bims-ginsta 2026-01-18 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–01–18
twenty-two papers selected by
Jinrong Hu, National University of Singapore

OCT4 enhances the firing efficiency of late DNA replication origins in mouse embryonic stem cells.
Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
Sequential RNA polymerase II activation drives human hematopoiesis.
Integrated multi-omic atlas reveals the hierarchy of spatiotemporal regulatory networks of mouse gastrulation.
Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling.
Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2-Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging.
Visualization and quantification of rDNA instabilities in mammalian cells and mouse models.
Gene expression noise in development: genome-wide dynamics.
Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness.
Mechanical states of a motor protein in the spindle.
Deep-learning analysis of 3D microarchitectural remodeling in hypertrophic cardiomyopathy.
Interplay between cohesin and RNA polymerase II in regulating chromatin interactions and gene transcription.
The intrinsic impact of mechanical stress on the maintenance of oocyte dormancy.
CFAP20 salvages arrested RNAPII from the path of co-directional replisomes.
A mouse circadian proteome atlas.
Lactylation-driven nuclear RIG-I promoted by lactate transporter inhibitor suppresses DNA damage repair through inhibiting PARP1 activity.
Temporal inhibition of ADAM17 in fibroblasts reduces stiffness and promotes vascularization following myocardial infarction.
Endogenous FGFs drive ERK-dependent cell fate patterning in 2D human gastruloids.
Polyamine-dependent metabolic shielding regulates alternative splicing.
Intermittent hypobaric pressure induces selective senescent cell death and alleviates age-related osteoporosis.
Mitochondrial transfer from immune to tumor cells enables lymph node metastasis.

Nat Commun. 2026 Jan 15.

OCT4 enhances the firing efficiency of late DNA replication origins in mouse embryonic stem cells.

Eddie Rodriguez-Carballo, Vasilis S Dionellis, Sotirios G Ntallis, Lilia Bernasconi, Ezgi G Keskin, Thanos D Halazonetis.

DNA replication initiates at specific genomic regions known as initiation zones (IZs), which follow a defined spatiotemporal program that is partially dependent on cell type. Here, we examine the replication-initiation patterns of pluripotent mouse embryonic stem cells (mESCs), which are characterized by a very short G1 phase and rapid entry into S phase. Using EdU-seq combined with cell-cycle synchronization and Repli-seq, we identify IZs that activate during S phase in mESCs and classify them as early, mid, or late according to the replication-timing (RT) domain to which they map. Remarkably, we find that some IZs mapping to mid or late RT domains activate within 1-2 hours of entry into S phase. Chromatin and nascent-transcriptome profiling reveal that these IZs associate with regions of open chromatin structure that are bound by the pluripotency factor OCT4. Transient OCT4 depletion reduces both chromatin accessibility and replication-initiation efficiency at these sites. These results provide an example of a pioneer factor, OCT4, facilitating DNA replication initiation by promoting local chromatin accessibility.

DOI: https://doi.org/10.1038/s41467-026-68389-1
Nat Aging. 2026 Jan 16.

Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.

Takuya Kumazawa, Yanxin Xu, Yu Wang, Ji-Won Lee, Tara C O'Brien, Chia-Kang Ho, Murat Cetinbas, Aaron Weiner, Konrad Hochedlinger, Ruslan I Sadreyev, Nabeel Bardeesy, Chia-Wei Cheng, Bin He, Zhixun Dou.

Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.

DOI: https://doi.org/10.1038/s43587-025-01048-0
Cell Rep. 2026 Jan 09. pii: S2211-1247(25)01574-8. [Epub ahead of print]45(1): 116802

Sequential RNA polymerase II activation drives human hematopoiesis.

Derek H Janssens, Christine A Codomo, Dominik J Otto, Lev Silberstein, Kami Ahmad, Steve Henikoff.

  Promoter-proximal pausing of RNA polymerase II (Pol II) primes genes for rapid activation, yet how Pol II dynamics are temporally organized in adult stem cells to enable fast and flexible responses to environmental cues remain unknown. To address this, we developed sciCUT&Tag2in1 for joint profiling of Pol II and histone modifications in single cells. By profiling over 200,000 CD34+ hematopoietic stem cells (HSCs) and progenitors, we identify a Pol II regulatory cascade that directs the response to granulocyte colony-stimulating factor (G-CSF)-induced inflammatory stress. HSCs are activated by elevated Pol II occupancy and reduced Polycomb repression of immune response genes. Lineage commitment proceeds through sequential modes of Pol II activation, beginning with rapid pause-and-release genes, followed by slower initiate-and-release of Polycomb-repressed targets. sciCUT&Tag2in1 defines the temporal logic of how adult stem cells use paused Pol II to enable flexible lineage decisions, providing a powerful tool for studying the intersection of development, inflammation, and disease.

