Cell reports最新文献

{"title":"The histone core domain evolves at single-residue resolution to directly orchestrate transcription.","authors":"Zachary H Harvey, Kathryn M Stevens, Jian Yi Kok, Akihisa Osakabe, Jiaying Liu, Tobias Warnecke, Frédéric Berger","doi":"10.1016/j.celrep.2025.116079","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116079","url":null,"abstract":"<p><p>Nucleosomes are thought to be structural barriers to transcription, establishing a restrictive ground state that must be destabilized for gene expression. However, structural insights have revealed that transcription can proceed in the presence of nucleosomes, suggesting that this model is incomplete. Here, we reconstituted H2A.Z sequences resulting from more than a billion years of eukaryotic evolution in a single synthetic host system, interrogating their impact on transcription. We identified single-residue substitutions within the ultra-conserved core domain loop 2 (L2) of H2A.Z as sufficient to confer emergent properties and drive neofunctionalization. Such L2 neomorphs acquired a direct interaction with transcription elongation factor Spt6, rewiring gene expression by tuning polymerase processivity. We conclude that even minimal changes in histone sequences can transform their function, underscoring the evolutionary potential of the histone core domain to drive regulatory innovation and highlighting a previously unappreciated role of the histone core domain in transcriptional regulation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116079"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752533","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":"Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals.","authors":"Jingyi Li, Jiansen Lu, Jiayu Chen, Qianzheng Fu, Zhenhuan Jiang, Shaorong Gao, Fuchou Tang","doi":"10.1016/j.celrep.2025.116082","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116082","url":null,"abstract":"<p><p>Meiotic recombination initiates via DNA double-strand breaks (DSBs) at specialized hotspots, while the regulation of meiotic recombination hotspots in females remain elusive due to the scarcity of embryonic stage germ cells (EGCs). Here, we mapped genome-wide active recombination hotspots and estimated their activities in female EGCs at single-cell resolution, revealing the high variability in hotspot usage frequency among individual germ cells. Further investigation of nucleosome positioning and histone modifications at recombination hotspots revealed that PRDM9-mediated open chromatin and flanking H3K4me3 established earlier at high-frequency hotspots compared with less frequently used ones. Unexpectedly, although recombination hotspots usually distributed outside of heterochromatin, H3K9me3 was clearly enriched around hotspots in females, forming a unique H3K4me3/H3K9me3 bivalent state. And we showed that an appropriate H3K9me3 level may be required for downstream DSB repairs. Together, our results provided understanding about the landscape and epigenomic regulation of recombination hotspots in females.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116082"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752532","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":"Integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D-associated genes and regulatory signals.","authors":"Ricardo D'Oliveira Albanus, Xiaoshan Zhang, Zeping Zhao, Henry J Taylor, Xuming Tang, Yuling Han, Peter Orchard, Arushi Varshney, Tuo Zhang, Nandini Manickam, Michael R Erdos, Narisu Narisu, Leland Taylor, Xiaxia Saavedra, Xinyi Liu, Aaron Zhong, Bo Li, Ting Zhou, Ali Naji, Chengyang Liu, Francis S Collins, Stephen C J Parker, Shuibing Chen","doi":"10.1016/j.celrep.2025.116065","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116065","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have identified over 100 signals associated with type 1 diabetes (T1D). However, it has been challenging to translate any given T1D GWAS signal into mechanistic insights, such as causal variants, their target genes, and the specific cell types involved. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in human pancreatic islets under baseline and T1D-stimulating conditions. We nominate effector cell types for all T1D GWAS signals and the regulatory elements and genes for three independent T1D signals acting through β cells at the DLK1/MEG3, RASGRP1, and TOX loci. Subsequently, we validated the functional impact of these genes and regulatory regions using isogenic human embryonic stem cells (hESCs). We found that loss of RASGRP1 or DLK1, as well as disruption of their corresponding regulatory regions, led to increased β cell apoptosis. Furthermore, β cells derived from isogenic hESCs carrying the T1D risk allele of rs3783355 associated with DLK1 showed elevated β cell death. Through additional RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses, we identified five genes upregulated in both RASGRP1^-/- and DLK1^-/- β-like cells, four of which are near T1D GWAS signals. This integrative approach combining single-cell multi-omics, GWASs, and isogenic human pluripotent stem cell (hPSC)-derived β-like cells illuminates cell type context, genes, single nucleotide polymorphisms (SNPs), and regulatory elements underlying T1D-associated signals, providing insights into the biological functions and molecular mechanisms involved.