bims-ginsta Biomed News
on Genome instability
Issue of 2025–08–17
twenty-six papers selected by
Jinrong Hu, National University of Singapore
  1. Principles of cotranslational mitochondrial protein import.
  2. Establishment of chromatin architecture interplays with embryo hypertranscription.
  3. Mouse trophectoderm stem cells generated with morula signalling inducers capture an early trophectoderm state.
  4. Traction force and mechanosensitivity mediate species-specific implantation patterns in human and mouse embryos.
  5. RNA triggers chronic stress during neuronal aging.
  6. Multi-omic Profiling of Senescence Following Myocardial Infarction Reveals Dynamic Characteristics in Cardiac Remodeling.
  7. Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
  8. A SETD2-CDK1-lamin axis maintains nuclear morphology and genome stability.
  9. Immune surveillance of senescent cells in aging and disease.
  10. Co-translational ribosome pairing enables native assembly of misfolding-prone subunits.
  11. Distinct specificity and functions of PRC2 subcomplexes in human stem cells and cardiac differentiation.
  12. A multichaperone condensate enhances protein folding in the endoplasmic reticulum.
  13. Epithelial cells provide immunocompetence to the early embryo for bacterial clearance.
  14. Systematic profiling reveals betaine as an exercise mimetic for geroprotection.
  15. TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis.
  16. Restoring resident tissue macrophages to combat aging and cancer.
  17. Cargo-selective regulation of clathrin-mediated endocytosis by AMP-activated protein kinase.
  18. Co-profiling of in situ RNA-protein interactions and transcriptome in single cells and tissues.
  19. Ribo-ITP expands the translatome of limited input samples.
  20. Protein Storage in Oocytes: Implications for Oocyte Quality, Embryonic Development, and Female Fertility.
  21. Membraneless protocell confined by a heat flow.
  22. Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging.
  23. Mechanisms underlying low mutation rates in mammalian oocytes and preimplantation embryos.
  24. Origin of chromosome 12 trisomy surge in human induced pluripotent stem cells.
  25. Compressed Cells Facilitate Adhesion Through Glycocalyx.
  26. On-demand delivery of fibulin-1 protects the basement membrane during cyclic stretching in C. elegans.
  1. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  2. Nature. 2025 Aug 13.
    Establishment of chromatin architecture interplays with embryo hypertranscription.
    Guang Yu, Kai Xu, Weikun Xia, Ke Zhang, Qianhua Xu, Lijia Li, Zili Lin, Ling Liu, Bofeng Liu, Zhenhai Du, Xia Chen, Qiang Fan, Fangnong Lai, Wenying Wang, Lijuan Wang, Feng Kong, Chao Wang, Haiqiang Dai, Huili Wang, Wei Xie.
      After fertilization, early embryos undergo dissolution of conventional chromatin organization, including topologically associating domains (TADs)1,2. Zygotic genome activation then commences amid unusually slow de novo establishment of three-dimensional chromatin architecture2. How chromatin organization is established and how it interplays with transcription in early mammalian embryos remain elusive. Here we show that CTCF occupies chromatin throughout mouse early development. By contrast, cohesin poorly binds chromatin in one-cell embryos, coinciding with TAD dissolution. Cohesin binding then progressively increases from two- to eight-cell embryos, accompanying TAD establishment. Unexpectedly, strong 'genic cohesin islands' (GCIs) emerge across gene bodies of active genes in this period. GCI genes enrich for cell identity and regulatory genes, display broad H3K4me3 at promoters, and exhibit strong binding of transcription factors and the cohesin loader NIPBL at nearby enhancers. We show that transcription is hyperactive in two- to eight-cell embryos and is required for GCI formation. Conversely, induced transcription can also create GCIs. Finally, GCIs can function as insulation boundaries and form contact domains with nearby CTCF sites, enhancing both the transcription levels and stability of GCI genes. These data reveal a hypertranscription state in early embryos that both shapes and is fostered by the three-dimensional genome organization, revealing an intimate interplay between chromatin structure and transcription.
    DOI:  https://doi.org/10.1038/s41586-025-09400-5
  3. Nat Cell Biol. 2025 Aug 14.
    Mouse trophectoderm stem cells generated with morula signalling inducers capture an early trophectoderm state.
    Yake Gao, Mingying Li, Wei Guan, Wei Guo, Shu Wei, Fang Yan, Wenrui Han, Xueting Zhang, Tong Yin, Yunkun Dang, Huanhuan Li, José C R Silva, Jian Zhang.