Keywords:  CP: molecular biology; CP: stem cell research; CUT&Tag; G-CSF response; RNA polymerase II; hematopoietic stem cells; inflammatory memory; lineage commitment; polycomb repression; sciCUT&Tag2in1; single-cell genomics; transcriptional pausing

DOI:  https://doi.org/10.1016/j.celrep.2025.116802
Nat Commun. 2026 Jan 12.

Integrated multi-omic atlas reveals the hierarchy of spatiotemporal regulatory networks of mouse gastrulation.

Xianfa Yang, Bingbing Xie, Penglei Shen, Yingying Chen, Chunjie Li, Fengxiang Tan, Yumeng Yang, Yun Yang, Rui Song, Panpan Mi, Zhiwen Liu, Mingzhu Wen, Patrick P L Tam, Shengbao Suo, Naihe Jing.

Spatiotemporal coordination of cellular and molecular events is crucial for cell fate commitment during mouse gastrulation. However, the high-precision mechanisms governing the timing and spatial dynamics remain poorly understood. Here, we present a time-series single-cell multi-omic dataset of the gastrulating mouse embryos and construct a hierarchical gene regulatory landscape. Integrating this with real three-dimensional transcriptomic coordinate, we created ST-MAGIC and ST-MAGIC (+) atlas, dissecting the spatiotemporal logics of regulatory networks and signaling responsiveness underpinning the lineage commitment at gastrulation. Specifically, we delineated the multi-omic basis for left-right symmetry breaking events in the gastrula and also revealed the spatiotemporal molecular relay for axial mesendoderm lineage, where early and intermediate transcription factors first open the chromatin regions and setup the responsiveness to signaling, followed by terminal factors to consolidate the transcriptomic architecture. In summary, our study presents a spatiotemporal regulatory logic framework of mouse gastrulation for advancing our understanding of mammalian embryogenesis.

DOI: https://doi.org/10.1038/s41467-026-68291-w
Nat Cell Biol. 2026 Jan 12.

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.

Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.

DOI: https://doi.org/10.1038/s41556-025-01854-z
Nat Aging. 2026 Jan 12.

Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling.

Javier Moral-Sanz, Isabel Fernández-Carrasco, Valentina Ramponi, Amanda Garrido, Izhar Karbat, Pablo Cabezas-Sainz, Esperanza Rivera-de-Torre, Osama Elsallabi, Roberto Martín-Hernández, José L López-Aceituno, Nathan L Price, Laura Sanchez, Gonzalo Colmenarejo, Álvaro Martínez-Del-Pozo, Irina Vetter, Angel Cogolludo, Francisco Perez-Vizcaino, Jorge Del-Pozo, Eitan Reuveny, Manuel A Fernández-Rojo, Paul D Robbins, Rafael de Cabo, Manuel Serrano, Maria P Ikonomopoulou.

Senescence is a driver of aging and a barrier to tumor progression, but its persistent accumulation drives inflammation and relapse. Thus, the success of chemotherapy could be jeopardized when senescence emerges in the tumor microenvironment. Here we identified the senolytic properties of a pore-forming toxin, sticholysin I (StnI). StnI and our engineered improved form, StnIG, selectively hampers viability of chemotherapy-induced senescent cancer cells, as well as senescent primary cells. We show that its selectivity is mediated by specific binding and lipid ratios associated with senescence, including compromised membrane bilayer asymmetry. Mechanistically, StnIG triggers sodium and calcium influx and an enduring potassium efflux in senescent cells. Calcium triggers the opening of calcium-activated potassium channels, leading to cell death by apoptosis and pyroptosis. Finally we show that StnIG synergizes with senescence-inducing chemotherapy to drive remission of solid tumors in mice. Our findings define StnI and StnIG as senotoxins with translational potential for cancer therapy.

DOI: https://doi.org/10.1038/s43587-025-01030-w
Aging Cell. 2026 Feb;25(2): e70374

Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2-Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging.

Sainan Zhang, Jiahui Qi, Chuanming Liu, Huidan Zhang, Bichun Guo, Die Wu, Yicen Liu, Xin Zhen, Yang Zhang, Nannan Kang, Jidong Zhou, Guijun Yan, Chaojun Li, Lijun Ding, Haixiang Sun.

