CellPub Date : 2025-08-27DOI: 10.1016/j.cell.2025.08.002
Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L. Hickey, Zebulon G. Levine, J. Wade Harper, Alice Y. Ting, Jonathan S. Weissman
{"title":"Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation","authors":"Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L. Hickey, Zebulon G. Levine, J. Wade Harper, Alice Y. Ting, Jonathan S. Weissman","doi":"10.1016/j.cell.2025.08.002","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.002","url":null,"abstract":"Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"24 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906043","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.07.048
Lin Yuan, Navdeep S. Chandel, David Julius
{"title":"Mitochondrial activity tunes nociceptor resilience to excitotoxicity","authors":"Lin Yuan, Navdeep S. Chandel, David Julius","doi":"10.1016/j.cell.2025.07.048","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.048","url":null,"abstract":"The capsaicin receptor, TRPV1, mediates the detection of noxious chemical and thermal stimuli by nociceptors, primary sensory neurons of the pain pathway. Overactivation of TRPV1 leads to cellular damage or death through calcium entry and excitotoxicity. We have exploited this phenomenon to conduct a systematic analysis of excitotoxicity through a genome-wide CRISPRi screen, thereby revealing a comprehensive network of regulatory pathways. We show that decreased expression of mitochondrial electron transport chain (ETC) components protects against capsaicin-induced toxicity and other challenges by mitigating both calcium imbalance and the generation of mitochondrial reactive oxygen species via distinct pathways. Moreover, we confirm the regulatory roles of the ETC in sensory neurons through gain-of-function and loss-of-function experiments. Interestingly, TRPV1<sup>+</sup> sensory neurons maintain lower expression of ETC components and can better tolerate excitotoxicity and oxidative stress compared with other sensory neuron subtypes, implicating ETC tuning as an intrinsic cellular strategy that protects nociceptors against excitotoxicity.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"198 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900346","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.08.016
Yuqi Shi, Yuxing Li, Haipeng Li, Ayidana Haerheng, Vanessa R. Marcelino, Meng Lu, Philippe Lemey, Jia Tang, Yuhai Bi, John H.-O. Pettersson, Jon Bohlin, Joon Klaps, Zuowei Wu, Wenbo Wan, Bowen Sun, Mei Kang, Edward C. Holmes, Na He, Shuo Su
{"title":"Extensive cross-species transmission of pathogens and antibiotic resistance genes in mammals neglected by public health surveillance","authors":"Yuqi Shi, Yuxing Li, Haipeng Li, Ayidana Haerheng, Vanessa R. Marcelino, Meng Lu, Philippe Lemey, Jia Tang, Yuhai Bi, John H.-O. Pettersson, Jon Bohlin, Joon Klaps, Zuowei Wu, Wenbo Wan, Bowen Sun, Mei Kang, Edward C. Holmes, Na He, Shuo Su","doi":"10.1016/j.cell.2025.08.016","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.016","url":null,"abstract":"Non-traditional farmed and wild mammals are often neglected in pathogen surveillance. Through metagenomic and metatranscriptomic sequencing of fecal and tissue samples from 973 asymptomatic mammals, we identified 128 viruses (30 novel), including a new coronavirus genus, 10,255 bacterial species (over 7,000 undescribed), 201 fungi, and 7 parasites. Farmed and wild mammals shared 13.3% of virus species, including canine coronavirus in Asiatic black bears and Getah virus in rabbits, while the 2.3.4.4b clade of H5N1 avian influenza virus was found in a wild leopard cat. We identified potential bacterial pathogen transmission between farmed and wild mammals and bacterial strains with high genetic similarity to those found in humans. We observed 157 clinically prioritized antibiotic resistance genes (ARGs) in mammalian microbiomes with greater than 99% identity to ARGs from human microbiomes, often co-occurring with mobile genetic elements. Overall, this work highlights cross-species risks at the human-animal interface.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"18 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900353","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.07.040
Annalisa Meola, Riccardo Vernuccio, Leandro Battini, Guillermo Albericio, Pilar Delgado, Rebecca Bamford, Laura Pokorny, Manon Broutin, Alejandro Martínez León, Sébastien Gallien, María Gil, María A. Noriega, Florence Guivel-Benhassine, Françoise Porrot, Jeanne Postal, Julian Buchrieser, Mathieu Hubert, Ahmed Haouz, Pierre Lafaye, Mariano Esteban, Pablo Guardado-Calvo