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116065"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752531","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":"Heat stress responses mediated by N6-methyladenine DNA methylation in maize.","authors":"Weijun Guo, Liang Le, Daolei Zhang, Ziwei Wei, Yifan Wang, Yue Wu, Hada Wuriyanghan, Xiaofeng Gu, Li Pu","doi":"10.1016/j.celrep.2025.116058","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116058","url":null,"abstract":"<p><p>N6-methyladenine (6mA) plays an important role in eukaryotic development and stress responses, yet its function under heat stress (HS) in crops remains unclear. Here, we show that 6mA dynamics in two maize inbred lines, B73 and Mo17, correlate with their responses to HS. Genome-wide 6mA profiling reveals enrichment in promoters, intergenic regions, and transposable elements (TEs), with inverse correlation with gene/TE expression. Upon HS, heat-tolerant plants show elevated 6mA levels, with differential 6mA patterning on key HS-related genes underlying thermotolerance variation between B73 and Mo17. We identified ZmALKBH1 as a 6mA demethylase, and its mutation enhances HS tolerance. A deep learning model based on 6mA methylomes of B73 and Mo17 accurately predicts and experimentally validates 6mA distribution and HS response in additional W22 and B104 lines. These findings uncover the role of 6mA in transcriptional regulation of crop stress adaptation and offer potential targets for improving thermotolerance in maize.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116058"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741322","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":"A spatiotemporal atlas of mouse gastrulation and early organogenesis to explore axial patterning and project in vitro models onto in vivo space.","authors":"Luke T G Harland, Tim Lohoff, Noushin Koulena, Nico Pierson, Constantin Pape, Farhan Ameen, Jonathan Griffiths, Bart Theeuwes, Nicola K Wilson, Anna Kreshuk, Wolf Reik, Jennifer Nichols, Long Cai, John C Marioni, Berthold Göttgens, Shila Ghazanfar","doi":"10.1016/j.celrep.2025.116047","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116047","url":null,"abstract":"<p><p>During gastrulation, mouse epiblast cells form the three germ layers that establish the body plan and initiate organogenesis. While single-cell atlases have advanced our understanding of lineage diversification, spatial aspects of differentiation remain poorly defined. Here, we applied spatial transcriptomics to mouse embryos at embryonic (E) E7.25 and E7.5 days and integrated these data with existing E8.5 spatial and E6.5-E9.5 single-cell RNA-seq atlases. This resulted in a spatiotemporal atlas of over 150,000 cells with 82 refined cell-type annotations. The resource enables exploration of gene expression dynamics across anterior-posterior and dorsal-ventral axes, uncovering spatial logic guiding mesodermal fate decisions in the primitive streak. We also developed a computational pipeline to project additional single-cell datasets into this framework for comparative analysis. Freely accessible through an interactive web portal, this atlas offers a valuable tool for the developmental and stem cell biology communities to investigate mouse embryogenesis in a spatial and temporal context.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116047"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741321","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":"Neuroimmune axis in gastrointestinal cancers: From mechanisms to therapeutic breakthrough.","authors":"Yixuan Zhang, Jintian Chen, Yiwei Zhou, Yanjun Jiang, Jielun Hu, Xiaodong Liu, Jingying Zhou","doi":"10.1016/j.celrep.2025.116059","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116059","url":null,"abstract":"<p><p>Accumulating evidence has demonstrated that tumor cells can co-opt the nervous and immune systems to facilitate their growth, progression, and metastasis. Tumor innervation has been reported to regulate cancer development either directly or indirectly by modulating immune evasion through the neuroimmune axis. Building on insights into the mechanisms of cancer-neuroimmune interactions, attention is turning to developing novel therapeutics by repurposing neuropsychiatric drugs or using neuromodulation. Given the rich innervation of the gastrointestinal (GI) tract and its accessory organs, we summarize the current understanding of neuroimmune networks in GI cancers, focusing on the most recent updates of neurotransmitter-receptor pathways and tumor-innervating nociceptors. Additionally, we discuss the underlying mechanisms of these pathways and explore their therapeutic implications, which may potentially lead to new approaches for combinatory immunotherapies in GI cancers.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116059"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741323","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":"A trans-kingdom T6SS RNase effector targeting both prokaryotic and host cells for pathogenesis.","authors":"Yudi Wang, Yongdong Li, Zonglan Yu, Wenjing Zhang, Zhaorui Ren, Hongyun Zhang, Lu Xiao, Shengzhi Guo, Jinfang Zhou, Lingfang Zhu, Changfu Li, Lei Xu, Yao Wang, Yi Chen, Xihui Shen, Yantao Yang","doi":"10.1016/j.celrep.2025.116074","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116074","url":null,"abstract":"<p><p>The bacterial type VI secretion system (T6SS) mediates interactions with neighboring cells or the environment by secreting various effectors, yet T6SS RNase effectors have barely been studied. Here, we report a multifunctional