  With the increasing trend of delayed childbearing, the decline in oocyte quality associated with advanced maternal age has emerged as a pressing concern. However, the mechanism remains unclear, and effective strategies for improvement are currently lacking. Previously, we reported that the downregulation of the mevalonate pathway in aged granulosa cells (GCs) contributed to meiotic defects in oocytes, which may implicate farnesyl pyrophosphate-mediated protein farnesylation. Nevertheless, the role of farnesylation in ovarian aging and its impact on oocytes requires further investigation. In this study, using cumulus-oocyte complexes (COCs) from young and aged female mice, we observed impaired cumulus expansion and concurrent meiotic defects during aged oocyte maturation, accompanied by significantly reduced protein farnesylation in aged GCs. Furthermore, inhibiting farnesylation with FTI-277 in young COCs recapitulated the aging phenotype, disrupting cumulus expansion and inducing meiotic defects similar to those in aged COCs. Conversely, restoring farnesylation via farnesol supplementation effectively ameliorated these deficits in both aged COCs (in vitro) and aged mice (in vivo). Proteomic analysis and experimental validation identified prostaglandin E2 synthase 2 (PTGES2) as a farnesylated protein. Mechanistically, age-related decline in PTGES2 farnesylation in GCs reduces its endoplasmic reticulum localization and impairs prostaglandin E2 (PGE2) production, thereby compromising PGE2-dependent cumulus expansion and oocyte maturation. Collectively, our findings highlight the detrimental effects of decreased farnesylation in aged GCs on oocyte quality and propose a potential therapeutic strategy for improving the developmental competence of aged oocytes.

Keywords:  PTGES2; cumulus expansion; farnesylation; oocyte maturation; ovarian aging

DOI:  https://doi.org/10.1111/acel.70374
Nucleic Acids Res. 2026 Jan 14. pii: gkaf1523. [Epub ahead of print]54(2):

Visualization and quantification of rDNA instabilities in mammalian cells and mouse models.

Xiaolu Zhu, Wenxia Jiang, Wei Wu, Brian J Lee, Demis Menolfi, Anthony Tubbs, Olivia M Cupo, Eli Malkovskiy, Mattie Nester, Xiaobin S Wang, Peter A Sims, Chyuan-Sheng V Lin, Lorraine Symington, Andre Nussenzweig, Brian McStay, Shan Zha.

Ribosomal DNA (rDNA) encodes the 18S, 5.8S, and 28S rRNA, accounting for ∼70% of cellular transcription. Despite its essential role and links to cancer and aging, quantifying rDNA instability in mammals remains challenging due to its repetitive organization and inherent heterogeneity. Here, we developed a murine rDNA FISH probe and genomic tools tailored for laboratory mouse strains. The results confirmed rDNA cluster locations, revealed substantial inter- and intra-strain as well as intercellular heterogeneity in rDNA organization within inbred mice and unstressed cells, and identified sources of spontaneous and replication-associated DNA double-strand breaks in the rDNA transcription termination region. Using mouse embryonic stem cells, we showed that BRCA1-mediated homologous recombination promotes rDNA instability, the non-homologous end joining factor XRCC1, but not Ku, suppresses intra-cluster deletions, and ATM kinase preserves rDNA cluster stability. Together, these findings establish a platform and tools for studying rDNA instability in animal models relevant to aging and cancer research.

DOI: https://doi.org/10.1093/nar/gkaf1523
Trends Genet. 2026 Jan 12. pii: S0168-9525(25)00292-6. [Epub ahead of print]

Gene expression noise in development: genome-wide dynamics.

Danique J C Bax, Jeske Strik, Lynn A P Schepens, Tineke L Lenstra, Maike M K Hansen, Hendrik Marks.

  Gene expression noise underlies cell-to-cell variability in RNA and protein levels of a seemingly homogeneous population of cells. Emerging evidence suggests a functional role for this variability in the specification of cell fates during mammalian development. Advances in genome-wide and single-cell technologies now enable the quantification and deciphering of transcriptome variability with increasing precision. In this review, we highlight recent insights into the significance of gene expression noise during early embryogenesis, focusing on RNA variability. We discuss new approaches to further quantify and unravel different sources of gene expression noise and how this yields insights into early mammalian development.

Keywords:  bursting dynamics; embryonic development; gene expression noise; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.tig.2025.12.001
Cell Stem Cell. 2026 Jan 13. pii: S1934-5909(25)00452-7. [Epub ahead of print]

Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness.