      The first embryonic cell differentiation in mice segregates the trophectoderm and the inner cell mass. Successful derivation of mouse trophoblast stem cells (TSCs) and trophectoderm stem cells (TESCs) has greatly facilitated the understanding of trophoblast differentiation. However, our understanding of early trophectoderm differentiation remains incomplete. Here we report the establishment of a morula-derived trophectoderm stem cell (MTSC) line from 32-cell embryos that show enhanced and uniform trophoblast core gene expression. Importantly, distinct from TSCs or TESCs, MTSCs represent a much earlier trophectoderm state (E3.5) than that of TSCs (E5.5-6.5) and TESCs (E4.5-5.5). MTSCs can robustly integrate into all cell lineages of the placenta. Moreover, MTSCs can self-organize to form placenta organoids. When partially differentiated MTSCs aggregate with embryonic stem cells, they form blastoids that efficiently implant uteruses. Finally, MSTC medium can efficiently convert embryonic stem cells, TSCs and TESCs into MTSC-like cells. Thus, MTSCs capture an early blastocyst trophectoderm state and provide a research model for studying trophoblast development.
    DOI:  https://doi.org/10.1038/s41556-025-01732-8
  4. Sci Adv. 2025 Aug 15. 11(33): eadr5199
    Traction force and mechanosensitivity mediate species-specific implantation patterns in human and mouse embryos.
    Amélie Luise Godeau, Anna Seriola, Oren Tchaicheeyan, Marc Casals, Denitza Denkova, Ester Aroca, Ot Massafret, Albert Parra, Maria Demestre, Anna Ferrer-Vaquer, Shahar Goren, Anna Veiga, Miquel Solé, Montse Boada, Jordi Comelles, Elena Martínez, Julien Colombelli, Ayelet Lesman, Samuel Ojosnegros.
      The invasion of human embryos in the uterus overcoming the maternal tissue barrier is a crucial step in embryo implantation and subsequent development. Although tissue invasion is fundamentally a mechanical process, most studies have focused on the biochemical and genetic aspects of implantation. Here, we fill the gap by using a deformable ex vivo platform to visualize traction during human embryo implantation. We demonstrate that embryos apply forces remodeling the matrix with species-specific displacement amplitudes and distinct radial patterns: principal displacement directions for mouse embryos, expanding on the surface while human embryos insert in the matrix generating multiple traction foci. Implantation-impaired human embryos showed reduced displacement, as well as mouse embryos with inhibited integrin-mediated force transmission. External mechanical cues induced a mechanosensitive response, human embryos recruited myosin, and directed cell protrusions, while mouse embryos oriented their implantation or body axis toward the external cue. These findings underscore the role of mechanical forces in driving species-specific invasion patterns during embryo implantation.
    DOI:  https://doi.org/10.1126/sciadv.adr5199
  5. bioRxiv. 2025 Aug 05. pii: 2025.08.04.668575. [Epub ahead of print]
    RNA triggers chronic stress during neuronal aging.
    Kevin Rhine, Elle Epstein, Natasha M Carlson, Xuezhen Ge, Orel Mizrahi, Anika Kamat, Anita Hermann, William R Brothers, John Ravits, Eric J Bennett, Gülçin Pekkurnaz, Gene W Yeo.
      Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might contribute to aging and neurodegeneration. Here, we leverage directed transdifferentiation of human fibroblasts into aged neurons to determine the source of ISR activation. We demonstrate that increased accumulation of cytoplasmic double-stranded RNA (dsRNA) activates the eIF2α kinase PKR, which in turn triggers the ISR in aged neurons and leads to sequestration of dsRNA in stress granules. Aged neurons accumulate endogenous mitochondria-derived dsRNA that directly binds to PKR. This mitochondrial dsRNA leaks through damaged mitochondrial membranes and forms cytoplasmic foci in aged neurons. Finally, we demonstrate that PKR inhibition leads to the cessation of stress, resumption of cellular translation, and restoration of RNA-binding protein expression. Together, our results identify a source of RNA stress that destabilizes aged neurons and may contribute to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.08.04.668575
  6. bioRxiv. 2025 Aug 06. pii: 2025.08.04.667980. [Epub ahead of print]
    Multi-omic Profiling of Senescence Following Myocardial Infarction Reveals Dynamic Characteristics in Cardiac Remodeling.
    Jielin Deng, Di Ren, Heather Zhou, Yunqiu Jiang, Qiutang Xiong, Yanbo Zhao, Yin Wang, Hao Wu, Makoto Nakanishi, Yingfeng Deng, Zhao V Wang.
      Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a gradual increment number of senescent cells within the ischemic heart, peaking at day 7 post-MI, in both wild-type and p16 Ink4a -Cre ERT2 -mT/mG senescence reporter mice. Lineage tracing shows that senescent cells transition to non-senescent state within 4 weeks after MI. We perform single-nucleus (sn) Multiome and fluorescence-based spatial transcriptomics analyses to profile senescent cells. We next generate a reference (query dataset) based on SPiDER-βGal/p16-EGFP positivity and map it back to the snMultiome dataset. We then deconvolute senescent cells in the integrated dataset using multiple computational algorisms. Through these approaches, we reveal that fibroblasts and its subpopulation-late myofibroblasts (MF)-constitute a major proportion of senescent cells, which functionally reduce ECM production. Importantly, ischemia-induced senescent MF show less soluble collagen production compared to TGF-β1-induced non-senescent MF in vitro . At the functional level, depletion of senescent cells in vivo augments fibrosis and worsens cardiac myopathy post-MI. Our findings highlight the transient nature of senescent cells in the heart and underscore the importance of dynamic regulation of senescent cells post-MI.
    DOI:  https://doi.org/10.1101/2025.08.04.667980
  7. Elife. 2025 Aug 11. pii: RP99936. [Epub ahead of print]13
    Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
    Haruna Gekko, Ruri Nomura, Daiki Kuzuhara, Masato Kaneyasu, Genpei Koseki, Deepak Adhikari, Yasuyuki Mio, John Carroll, Tomohiro Kono, Hiroaki Funahashi, Takuya Wakai.
      In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage.
    Keywords:  Dynamin-related protein 1; binuclear formation; chromosome segregation; developmental biology; mitochondrial dynamics; mouse; organelle inheritance; preimplantation development
    DOI:  https://doi.org/10.7554/eLife.99936
  8. Nat Cell Biol. 2025 Aug;27(8): 1327-1341
    A SETD2-CDK1-lamin axis maintains nuclear morphology and genome stability.
    Abid Khan, Cheng Zhang, Phu G Nguyen, James M Metts, Lucas C Collins, Kanishk Jain, C Allie Mills, Logan Vlach, Kelin Li, Amanda L Brademeyer, Brittany M Bowman, Michael B Major, Jeffrey Aubé, Laura E Herring, W Kimryn Rathmell, Frank M Mason, Ian J Davis, Qing Zhang, Brian D Strahl.
      Histone methyltransferases regulate chromatin organization and are frequently mutated in human diseases, including cancer. One such often mutated methyltransferase, SETD2, associates with transcribing RNA polymerase II and catalyses H3K36me3-a modification that contributes to gene transcription, splicing and DNA repair. Although its catalytic function is well-characterized, its non-catalytic roles remain unclear. Here we reveal a catalysis-independent function of SETD2 in nuclear lamina stability and genome integrity. Through its intrinsically disordered amino terminus, SETD2 associates with lamina-associated proteins, including lamin A/C, lamin B1 and emerin. Loss of SETD2 or its N terminus leads to severe nuclear morphology defects and genome instability, mirroring lamina dysfunction. Mechanistically, the N terminus of SETD2 serves as a scaffold for the mitotic kinase CDK1 and lamins, facilitating lamin phosphorylation and depolymerization during mitosis. Restoration of the N-terminal regions required for interaction with CDK1 and lamins rescues nuclear morphology and suppresses tumorigenic growth in a clear cell renal cell carcinoma model with SETD2 haploinsufficiency. These findings reveal a previously unrecognized role of SETD2 in nuclear lamina organization and genome maintenance that probably extends to its role as a tumour suppressor.
    DOI:  https://doi.org/10.1038/s41556-025-01723-9
  9. Nat Aging. 2025 Aug;5(8): 1415-1424
    Immune surveillance of senescent cells in aging and disease.
    Julia Majewska, Valery Krizhanovsky.
      Senescent cells are intrinsically immunogenic and can be eliminated by the immune system to facilitate tissue repair and regeneration. However, immune-mediated elimination is compromised with age, causing senescent cell accumulation in tissues, thus limiting healthspan and lifespan and promoting age-related diseases such as cancer. Here, we review how different components of the innate and adaptive immune systems, including natural killer cells, macrophages, neutrophils, dendritic cells, T cells and B cells, target senescent cells and how the intrinsic properties of senescent cells can lead to their escape from surveillance. We also discuss the phenomenon of senescence in immune cells themselves and how this affects the surveillance of senescent and cancerous cells. Finally, we touch on emerging therapeutic strategies to enhance the immunosurveillance of senescent cells, as understanding the molecular basis of senescence immunosurveillance and why its potency fails during aging may offer opportunities to treat senescence-mediated age-associated diseases and tissue dysfunction.
    DOI:  https://doi.org/10.1038/s43587-025-00910-5
  10. Nat Commun. 2025 Aug 15. 16(1): 7626
    Co-translational ribosome pairing enables native assembly of misfolding-prone subunits.
    Florian Wruck, Jaro Schmitt, Katharina Till, Kai Fenzl, Matilde Bertolini, Frank Tippmann, Alexandros Katranidis, Bernd Bukau, Günter Kramer, Sander J Tans.