{"title":"Structural basis of poxvirus fusion regulation and anti-A16/G9 antibody-mediated neutralization and protection","authors":"Annalisa Meola, Riccardo Vernuccio, Leandro Battini, Guillermo Albericio, Pilar Delgado, Rebecca Bamford, Laura Pokorny, Manon Broutin, Alejandro Martínez León, Sébastien Gallien, María Gil, María A. Noriega, Florence Guivel-Benhassine, Françoise Porrot, Jeanne Postal, Julian Buchrieser, Mathieu Hubert, Ahmed Haouz, Pierre Lafaye, Mariano Esteban, Pablo Guardado-Calvo","doi":"10.1016/j.cell.2025.07.040","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.040","url":null,"abstract":"Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Poxviruses enter host cells via a conserved entry-fusion complex (EFC), which mediates viral fusion to the cell membrane. The EFC is a promising therapeutic target, but the absence of structural data has limited the development of fusion-inhibiting treatments. Here, we investigated A16/G9, a subcomplex of the EFC that controls fusion timing. Using cryo-electron microscopy, we showed how A16/G9 interacts with A56/K2, a viral fusion suppressor that prevents superinfection. Immunization with A16/G9 elicited a protective immune response in mice. Using X-ray crystallography, we characterized two neutralizing antibodies and engineered a chimeric antibody that cross-neutralizes several poxviruses more efficiently than 7D11, the most potent antibody targeting the EFC described to date. These findings highlight the potential of A16/G9 as a candidate for subunit vaccines and identify regions of the EFC as targets for antiviral development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"18 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900347","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.07.045
Zachary T. McEachin, Mingee Chung, Sabrina A. Stratton, Changhee Han, Woo Jae Kim, Udit Sheth, Eleanor V. Thomas, Ethan Issenberg, Tanvi Kamra, Paola Merino, Yona Levites, Nisha Raj, Eric B. Dammer, Duc M. Duong, Lingyan Ping, Anantharaman Shantaraman, Adam N. Trautwig, Joshna Gadhavi, Ezana Assefa, Marla Gearing, Jonathan D. Glass
{"title":"Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS","authors":"Zachary T. McEachin, Mingee Chung, Sabrina A. Stratton, Changhee Han, Woo Jae Kim, Udit Sheth, Eleanor V. Thomas, Ethan Issenberg, Tanvi Kamra, Paola Merino, Yona Levites, Nisha Raj, Eric B. Dammer, Duc M. Duong, Lingyan Ping, Anantharaman Shantaraman, Adam N. Trautwig, Joshna Gadhavi, Ezana Assefa, Marla Gearing, Jonathan D. Glass","doi":"10.1016/j.cell.2025.07.045","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.045","url":null,"abstract":"<em>C9orf72</em>-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic G<sub>4</sub>C<sub>2</sub> repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system (CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSF from BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers, including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNS tissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures in c9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundance that correlated with BIIB078 concentration was observed. Thus, despite widespread distribution, BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASO therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900350","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}
{"title":"Structurally conserved human anti-A35 antibodies protect mice and macaques from mpox virus infection","authors":"Bin Ju, Congcong Liu, Jingjing Zhang, Yaning Li, Haonan Yang, Bing Zhou, Baoying Huang, Jianrong Ma, Jiahan Lu, Lin Cheng, Zhe Cong, Lin Zhu, Tianhao Shi, Yuehong Sun, Na Li, Ting Chen, Miao Wang, Shilong Tang, Xiangyang Ge, Juanjuan Zhao, Zheng Zhang","doi":"10.1016/j.cell.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.005","url":null,"abstract":"The A35 protein, expressed on the enveloped virion of monkeypox (mpox) virus (MPXV), is essential for viral infection and spread within the host, making it an effective antiviral target. In this study, we demonstrated two human anti-A35 monoclonal antibodies (mAbs) displayed potential protection against MPXV in CAST/EiJ mice and rhesus macaques. Using cryo-electron microscopy, we determined two high-resolution structures of the A35 dimer in complex with the fragment of antigen binding of mAb 975 or mAb 981, revealing detailed interactions at the antigen-antibody interfaces. Structural analysis showed that these structurally conserved mAbs bind to a groove region at the interface of A35 dimer. Overall, we provided a proof of concept for a single administration of anti-A35 mAbs mitigating the pathogenic effects of MPXV infection in rhesus macaques. These human-derived mAbs could be served as antibody drug candidates, and their binding models to the A35 dimer will provide valuable insights for future vaccine design.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"127 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900348","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.08.004