James Bartram, Sydney Treichel, Baobao Annie Song, Juying Xu, Devyani Sharma, Waseem Nasr, Madeline Frangiosa, Andrew Harley, Travis Nemkov, Angelo D'Alessandro, Nathan Salomonis, H Leighton Grimes, Marie-Dominique Filippi.

  Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but their self-renewal is limited. A long-standing question has been why replicative history negatively impacts HSC functions. We found that accrued divisions alter HSC production, generating low-output bone-marrow landscapes that are highly variable in lineage contribution and transcriptionally divergent within individual lineages. Division-driven HSC functional alterations arise from redirecting branched-chain amino acid (BCAA) usage from catabolic toward anabolic activity, causing faster HSC cell-cycle kinetics. Adding a BCAA transamination product overcomes the BCAA catabolic checkpoint and slows down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests the paradigm whereby replicative history causes metabolic and transcriptional drift, generating divergent HSC output. Division-dependent HSC functional drift can be restored by metabolite replacement, which has long-term therapeutic implications for HSC regenerative medicine.

Keywords:  branch chain amino acid catabolism; hematopoietic stem cells; metabolism; self-renewal

DOI:  https://doi.org/10.1016/j.stem.2025.12.018
Curr Biol. 2026 Jan 12. pii: S0960-9822(25)01626-4. [Epub ahead of print]

Mechanical states of a motor protein in the spindle.

Kevin K Do, Ian Greear, Umika S Paul, Neil Billington, Zimiao Meng, Matthew Y Wang, Rong Liu, Brenton D Hoffman, Sharyn A Endow.

  Motor proteins perform essential roles in spindle assembly and division, but little is known about the forces that motors produce in spindles. Here, we report new tension sensors designed to measure loads across a kinesin-14 motor protein that both slides and crosslinks microtubules in spindles. The new tension sensors are motors that show active motility in vitro-they also produce fluorescence in spindles that is sensitive to loads across the motor. We find that assembling and mature spindles respond differently to increased loads caused by osmotic shock and show differences in binding by the tension-sensor motors. Binding to spindles that are still forming is dominated by rapid, transient microtubule binding and unbinding and sliding interactions. By contrast, the motors bind tightly to mature spindles, crosslinking microtubules and resisting opposing forces, bearing higher loads. Tension sensors created from motor variants or mutants that bind more tightly to microtubules than wild type bear even greater loads. The higher motor loads in mature spindles greatly exceed the forces that the wild-type motor produces-this implies that the motor in mature spindles acts primarily to oppose forces from microtubule dynamics or other motors rather than producing force as a motor. Thus, our studies define mechanical states of a spindle motor that are characterized by loads and microtubule-binding interactions and dominated by microtubule sliding or crosslinking, resisting opposing forces. These findings provide a new way of thinking about how motors create tension and contribute to forces in the spindle.

Keywords:  FRET tension sensor; kinesin-14; load-bearing motor protein; microtubule crosslinking; microtubule sliding; motor force production; osmotic shock; resisting forces; spindle assembly; spindle mechanics

DOI:  https://doi.org/10.1016/j.cub.2025.12.005
Science. 2026 Jan 15. 391(6782): eady6443

Deep-learning analysis of 3D microarchitectural remodeling in hypertrophic cardiomyopathy.

Eric Q Wei, Martin Beyer, Kemar J Brown, Alexander J Bansbach, Joshua M Gorham, Barbara McDonough, Huachen Chen, Mobin Khoramjoo, Anran Zhang, Brian Bishop, Ferhaan Ahmad, Carlos Del Rio, Ching-Pin Chang, David M Ryba, Sharlene M Day, Diane Fatkin, Gavin Y Oudit, Christine E Seidman, Jonathan G Seidman.

Hypertrophic cardiomyopathy (HCM), a genetic heart disease defined by unexplained cardiac wall thickening, is a leading cause of sudden death worldwide. However, the three-dimensional organization of cardiac tissue underlying left ventricular hypertrophy remains poorly understood. We developed CaMVIA-3D, a deep-learning volumetric imaging and analysis pipeline to characterize cardiac microarchitecture. Analysis of tissues from HCM hearts revealed genotype-specific differences in cardiomyocyte volume, morphology, and extracellular volume, with pathogenic variants exhibiting greater concentric cellular hypertrophy and disarray and variant-negative cases showing predominant fibrosis. Longitudinal profiling of a pig HCM model revealed early-onset fibrosis preceding cardiomyocyte hypertrophy. Integrating transcriptomic and morphologic changes, we identified genes associated with cellular and extracellular remodeling. These findings define genotype-specific microstructural differences in HCM, offering insights to improve diagnostics and targeted therapies.