trans-kingdom T6SS RNase effector, TseR, from Yersinia pseudotuberculosis (Yptb). TseR, an Ntox44 domain-containing effector secreted by T6SS-3, is a divalent cation-dependent RNase that preferentially cleaves single-stranded RNA, which can be inhibited by the cognate immunity protein TsiR. TseR mediated both contact-dependent and contact-independent T6SS killing of bacteria, with OmpC facilitating its entry into target cells during contact-independent killing. The global cleavage targets of TseR in Escherichia coli were identified via RNA-seq analysis. During infections, TseR facilitated pathogenicity by altering the gut microbiome and directly targeting eukaryotic host cells. This study provides valuable insights into the roles of the T6SS RNase effector and the Ntox44 family protein in bacterial competition and bacteria-host interactions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116074"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728310","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":"Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling.","authors":"Chenxu Yang, Makoto Arai, Eko Fuji Ariyanto, Ji Zhang, Debby Mirani Lubis, Ryo Ito, Shiyu Xie, Mio Nitta, Fuka Kawashima, Tomofumi Ishitsuka, Chaoran Yang, Tomohiro Suzuki, Tetsuro Komatsu, Hina Sagae, Hitomi Jin, Hiroki Takahashi, Eri Kobayashi, Yuchen Wei, Bohao Liu, Hyunmi Choi, Youichiro Wada, Toshiya Tanaka, Tsuyoshi Osawa, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Makoto Tachibana, Yoichi Shinkai, Takeshi Inagaki, Tomoyoshi Soga, Timothy F Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai","doi":"10.1016/j.celrep.2025.116060","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116060","url":null,"abstract":"<p><p>Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116060"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728311","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":"Metal-induced nanoscale clusterization initiates protein liquid-liquid phase separation.","authors":"Sijia Xiang, Zhuanghao Hou, Yu Wang, Yang Yang, Hongze Hu, Chang Yin, Guangming Huang, Kaiming Cao, Yangzhong Liu","doi":"10.1016/j.celrep.2025.116067","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116067","url":null,"abstract":"<p><p>Liquid-liquid phase separation (LLPS) of biomolecules is a crucial mechanism in regulating cellular functions through dynamic formation of membrane-less organelles. The assembly of nucleation seeds is a key step that triggers LLPS; however, it is challenging to precisely study its assembly mechanism due to the complexity of the condensation process. Recently, metal ions have been found to play important roles in inducing LLPS. To elucidate the assembling mechanism, a small ubiquitin-like modifier (SUMO) protein was employed as a model protein to study metal-induced condensation. The results indicate that SUMO possesses two weak Cu(II)-binding sites across the protein surface, enabling intermolecular bridging among SUMO molecules. The formation of assembling seeds is confirmed by mass photometry analysis, showing the Cu(II)-induced dynamic clusterization of SUMO at nanoscale. Increasing the Cu(II) binding affinity of SUMO significantly promotes the protein condensation, underscoring the pivotal role of Cu(II) coordination in LLPS. This work provides insights into the protein assembly mechanism through non-specific intermolecular metal coordination.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116067"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728313","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":"Identification and engineering of potent bispecific antibodies that protect against herpes simplex virus recurrent disease.","authors":"Chingwei V Lee, Hector Viadiu, Apurva Kalamkar, David I Bernstein, Andrew Pae, Xinchao Yu, Sylvia Wong, Fernando J Bravo, Sheng Ding, Elbert Seto, Magdeleine Hung, Yu Yu, Weimei Xing, Giuseppe A Papalia, Wei Kan, Brian Carr, Majlinda Thomas, Leah Tong, Priyanka Desai, Nadine Jarrousse, Alexandre Mercier, Meghan M Holdorf, Simon P Fletcher, Emma Abernathy","doi":"10.1016/j.celrep.2025.116063","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116063","url":null,"abstract":"<p><p>Herpes simplex virus (HSV) causes lifelong infections, including oral and genital herpes. There is no vaccine, and current antivirals are only partially effective at reducing symptoms and transmission. Therapeutic antibodies offer a potentially long-acting treatment option, although efforts to pursue this have been limited. We performed an alpaca immunization campaign and discovered high-affinity antibodies that both neutralized and completely blocked cell-to-cell spread (CCS), a key mechanism by which HSV evades neutralizing antibodies. Unexpectedly, we found that engineering antibodies into a bispecific format targeting two viral glycoproteins dramatically increased antiviral potency. Solving the structures of three antibodies using cryo-electron microscopy (cryo-EM) revealed a mechanistic understanding of how the bispecific format could enhance potency. Lastly, these bispecific antibodies significantly reduced lesion development in the guinea pig model of genital herpes, demonstrating that delayed dosing after latency establishment can reduce disease and confirming their potential as a transformative treatment option.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116063"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728312","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}