      Protein complexes are pivotal to most cellular processes. Emerging evidence indicating dimer assembly by pairs of ribosomes suggests yet unknown folding mechanisms involving two nascent chains. Here, we show that co-translational ribosome pairing allows their nascent chains to 'chaperone each other', thus enabling the formation of coiled-coil homodimers from subunits that misfold individually. We developed an integrated single-molecule fluorescence and force spectroscopy approach to probe the folding and assembly of two nascent chains extending from nearby ribosomes, using the intermediate filament lamin as a model system. Ribosome proximity during early translation stages is found to be critical: when interactions between nascent chains are inhibited or delayed, they become trapped in stable misfolded states that are no longer assembly-competent. Conversely, early interactions allow the two nascent chains to nucleate native-like quaternary structures that grow in size and stability as translation advances. We conjecture that protein folding mechanisms enabled by ribosome cooperation are more broadly relevant to intermediate filaments and other protein classes.
    DOI:  https://doi.org/10.1038/s41467-025-61500-y
  11. Mol Cell. 2025 Aug 07. pii: S1097-2765(25)00615-X. [Epub ahead of print]
    Distinct specificity and functions of PRC2 subcomplexes in human stem cells and cardiac differentiation.
    Christian Much, Sandy M Rajkumar, Liming Chen, John M Cohen, Aravind R Gade, Geoffrey S Pitt, Yicheng Long.
      The dynamic regulation of epigenetic states relies on complex macromolecular interactions. PRC2, the methyltransferase complex depositing H3K27me3, interacts with distinct accessory proteins to form the mutually exclusive subcomplexes PHF1-PRC2.1, MTF2-PRC2.1, PHF19-PRC2.1, and PRC2.2. The functions of these subcomplexes are thought to be largely redundant. Here, we show that PRC2 subcomplexes have distinct roles in epigenetic repression of lineage-specific genes and stem cell differentiation. Using human pluripotent stem cells, we engineered a comprehensive set of separation-of-function mutants to dissect the roles of individual protein-protein and DNA-protein interactions. Our results show that PRC2.1 and PRC2.2 deposit H3K27me3 locus-specifically, resulting in opposing outcomes in cardiomyocyte differentiation. We find that MTF2 stimulates PRC2.1-mediated repression in stem cells and cardiac differentiation through its interaction with DNA and H3K36me3, while PHF19 antagonizes it. Together, these results reveal the importance and specificity of individual macromolecular interactions in Polycomb-mediated epigenetic repression in human stem cells and differentiation.
    Keywords:  H3K27me3; PRC2; Polycomb; cardiac differentiation; epigenetics; human pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.014
  12. Nat Cell Biol. 2025 Aug 11.
    A multichaperone condensate enhances protein folding in the endoplasmic reticulum.
    Anna Leder, Guillaume Mas, Viktória Szentgyörgyi, Roman P Jakob, Timm Maier, Anne Spang, Sebastian Hiller.
      Protein folding in the endoplasmic reticulum (ER) relies on a network of molecular chaperones that facilitates the folding and maturation of client proteins. How the ER chaperones organize in a supramolecular manner to exert their cooperativity has, however, remained unclear. Here we report the discovery of a multichaperone condensate in the ER lumen, which is formed around the chaperone PDIA6 during protein folding homeostasis. The condensates form in a Ca2+-dependent manner and we resolve the underlying mechanism at the atomic and cellular levels. The PDIA6 condensates recruit further chaperones-Hsp70 BiP, J-domain protein ERdj3, disulfide isomerase PDIA1 and Hsp90 Grp94-which constitute some of the essential components of the early folding machinery. The chaperone condensates enhance folding of proteins, such as proinsulin, and prevent protein misfolding in the ER lumen. The PDIA6-scaffolded chaperone condensates hence provide the functional basis for spatial and temporal coordination of the dynamic ER chaperone network.
    DOI:  https://doi.org/10.1038/s41556-025-01730-w
  13. Cell Host Microbe. 2025 Jul 09. pii: S1931-3128(25)00208-2. [Epub ahead of print]33(7): 1106-1120.e8
    Epithelial cells provide immunocompetence to the early embryo for bacterial clearance.
    Joan Roncero-Carol, June Olaizola-Muñoa, Begoña Arán, Loris Sebastiano Mularoni, Marta Miret Cuesta, Nuria Blanco-Cabra, Marc Casals, Mireia Rumbo, Miquel Solé Inarejos, Samuel Ojosnegros, Berta Alsina, Eduard Torrents, Anna Veiga, Manuel Irimia, Esteban Hoijman.