DOI: https://doi.org/10.1126/science.ady6443
Nat Struct Mol Biol. 2026 Jan 13.

Interplay between cohesin and RNA polymerase II in regulating chromatin interactions and gene transcription.

Minji Kim, Ping Wang, Patricia A Clow, Eli Chien, Xiaotao Wang, Jianhao Peng, Haoxi Chai, Xiyuan Liu, Byoungkoo Lee, Chew Yee Ngan, Olgica Milenkovic, Jeffrey H Chuang, Chia-Lin Wei, Rafael Casellas, Albert W Cheng, Yijun Ruan.

Cohesin is required for chromatin loop formation. However, its precise role in regulating gene transcription remains largely debated. Here we investigated the relationship between cohesin and RNA polymerase II (RNAPII) using single-molecule mapping and live-cell imaging methods in human cells. Cohesin-mediated transcriptional loops were highly correlated with those of RNA polymerase II and followed the direction of gene transcription. Depleting RAD21, a subunit of cohesin, resulted in the loss of long-range (>100 kb) loops between distal (super-)enhancers and promoters of cell-type-specific downregulated genes. By contrast, short-range (<50 kb) loops were insensitive to RAD21 depletion and connected genes that are mostly constitutively expressed. This result explains why only a small fraction of genes are affected by the loss of long-range chromatin interactions in cohesin-depleted cells. Remarkably, RAD21 depletion appeared to upregulate genes that were involved in initiating DNA replication and disrupted DNA replication timing. Our results elucidate the multifaceted roles of cohesin in establishing transcriptional loops, preserving long-range chromatin interactions for cell-specific genes and maintaining timely DNA replication.

DOI: https://doi.org/10.1038/s41594-025-01708-0
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2526249123

The intrinsic impact of mechanical stress on the maintenance of oocyte dormancy.

Go Nagamatsu, Kenjiro Shirane, Yuzuru Kato, Hiroko Nakamura, Norio Hamada, Kiyoko Kato, Hiroshi Kimura, Katsuhiko Hayashi.

  In the mammalian ovary, most oocytes remain dormant, and their dormant status plays a central role in maintaining the reservoir population of the female germ line. The equilibrium between the dormant and active states, the latter of which is responsible for producing mature oocytes, is therefore crucial for ensuring the sustained reproductive capability of females. We have previously reported that mechanical stress in the ovary plays a crucial role in oocyte dormancy. However, the mechanism underlying this relation remains unclear. Here, we demonstrated that the mechanical stress is directly transduced into the oocytes, rather than to the surrounding granulosa cells. Culture experiments and live-imaging analysis revealed the nuclear localization of FOXO3, a hallmark of oocyte dormancy, within oocytes cultured alone in response to mechanical stress. Interestingly, we found that the cytological response to mechanical stress was accompanied by ligand-independent internalization of the c-kit receptor, which dampens intracellular signaling and prevents oocyte activation. These results shed light on the relation between mechanical stress and oocyte dormancy and provide clues toward a greater understanding of female reproductive capability.

Keywords:  FOXO3; oocyte; ovary

DOI:  https://doi.org/10.1073/pnas.2526249123
Nature. 2026 Jan 14.

CFAP20 salvages arrested RNAPII from the path of co-directional replisomes.

Sidrit Uruci, Daphne E C Boer, Paul W Chrystal, Maxime Lalonde, Andreas Panagopoulos, George Yakoub, Idil Kirdök, Klaas de Lint, Melanie van der Woude, Tiemen J Wendel, Sem J Brussee, Annelotte P Wondergem, Nila K van Overbeek, Nini Schotman, Jolanthe Lingeman, Mats Ljungman, Alexander van Oudenaarden, Haico van Attikum, Alfred C O Vertegaal, Sylvie M Noordermeer, Rob M F Wolthuis, Matthias Altmeyer, Stephan Hamperl, Vincent Tropepe, Jeroen van den Berg, Diana van den Heuvel, Martijn S Luijsterburg.