Raianna F. Fantin, Meng Yuan, Seok-Chan Park, Bailey Bozarth, Hallie Cohn, Maxinne Ignacio, Patricia Earl, Alesandro Civljak, Gabriel Laghlali, Ding Zhang, Xueyong Zhu, Jameson Crandell, Valter Monteiro, Jordan J. Clark, Catherine Cotter, Martin Burkhardt, Gagandeep Singh, Prajakta Warang, Juan García-Bernalt Diego, Komal Srivastava, Camila H. Coelho
{"title":"Human monoclonal antibodies targeting A35 protect from death caused by mpox","authors":"Raianna F. Fantin, Meng Yuan, Seok-Chan Park, Bailey Bozarth, Hallie Cohn, Maxinne Ignacio, Patricia Earl, Alesandro Civljak, Gabriel Laghlali, Ding Zhang, Xueyong Zhu, Jameson Crandell, Valter Monteiro, Jordan J. Clark, Catherine Cotter, Martin Burkhardt, Gagandeep Singh, Prajakta Warang, Juan García-Bernalt Diego, Komal Srivastava, Camila H. Coelho","doi":"10.1016/j.cell.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.004","url":null,"abstract":"The 2022 mpox outbreak highlighted the serious threat of monkeypox virus (MPXV), yet effective treatments are lacking. From an mpox-convalescent individual, we identified three high-affinity human monoclonal antibodies (mAbs) (named EV35-2, EV35-6, and EV35-7) that target the A35 protein in MPXV. These antibodies block viral spread <em>in vitro</em> and protect mice against lethal MPXV and vaccinia virus infection via both Fc-dependent and independent mechanisms. Levels of serum antibodies targeting the same epitopes are increased in mpox-convalescent humans, and higher levels of these antibodies in the sera are linked to shorter symptom duration and no hospitalization. Systems-level multivariate analysis indicated that mpox-convalescent serum antibodies targeting the same epitopic region as these three mAbs may function cooperatively, with additive associations to clinical protection. Two of the antibodies use a conserved IGHD2-21-encoded CxGGDCx motif in their CDRH3 region to bind a highly conserved poxvirus epitope. These findings establish A35 as a critical therapeutic target and highlight A35-specific mAbs as promising candidates for next-generation orthopoxvirus treatments.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900349","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.08.001
Raya Faigenbaum-Romm, Noam Yedidi, Orit Gefen, Naama Katsowich-Nagar, Lior Aroeti, Irine Ronin, Maskit Bar-Meir, Ilan Rosenshine, Nathalie Q. Balaban
{"title":"Uncovering phenotypic inheritance from single cells with Microcolony-seq","authors":"Raya Faigenbaum-Romm, Noam Yedidi, Orit Gefen, Naama Katsowich-Nagar, Lior Aroeti, Irine Ronin, Maskit Bar-Meir, Ilan Rosenshine, Nathalie Q. Balaban","doi":"10.1016/j.cell.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.001","url":null,"abstract":"Uncovering phenotypic heterogeneity is fundamental to understanding processes such as development and stress responses. Due to the low mRNA abundance in single bacteria, determining biologically relevant heterogeneity remains a challenge. Using Microcolony-seq, a methodology that captures inherited heterogeneity by analyzing microcolonies originating from single bacterial cells, we uncover the ubiquitous ability of bacteria to maintain long-term inheritance of the host environment. Notably, we observe that growth to stationary phase erases the epigenetic inheritance. By leveraging this memory within each microcolony, Microcolony-seq combines bulk RNA sequencing (RNA-seq) with whole-genome sequencing and phenotypic assays to detect the distinct subpopulations and their fitness advantages. Applying this directly to infected human samples enables us to uncover a wealth of diverse inherited phenotypes. Our observations suggest that bacterial memory may be a widespread phenomenon in both Gram-negative and Gram-positive bacteria. Microcolony-seq provides potential targets for the rational design of therapies with the power to simultaneously target the coexisting subpopulations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"22 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900351","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.07.042