      Early embryos are exposed to environmental perturbations that may influence their development, including bacteria. Despite lacking a proper immune system, the surface epithelium of early embryos (trophectoderm in mammals) can phagocytose defective pluripotent cells. Here, we explore the dynamic interactions between early embryos and bacteria. Quantitative live imaging of infection models developed in zebrafish embryos reveals the efficient phagocytic capability of surface epithelia in detecting, ingesting, and destroying infiltrated E. coli and S. aureus. In vivo single-cell interferences uncover actin-based epithelial zippering protrusions mediating bacterial phagocytosis, safeguarding developmental robustness upon infection. Transcriptomic and inter-scale dynamic analyses of phagocyte-bacteria interactions identify specific features of this epithelial phagocytic program. Notably, live imaging of mouse and human blastocysts supports a conserved role of the trophectoderm in bacterial phagocytosis. This defensive role of the surface epithelium against bacterial infection provides immunocompetence to early embryos, with relevant implications for understanding failures in human embryogenesis.
    Keywords:  bacterial infections; cell dynamics; embryonic development; epithelial tissue; host-pathogen interactions; human embryo; phagocytosis; quantitative live imaging; zebrafish
    DOI:  https://doi.org/10.1016/j.chom.2025.05.025
  14. Cell. 2025 Aug 12. pii: S0092-8674(25)00852-9. [Epub ahead of print]
    Systematic profiling reveals betaine as an exercise mimetic for geroprotection.
    Lingling Geng, Jiale Ping, Ruochen Wu, Haoteng Yan, Hui Zhang, Yuan Zhuang, Taixin Ning, Jun Wang, Chuqian Liang, Jiachen Zhang, Qingqing Chu, Jing Zhang, Yifan Wen, Yaobin Jing, Shuhui Sun, Qin Qiao, Qian Zhao, Qianzhao Ji, Shuai Ma, Yusheng Cai, Yandong Zheng, Zhiran Zou, Zhiqing Diao, Mingheng Li, Hao Zhang, Jianli Hu, Liangzheng Fu, Wang Kang, Ruijun Bai, Hongkai Zhao, Sheng Zhang, Yingjie Ding, Jinghui Lei, Wei Wang, Yun Ji, Bo Gou, Guoqiang Sun, Jian Yin, Pengze Yan, Hao Li, Zehua Wang, Shikun Ma, Zunpeng Liu, Hezhen Shan, Qiaoran Wang, Tianling Cao, Shanshan Yang, Cui Wang, Ping Yang, Yanling Fan, Yanxia Ye, Jinghao Hu, Mengmeng Jiang, Ye Wang, Kan Liu, Yujing Li, Yuanxiang Li, Jingyi Li, Weimin Ci, Zi-Bing Jin, Xiaobing Fu, Xu Zhang, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Si Wang, Moshi Song, Weiqi Zhang, Jing Qu, Guang-Hui Liu.
      
    DOI:  https://doi.org/10.1016/j.cell.2025.07.030
  15. Circulation. 2025 Aug 13.
    TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis.
    Mason E Sweat, Wei Shi, Yan Y Sweat, Jie Li, Jiajin Li, Erin M Keating, Anna Ponek, Qing Ma, Chaehyoung Park, Michael A Trembley, Yi Wang, Cuilan Hou, Vassilios J Bezzerides, Frank L Conlon, William T Pu.
       BACKGROUND: Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex.
    METHODS: We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays.
    RESULTS: We found that TBX5 recruits CHD4 to 33 170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in Chd4AKO atria demonstrated that CHD4 also promotes TBX5 binding at >10 000 genomic loci, including 3051 TBX5-enhanced CHD4 sites. Consistent with its requirement to maintain normal atrial rhythm, CHD4 was implicated in the regulation of 42 genes linked to atrial fibrillation in humans. Nine had the hallmarks of TBX5-dependent, CHD4-mediated transcriptional activation.
    CONCLUSIONS: Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.
    Keywords:  arrhythmias, cardiac; atrial fibrillation; transcription factors
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.073833
  16. Nat Aging. 2025 Aug;5(8): 1383-1392
    Restoring resident tissue macrophages to combat aging and cancer.
    Matthew D Park, Nader Yatim, Jing Zhang, Byuri Angela Cho, Seong-Keun Yoo, Maximilian M Schaefer, Diego Chowell, Daniel J Puleston, Miriam Merad.
      Perturbations to the immune system influence organismal aging, yet identifying effective therapeutic targets that mitigate aging-related tissue decline or the pathogenesis of aging-related diseases, such as cancer, remains challenging. In this Perspective, we focus on the dysfunction and loss of resident tissue macrophages (RTMs) with aging of certain tissues, which promote local inflammation, compromise tissue health and contribute to tumorigenesis. The abnormal genesis of RTMs from the bone marrow is a defining hallmark of both healthy and unhealthy aging. So, we propose that restoring RTMs-either by reshaping their niche and rescuing local self-renewal or by rejuvenating aging-associated myelopoiesis in the bone marrow-should be a major objective of interventions to promote healthy aging. We summarize the body of work supporting this conceptual framework and outline key future directions for the development of versatile myeloid-targeting therapies.