Fine-tuning DNA replication and transcription is crucial to prevent collisions between their machineries1. This is particularly important near promoters, where RNA polymerase II (RNAPII) initiates transcription and frequently arrests, forming R-loops2-4. Arrested RNAPII can obstruct DNA replication, which often initiates near promoters5,6. The mechanisms that rescue arrested RNAPII during elongation to avoid conflicts with co-directional replisomes remain unclear. Here, using genome-wide approaches and genetic screens, we identify CFAP20 as part of a protective pathway that salvages arrested RNAPII in promoter-proximal regions, diverting it from the path of co-directional replisomes. CFAP20-deficient cells accumulate R-loops near promoters, which leads to defects in replication timing and dynamics. These defects stem from accelerated replication-fork speeds that cause a secondary reduction in origin activity. Co-depletion of the Mediator complex or removal of R-loop-engaged RNAPII restores normal replication. Our findings suggest that transcription-dependent fork stalling in cis induces accelerated fork progression in trans, generating single-stranded DNA gaps. We propose that CFAP20 facilitates RNAPII elongation under high levels of Mediator-driven transcription, thereby preventing replisome collisions. This study provides a transcription-centred view of transcription-replication encounters, revealing how locally arrested transcription complexes propagate genome-wide replication phenotypes and defining CFAP20 as a key factor that safeguards genome stability.

DOI: https://doi.org/10.1038/s41586-025-09943-7
Mol Cell. 2026 Jan 09. pii: S1097-2765(25)01019-6. [Epub ahead of print]

A mouse circadian proteome atlas.

Yuta Otobe, Norie Deki-Arima, Shao Xinyan, Kazuma Itabashi, Nobuhiro Kurabayashi, Utaro Nakamura, Anna Uchida, Ryutaro Shimazaki, Kaneyoshi Yamamoto, Takeshi Sakurai, Ying-Hui Fu, Louis J Ptáček, Arisa Hirano, Masao Doi, Hikari Yoshitane.

  The circadian clock drives daily rhythms of gene expression and physiology. Advances in next-generation DNA sequencing have provided extensive insights into RNA expression, but more functional information at the protein level with sufficient depth has been limited by technical challenges. In this study, we generated a comprehensive mouse circadian proteome atlas (https://chronoproteinology.org/circadian_atlas) by analyzing 32 tissues, including the suprachiasmatic nucleus (SCN), using the next-generation mass spectrometer Orbitrap Astral. Data-independent acquisition of 584 samples, including developmental samples, revealed the spatiotemporal profiles of about 19,000 proteins. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver revealed circadian changes in protein quantity and quality, as well as global changes in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.

Keywords:  circadian clock; circadian rhythm; mass spectrometry; nuclear localization; phosphorylation; proteome analysis

DOI:  https://doi.org/10.1016/j.molcel.2025.12.020
Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01626-2. [Epub ahead of print]45(1): 116854

Lactylation-driven nuclear RIG-I promoted by lactate transporter inhibitor suppresses DNA damage repair through inhibiting PARP1 activity.

Yulin Li, Chao Wang, Siru Zhou, Yuxin Shi, Dongyue Zhu, Xiaofeng Zheng.

  RIG-I (DDX58) is typically localized in the cytoplasm and activates innate immunity. However, the mechanisms governing its nuclear translocation and functions remain incompletely understood. Here, we discover that RIG-I undergoes lactylation, which is mediated by the acetyltransferase PCAF. Treatment with the lactate transporter inhibitor syrosingopine blocks the efflux of lactate from cancer cells, increasing intracellular lactate concentration, promoting RIG-I lactylation, and enhancing the nuclear translocation of lactylated RIG-I in an importin 8-dependent manner. The nuclear-localized RIG-I interacts with PARP1 and attenuates its activity, thereby inhibiting DNA damage repair. Moreover, we find that low RIG-I expression is associated with unfavorable prognosis and survival in lung adenocarcinoma (LUAD). Syrosingopine treatment sensitizes LUAD cells to PARP inhibitor (PARPi) and potentiates the therapeutic efficacy of olaparib in a mouse LUAD model. Altogether, our study reveals that lactylation drives RIG-I nuclear function to inhibit DNA damage repair via PARP suppression. This supports the potential co-administration of syrosingopine and PARPi for LUAD treatment.

Keywords:  CP: molecular biology; DNA damage response; PARP1; PARylation; RIG-I; lactylation; lung adenocarcinoma; syrosingopine

DOI:  https://doi.org/10.1016/j.celrep.2025.116854
Cardiovasc Res. 2026 Jan 12. pii: cvaf256. [Epub ahead of print]

Temporal inhibition of ADAM17 in fibroblasts reduces stiffness and promotes vascularization following myocardial infarction.

Yingxi Li, Razoan Al Rimon, Faqi Wang, Haoyang Li, Slava Epelman, Michelle D Tallquist, Lindsey Westover, Gavin Y Oudit, Zamaneh Kassiri.

