rompolas, Ann M. Haberman, Yohanns Bellaïche, Valentina Greco","doi":"10.1038/s41556-025-01825-4","DOIUrl":"10.1038/s41556-025-01825-4","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"208-208"},"PeriodicalIF":19.1,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01825-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484920","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 : 2025-11-06DOI: 10.1038/s41556-025-01796-6
Daniel Besser, Sina Bartfeld, Stefanie Mahler
The German Stem Cell Network (GSCN) connects science, society and policy to advance stem cell research. Since 2013, it has promoted innovation, ethics and public engagement. Recognizing Europe’s need for stronger collaboration, the GSCN aims to build a pan-European network to enhance research and translation, and to support young scientists.
{"title":"Bridging science, society and policy with the German Stem Cell Network","authors":"Daniel Besser, Sina Bartfeld, Stefanie Mahler","doi":"10.1038/s41556-025-01796-6","DOIUrl":"10.1038/s41556-025-01796-6","url":null,"abstract":"The German Stem Cell Network (GSCN) connects science, society and policy to advance stem cell research. Since 2013, it has promoted innovation, ethics and public engagement. Recognizing Europe’s need for stronger collaboration, the GSCN aims to build a pan-European network to enhance research and translation, and to support young scientists.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1877-1880"},"PeriodicalIF":19.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447340","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}
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