Emily Grist, Peter Dutey-Magni, Marina A. Parry, Larissa Mendes, Ashwin Sachdeva, James A. Proudfoot, Anis A. Hamid, Mazlina Ismail, Sarah Howlett, Stefanie Friedrich, Lia DePaula Oliveira, Laura Murphy, Christopher Brawley, Oluwademilade Dairo, Sharanpreet Lall, Yang Liu, Daniel Wetterskog, Anna Wingate, Karolina Nowakowska, Leila Zakka, Gerhardt Attard
{"title":"Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers","authors":"Emily Grist, Peter Dutey-Magni, Marina A. Parry, Larissa Mendes, Ashwin Sachdeva, James A. Proudfoot, Anis A. Hamid, Mazlina Ismail, Sarah Howlett, Stefanie Friedrich, Lia DePaula Oliveira, Laura Murphy, Christopher Brawley, Oluwademilade Dairo, Sharanpreet Lall, Yang Liu, Daniel Wetterskog, Anna Wingate, Karolina Nowakowska, Leila Zakka, Gerhardt Attard","doi":"10.1016/j.cell.2025.07.042","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.042","url":null,"abstract":"Advanced prostate cancers respond to hormone therapy but outcomes vary and no predictive tests exist for informed treatment selection. To identify novel biomarker-treatment pairings, we examined associations between biological pathways and 14-year survival outcomes of patients randomized in practice-changing phase 3 trials (testing docetaxel or abiraterone). We included transcriptome-wide expression signatures and immunohistochemistry markers (Ki-67 and PTEN) on prostate tumors from 1,523 patients (832 metastatic). Tumor androgen receptor signaling is associated with longer survival, whereas increased proliferation predicted shorter survival. In a pre-specified analysis, the previously identified decipher RNA signature was both prognostic and predicted survival benefit from docetaxel for metastatic cancers (biomarker-docetaxel interaction <em>p</em> = 0.039). Additionally, transcriptome-based classification of PTEN inactivation identified tumors more likely to have PTEN protein loss (<em>p</em> = 4 × 10<sup>−37</sup>) and metabolically perturbed metastatic cancers that had shorter survival with hormone therapies (<em>p</em> < 0.001) but exhibited docetaxel sensitivity (biomarker-docetaxel interaction <em>p</em> = 0.002). Transcriptome classifiers predict docetaxel benefit and could be clinically implemented for improved patient management.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"32 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906472","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}
CellPub Date : 2025-08-25DOI: 10.1016/j.cell.2025.07.039
Kevin C. Allan, Jesse J. Zhan, Andrew R. Morton, Erin F. Cohn, Marissa A. Scavuzzo, Anushka Nikhil, Matthew S. Elitt, Benjamin L.L. Clayton, Lucille R. Hu, H. Elizabeth Shick, Jost K. Vrabic, Hannah E. Olsen, Daniel C. Factor, Jonathan E. Henninger, Gemma Bachmann, Berit E. Powers, Richard A. Young, Charles Y. Lin, Peter C. Scacheri, Tyler E. Miller, Paul J. Tesar
{"title":"Transient gene melting governs the timing of oligodendrocyte maturation","authors":"Kevin C. Allan, Jesse J. Zhan, Andrew R. Morton, Erin F. Cohn, Marissa A. Scavuzzo, Anushka Nikhil, Matthew S. Elitt, Benjamin L.L. Clayton, Lucille R. Hu, H. Elizabeth Shick, Jost K. Vrabic, Hannah E. Olsen, Daniel C. Factor, Jonathan E. Henninger, Gemma Bachmann, Berit E. Powers, Richard A. Young, Charles Y. Lin, Peter C. Scacheri, Tyler E. Miller, Paul J. Tesar","doi":"10.1016/j.cell.2025.07.039","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.039","url":null,"abstract":"Cellular maturation is a crucial step for tissue formation and function, distinct from the initial steps of differentiation and cell fate specification. In the central nervous system, failure of oligodendrocyte maturation is linked to diseases such as multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After progenitor cells differentiate into immature oligodendrocytes, the transcription factor SOX6 redistributes from super-enhancers to cluster across specific gene bodies. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turn off upon maturation. Suppression of SOX6 deactivates these immaturity loci, accelerating the transition to mature, myelinating oligodendrocytes. Notably, cells harboring this immature SOX6 gene signature are enriched in multiple sclerosis patient brains and antisense oligonucleotide-mediated <em>Sox6</em> knockdown drives oligodendrocyte maturation in mice. Our findings establish SOX6 as a key regulator of oligodendrocyte maturation and highlight its potential as a therapeutic target to promote myelination in disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900357","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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