   AIMS: Myocardial infarction (MI) triggers a complex remodeling that, if uncontrolled, leads to heart failure. Increased levels of ADAM17 (disintegrin and metalloproteinase-17) in ischemic injury has been reported, but its direct role in scar formation and subsequent recovery from MI has not been identified. We investigated the role of ADAM17 in the function of homeostatic fibroblasts (FBs) vs. activated myofibroblasts (myoFBs) in scar formation, and recovery following MI.
METHODS AND RESULTS: Human myocardial specimens showed upregulated ADAM17 in the infarct tissue, colocalized to myofibroblasts. We generated two inducible genetic mouse models with Adam17 knockdown in FBs (Adam17FB-KD) or myoFB (Adam17myoFB-KD) and subjected them to MI. Loss of ADAM17 in FBs impaired infarct formation and increased mortality due to left ventricular (LV) rupture in males and females. In contrast, ADAM17 loss in myoFBs limited infarct expansion, LV dilation and dysfunction up to 4-wks post-MI. Macrophage infiltration was suppressed in both genotypes. Ex vivo and in vitro experiments revealed that loss of ADAM17 in myoFB resulted in scar tissue with reduced stiffness due to suppressed activation of epidermal growth factor receptor and the Yes-associated protein (YAP) pathway. This promoted VEGFR signaling, endothelial cell (EC) proliferation, and vascularization in the infarcted myocardium, limiting infarct expansion. RNAseq analyses showed drastic changes in extracellular matrix (ECM) genes in Adam17KD FB and myoFBs in hypoxia. In vitro co-culture of myoFB and ECs confirmed that the ECM deposited by Adam17-deficient myoFB promotes EC proliferation and sprouting. Pharmacological inhibition of ADAM17 before MI was ineffective, but short-term ADAM17 inhibition after MI (targeting the myoFBs), limited infarct expansion, LV dilation and dysfunction up to 4-weeks post-MI.
CONCLUSION: Short-term inhibition of ADAM17 after MI optimizes the compliance of the infarct tissue, promoting vascularization, limiting infarct expansion, preventing long-term adverse LV remodeling, dysfunction, and heart failure. Targeting the homeostatic FB vs. myoFB also highlights the critical timing of ADAM17 inhibition as its presence is essential for the initial healing of the infarcted heart, but inhibition of its persistent upregulation reduces scar stiffness and improves the outcome post-MI.

Keywords:  ADAM17; Fibrosis; Myocardial infarction; Myofibroblast

DOI:  https://doi.org/10.1093/cvr/cvaf256
Development. 2026 Jan 12. pii: dev.205459. [Epub ahead of print]

Endogenous FGFs drive ERK-dependent cell fate patterning in 2D human gastruloids.

Kyoung Jo, Zong-Yuan Liu, Gauri Patel, Zhiyuan Yu, LiAng Yao, Seth Teague, Craig Johnson, Jason Spence, Idse Heemskerk.

  The role of FGF is the least understood of the morphogens driving mammalian gastrulation. Here we investigated FGF function in a 2D gastruloid model for human gastrulation. We observed a ring of FGF-dependent ERK activity that closely follows the emergence of primitive streak (PS)-like cells but expands further inward. This ERK activity pattern depends on localized activation of basolateral FGF receptor 1 (FGFR1) by endogenous FGF gradients and is required for PS-like differentiation, with loss of PS-like cells upon FGF receptor inhibition rescued by direct ERK activation. Single cell transcriptome analysis confirmed that among the ligands, FGF2 is broadly expressed, FGF8 is transiently expressed during PS-like differentiation, and FGF4/17 are specifically expressed in PS-like cells - similar to the human and monkey embryo but different from the mouse. FGF4 knockdown greatly reduced PS-like differentiation, while FGF17 knockdown primarily affected subsequent mesoderm differentiation. FGF8 expression was spatially and temporally displaced from PS-markers and FGF4 expression, while knockdown expanded PS-like cells, suggesting FGF8 may limit PS-like differentiation. Thus, we have identified a novel role for FGF-dependent ERK signaling in 2D gastruloids and possibly the human embryo, where FGF4 and FGF17 signal through basalateral FGFR1 to induce PS-like cells and derivatives, potentially restricted by FGF8.

Keywords:  ERK signaling; FGF (fibroblast growth factor); Human gastrulation

DOI:  https://doi.org/10.1242/dev.205459
Nature. 2026 Jan 14.

Polyamine-dependent metabolic shielding regulates alternative splicing.