    DOI:  https://doi.org/10.1038/s43587-025-00898-y
  17. iScience. 2025 Aug 15. 28(8): 113131
    Cargo-selective regulation of clathrin-mediated endocytosis by AMP-activated protein kinase.
    Laura A Orofiamma, Ralph Christian Delos Santos, Ayshin Mehrabi, Nikol Leshchyshyn, Geoffrey G Hesketh, Sadia Rahmani, Aesha Patel, Farnaz Fekri, Rehman Ata, Colin D H Ratcliffe, Mathieu J F Crupi, Lois Mulligan, Morag Park, Anne-Claude Gingras, Costin N Antonescu.
      The cell surface abundance of many proteins is controlled by clathrin-mediated endocytosis (CME). CME is driven by the assembly of clathrin and other proteins on the inner leaflet of the plasma membrane into clathrin-coated pits (CCPs). Regulation of CCP dynamics allows for control of the function of specific cell surface proteins, impacting a range of cellular outcomes. AMP-activated protein kinase (AMPK) becomes activated upon metabolic insufficiency and facilitates cellular adaptation to nutrient stress. Here, we examined how AMPK regulates CME and the cell surface membrane traffic of β1-integrin. We find that AMPK controls CCP dynamics and regulates the abundance of the endocytic adaptor protein Dab2 within CCPs in a manner that requires the GTPase Arf6, thus selectively promoting the CCP recruitment and internalization of β1-integrin. This study reveals a signaling pathway for cargo-selective metabolic regulation of CME by AMPK that impacts the function of cell surface proteins such as integrins.
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113131
  18. Nat Methods. 2025 Aug 11.
    Co-profiling of in situ RNA-protein interactions and transcriptome in single cells and tissues.
    Qi-Xuan Cheng, Gang Xie, Xiangyu Zhang, Jie Wang, Shuangjin Ding, Yi-Xia Wu, Ming Shi, Fei-Fei Duan, Zi-Li Wan, Jing-Jia Wei, Junyu Xiao, Yangming Wang.
      RNA-binding proteins (RBPs) are essential regulators of RNA fate and function. A long-standing challenge in studying RBP regulation has been mapping RNA interactomes within the dynamic transcriptomic landscape, especially in single-cell contexts and primary tissues. Here we introduce MAPIT-seq (modification added to RBP interacting transcript-sequencing), which uses an antibody-directed editing strategy to map genome-wide in situ RBP-RNA interactions and gene expression concurrently. We demonstrate MAPIT-seq's robustness across multiple RBPs and systematically analyze RNA substrates associated with core polycomb repressive complex 2 (PRC2) components. MAPIT-seq is also applicable to frozen tissue sections, enabling the mapping of RBP roles during brain development. Importantly, we develop high-throughput single-cell MAPIT-seq (scMAPIT-seq) to reveal cell stage-specific RBP regulation. In summary, MAPIT-seq expands multi-omics profiling, providing an effective framework to study post-transcriptional regulation in dynamic biological processes and clinically relevant scenarios.
    DOI:  https://doi.org/10.1038/s41592-025-02774-4
  19. bioRxiv. 2025 Aug 04. pii: 2025.08.04.668486. [Epub ahead of print]
    Ribo-ITP expands the translatome of limited input samples.
    Vighnesh Ghatpande, Uma Paul, MacKenzie A Howard, Can Cenik.
      In the last decade, an unexpectedly large number of translated regions (translons) have been discovered using ribosome profiling and proteomics. Translons can regulate mRNA translation and encode micropeptides that contribute to multiprotein complex formation, Ca 2+ regulation in muscle, and signaling during embryonic development. However, identification of translons has been limited to cell lines or large organs due to high input requirements for conventional ribosome profiling and mass spectrometry. Here, we address this challenge using Ribo-ITP on difficult-to-collect samples like microdissected hippocampal tissues and single pre-implantation embryos. Comparative analysis of more than a thousand ribosome profiling datasets across a wide range of cell types revealed distinct sample specific expression patterns of the detected translons. To test the translational capacity of the identified translons, we engineered a translon-dependent GFP reporter system and detected expression of translons initiating at near-cognate start codons in mouse embryonic stem cells (mESCs). Mutating the translons in mESCs identified a small proportion that negatively impacted growth. Taken together, we present a proof-of-concept study to identify non-canonical translation events from low input samples which can be applied to cell and tissue types inaccessible to conventional methods.