Amaia Zabala-Letona, Mikel Pujana-Vaquerizo, Belen Martinez-Laosa, Maria Ponce-Rodriguez, Saioa Garcia-Longarte, Isabel Mendizabal, Ana Gimeno, Malgorzata Rogalska, Joycelyn Tan, Diana Cabrera, Sebastiaan van Liempd, Pilar Ximenez-Embun, Sergio Espinosa, Maider Fagoaga-Eugui, Francesca Peccati, Maciej Zakrzewski, Ianire Astobiza, Mikel Arana-Castañares, Sarah Cherkaoui, Maria Sendino, Inés Martín-Barros, Amaia Ercilla, Laura Bozal-Basterra, Onintza Carlevaris, Amaia Arruabarrena-Aristorena, Encarnación Pérez-Andrés, Telmo Santamaría-Zamorano, Juan A Ferrer-Bonsoms, Fernando Carazo, Maciej Cieśla, Cesar Lobato, Joan Seoane, Natalia Martín-Martín, Rosa Barrio, James D Sutherland, Ana M Aransay, Juan Manuel Falcón-Pérez, Barbara Martínez-Pastor, Angel Rubio, Francisco J Blanco, Michael D Hogarty, Raphael J Morscher, Edurne Berra, Remigiusz A Serwa, Jesús Jiménez-Barbero, Gonzalo Jiménez-Osés, Alejo Efeyan, Lydia Finley, Jose M Lizcano, Javier Muñoz, Juan Valcarcel, Arkaitz Carracedo.

Metabolites are central to cellular homeostasis. Although much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signalling molecules. Here we show that polyamines, small polycations that are critical to cellular homeostasis1-3, regulate the process of alternative pre-mRNA splicing. We find that inhibition of polyamine synthesis increases phosphorylation of spliceosomal proteins, concomitant with perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modelling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 small nuclear ribonucleoprotein SF3 subcomplex, thus preventing the action of upstream kinases. We refer to this molecular process by which polyamines regulate protein phosphorylation as metabolic shielding.

DOI: https://doi.org/10.1038/s41586-025-09965-1
Nat Biomed Eng. 2026 Jan 14.

Intermittent hypobaric pressure induces selective senescent cell death and alleviates age-related osteoporosis.

Bowen Meng, Yan Qu, Benyi Yang, Chaoran Fu, Yifan He, Jing Li, Rentao Wan, Xin Li, Zhulin Xue, Zeyuan Cao, Meng Hao, Xiao Zhang, Zhe An, Fen Chen, Ruibao Ren, Xueli Mao, Yang Cao, Songtao Shi.

Senescent cell accumulation contributes to aging, and their clearance represents an effective anti-aging strategy. Current senolytic strategies focus on drug-mediated senescent cell clearance, but it is unknown whether a hypobaric condition can induce senescent cell death. Here we show that hypobaric pressure (HP) at -375 mmHg without hypoxia induces cells to undergo lysosome-dependent cell death (LDCD). Mechanistically, we unveil that HP activates transmembrane protein 59 (TMEM59) to induce cellular Ca2+ influx, which triggers calpain 2 to cleave lysosomal associated membrane protein 2 (LAMP2), leading to lysosomal membrane permeabilization and subsequent LDCD. Furthermore, given that senescent cells contain elevated numbers of lysosomes, we report intermittent HP treatment to specifically induce senescent cells to undergo LDCD and reduce the senescence-associated secretory phenotype. Eventually, we report that intermittent HP treatment can substantially extend the lifespan and rescue the osteoporosis phenotype in aged mice. This study reveals a previously unknown role of HP as a natural senolytic to eliminate senescent cells, and identifies TMEM59 as a new HP-activated ion channel protein.

DOI: https://doi.org/10.1038/s41551-025-01584-5
Cell Metab. 2026 Jan 12. pii: S1550-4131(25)00545-5. [Epub ahead of print]

Mitochondrial transfer from immune to tumor cells enables lymph node metastasis.

Azusa Terasaki, Keshav Bhatnagar, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Han-Li Huang, Lukas Wiggers, Viviana Rodrigues, Cara C Rada, Vishnu Shankar, Suguru Saito, Peter Ofori Ankomah, Theodore Roth, Bill Chiu, Robert West, Lingyin Li, Nathan Reticker-Flynn, Jeffrey D Axelrod, Jonathan R Brestoff, Bo Li, Edgar Engleman, Derick Okwan-Duodu.

  Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood. Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells. In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs. Blocking mitochondrial transfer machinery-including cGAS, STING, or type I interferon-reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization.

Keywords:  MERCI; cGAS/STING; immune evasion; lymph node cancer metastasis; mitochondrial transfer

DOI:  https://doi.org/10.1016/j.cmet.2025.12.014