    DOI:  https://doi.org/10.1101/2025.08.04.668486
  20. Annu Rev Cell Dev Biol. 2025 Aug 13.
    Protein Storage in Oocytes: Implications for Oocyte Quality, Embryonic Development, and Female Fertility.
    Ida Marie Astad Jentoft, Melina Schuh.
      Maternal storage is a fundamental feature of female gametes and is essential for maintaining oocyte quality and preserving developmental competence. Embryonic development relies on maternally deposited proteins, transcripts, and nutrients, yet the mechanisms by which oocytes accumulate and store these critical factors-particularly proteins-remain poorly understood. Across eukaryotes, diverse protein storage strategies have evolved, reflecting both conserved and species-specific adaptations. Here, we review the mechanisms of oocyte protein storage, comparing different species to uncover functional similarities and differences. Additionally, germ cells must clear damaged molecules accumulated during the mother's lifetime to ensure the production of rejuvenated eggs. We examine the conserved proteostasis mechanisms that support this process. By integrating insights from various model organisms and cellular dormancy studies, this review highlights the molecular basis of oocyte protein storage and its vital role in reproductive success.
    DOI:  https://doi.org/10.1146/annurev-cellbio-101323-031045
  21. Nat Phys. 2025 ;21(8): 1303-1310
    Membraneless protocell confined by a heat flow.
    Alexander Floroni, Noël Yeh Martín, Thomas Matreux, Laura I Weise, Sheref S Mansy, Hannes Mutschler, Christof B Mast, Dieter Braun.
      In living cells, a complex mixture of biomolecules is assembled within and across membranes. This non-equilibrium state is maintained by sophisticated protein machinery, which imports food molecules, removes waste products and orchestrates cell division. However, it remains unclear how this complex cellular machinery emerged and evolved. Here we show how the molecular contents of a cell can be coupled in a coordinated way to non-equilibrium heat flow. A temperature difference across a water-filled pore assembled the core components of a modern cell, which could then activate the gene expression. The mechanism arose from the interplay of convection and thermophoresis, both driven by the same heat source. The cellular machinery of protein synthesis from DNA via RNA was triggered as a direct result of the concentration of cell components. The same non-equilibrium setting continued to attract food molecules from an adjacent fluid stream, keeping the cellular molecules in a confined pocket protected against diffusion. Our results show how a simple non-equilibrium physical process can assemble the many different molecules of a cell and trigger its basic functions. The framework provides a membrane-free environment to bridge the long evolutionary times from an RNA world to a protein-based cell-like proto-metabolism.
    Keywords:  Biological physics; Complex networks; Permeation and transport
    DOI:  https://doi.org/10.1038/s41567-025-02935-4
  22. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2514837122
    Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging.
    Hongen Lei, Dianrong Li, Jie Chen, Baowen Du, Kaiju Jiang, Tao Xu, Hu Han, Weiliang Fan, Long Tian, Xiaodong Wang.
      Male infertility remains a major unmet medical challenge, with poorly defined molecular mechanisms and no effective therapies. Here, we identify a stress granule-mediated necroptotic pathway as a key driver of non-obstructive azoospermia, a severe form of male infertility marked by the loss of spermatogenesis. Environmental or physiological stress activates eIF2α kinases, inducing stress granule formation and the recruitment of ZBP1 and RIPK3 into a cytoplasmic complex. This assembly triggers RIPK3 activation, MLKL phosphorylation, and necroptotic death of spermatogonia and Sertoli cells. Genetic ablation of Zbp1 or Ripk3 protects mice from heat-induced testicular degeneration, establishing their essential role in stress-induced testicular damage. Importantly, activation of this pathway is also observed in aged human testes, linking stress-responsive necroptosis to both pathological infertility and the broader process of reproductive aging. These findings reveal an unrecognized mechanism that couples cellular stress responses to regulated cell death in the male reproductive system.
    Keywords:  ZBP1; necroptosis; non-obstructive azoospermia; stress granule; testis aging
    DOI:  https://doi.org/10.1073/pnas.2514837122
  23. Nucleic Acids Res. 2025 Aug 11. pii: gkaf760. [Epub ahead of print]53(15):
    Mechanisms underlying low mutation rates in mammalian oocytes and preimplantation embryos.
    Nataliia Dudko, Jurek W Dobrucki, Helena Fulka.
      Mammalian oocytes and embryos are known to exhibit a markedly low frequency of de novo mutations compared to somatic cells. We still lack efficient tools to carry out functional studies of the intergenerational mechanism of genome protection, and our view of this phenomenon is constantly being modified in light of the new results. Although oocytes were originally considered a cell type lacking DNA repair, new results indicate that mammalian oocytes might possess a set of unique properties that make them and their descendants resistant to accumulation of DNA damage. Here, we review various factors that can influence oocyte and embryo genome stability and discuss the functional evidence for the uniquely efficient response to DNA damage, particularly in the presence of minor DNA lesions and single-strand breaks. We discuss whether high levels of DNA repair proteins might be the basis for the observed low mutation rate. Finally, we present the idea that the unique characteristics of the chromatin landscape, as well as the limited replication, rather than the abundance of repair factors alone, may be responsible for the intergenerational protection of the genome.
    DOI:  https://doi.org/10.1093/nar/gkaf760
  24. J Cell Biol. 2025 Nov 03. pii: e202501231. [Epub ahead of print]224(11):
    Origin of chromosome 12 trisomy surge in human induced pluripotent stem cells.
    Maria Narozna, Megan C Latham, Gary J Gorbsky.
      Trisomy 12 is the most common whole-chromosome abnormality in human pluripotent stem cells. Conventionally, this acquired aneuploidy is ascribed to a rare single-cell event followed by selective growth advantage. Instead, we show that trisomy 12 emerges simultaneously in a very high percentage of cells in critical transition passages. Mis-segregation and incorporation of chromosome 12 into micronuclei occur through bridging of the short p arms of chromosome 12. Subsequently, single, unreplicated chromosome 12 chromatids are observed in mitotic cells. Erosion of the subtelomeric regions of the 12p arms is found during the passages when chromosome 12 bridges become frequent and trisomy 12 increases. Trisomy 12 cells persist due to a slight growth advantage. Among the shortest telomeres in humans are those on the 12p arms, making them particularly vulnerable to damage and bridging during mitosis. These findings reveal a novel mechanism of whole-chromosome instability in human stem cells, with broad implications for understanding the genesis of aneuploidy across diverse biological systems.
    DOI:  https://doi.org/10.1083/jcb.202501231
  25. Adv Sci (Weinh). 2025 Aug 15. e13586
    Compressed Cells Facilitate Adhesion Through Glycocalyx.
    Xiaole Wang, Jonne Helenius, Daniel J Müller, Nico Strohmeyer.
      Exposed to mechanical confinement, mammalian cells can establish remarkable unspecific adhesion, which is independent of integrins. How cells facilitate such adhesion remains unclear. Here, it is investigated how mammalian cells exposed to compression initiate unspecific and integrin-mediated adhesion. It is observed that with increasing compression, cells increase adhesion to collagen I or fibronectin and strengthen adhesion faster. Under low and medium compression, cells minimally increase unspecific adhesion to substrates that lack specific binding sites for cell surface receptors, such as integrins. However, under high compression, mammalian cells switch to a strong unspecific adhesion state, which significantly contributes to cell-extracellular matrix (ECM) adhesion. Thereby cells use the glycocalyx to directly facilitate strong unspecific adhesion and to enhance early integrin-mediated adhesion. The mechanistic insight of how cells unspecifically adhere to substrates under confinement opens avenues to better understand cell adhesion in development, homeostasis, disease, and in a wide range of biotechnological and medical applications in which cells are exposed to mechanical confinement.
    Keywords:  cell adhesion initiation; collagen; compression; fibronectin; glycocalyx; integrin; single‐cell force spectroscopy
    DOI:  https://doi.org/10.1002/advs.202413586
  26. Dev Cell. 2025 Aug 08. pii: S1534-5807(25)00472-1. [Epub ahead of print]
    On-demand delivery of fibulin-1 protects the basement membrane during cyclic stretching in C. elegans.
    Adam W J Soh, Michael R Arnwine, Claire A Gianakas, Zachary D Clark, Qiuyi Chi, Erin J Cram, Brenton D Hoffman, David R Sherwood.
      Basement membrane (BM) extracellular matrices enwrap and structurally support tissues. Whether BMs are uniquely constructed for tissues to undergo repetitive stretching and recoil events is unknown. During C. elegans ovulation, the spermathecal BM stretches ∼1.7-fold and then recoils to its original shape every 20 min to passage hundreds of oocytes. Fluorescence microscopy demonstrated that ovulating oocytes deliver the extracellular matrix protein fibulin-1 (FBL-1) through the spermathecal cell junctions to the BM during stretching, where it forms a dynamic overlapping network with type IV collagen. FBL-1 depletion led to a breakdown in type IV collagen and BM organization, resulting in a more deformable BM and extended spermatheca. Moreover, perturbation to FBL-1 network formation via mutagenesis was sufficient to disrupt tissue recoil and shape. Together, our study identifies an on-demand FBL-1 delivery system that protects the BM network when it is stretched, thereby allowing repeated rounds of tissue expansion and recovery.
    Keywords:  basement membrane; basement membrane elasticity; extracellular matrix; fibulin-1; tissue stretching and recovery; type IV collagen; vasculature
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.015
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