bims-ginsta 2026-04-12 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–04–12
forty-two papers selected by
Jinrong Hu, National University of Singapore

Edge-vertex flow enables rapid adhesion reinforcement under tension.
Global stabilization of the transcriptome in mitotic cells.
Maternal IntS11 primes embryonic totipotency by organizing early zygotic transcription initiation.
BRCA2-dependent maturation of nascent strands during DNA replication.
NFYA regulates two sequential genome-wide transcriptional activation events during oocyte to embryo transition.
Boundary-guided cell alignment drives mouse epiblast maturation.
Hyaluronic acid and tissue mechanics orchestrate mammalian digit tip regeneration.
The H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation.
RNA polymerase II drives FUS and EWSR1 exclusion from damaged chromatin.
Regulation of DNA replication and 3D genome organization during early embryogenesis.
Asymmetric branched F-actin networks at apical clathrin coated pits support microvillar biogenesis.
Multiomics and deep learning dissect regulatory syntax in human development.
Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration.
The DNA damage response pathway is required for multiciliated cell differentiation.
Cell loss disrupts mechanical homeostasis to drive retinal pigment epithelium ageing-like phenotype in vitro.
Ferroptosis as an approach to leverage cancer metabolism.
Niche-dependent modular regulation of the stem cell transcriptome separates cell identity and potential.
Wnt-dependent Frizzled clustering is required for Dishevelled phosphorylation but insufficient for β-catenin stabilization.
An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease.
Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.
Systematic profiling of cytosolic membraneless organelles reveals enrichment of oncogenic mRNA upon oxidative stress.
Histone acetylation-dependent clustering of BRD2 instructs transcription dynamics.
Charged molecular glue discovery enabled by targeted degron display.
Spastin-mediated severing of glutamylated microtubules controls cardiomyocyte coupling.
PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.
PGC-derived migrasomes couple PGC proliferation with migration.
Haplotype-resolved centromeric chromatin organization from a complete diploid human genome.
Comparative single-cell atlases reveal injury-driven tubal epithelial regeneration as a window for ovarian carcinoma initiation.
Human cGAS Drives LINE-1 Transcriptional Activation to Trigger MAVS-Dependent Cellular Senescence.
Single-cell spatiotemporal dissection of the human maternal-fetal interface.
The molecular basis of tricalbin-mediated membrane contact site organization in cells.
Multivalent 28S rRNA expansion segments enable reconstitution of multilayered nucleolar architecture.
Translation in proximity to forming autophagosomes during sustained autophagy.
Engineered immunosuppressive dendritic cells protect against cardiac remodelling.
Microtubules in the axon are GDP bound but adopt a stable GTP-like expanded state.
Spatial inhibition of RhoA by RhoGAP15B promotes protrusive activity during collective migration.
Mapping the mammalian dark metabolome by in vivo isotope tracing.
Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF.
Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.
Fetal-restricted hematopoietic progenitors arise from hemogenic endothelium in vitelline and umbilical arteries.
Ring canals in the larval adipose of Drosophila buffer stress response.
Recruitment of Mre11 to recombination sites during meiosis.

J Cell Biol. 2026 Jun 01. pii: e202601182. [Epub ahead of print]225(6):

Edge-vertex flow enables rapid adhesion reinforcement under tension.

Qi-Hong Zheng, Chengge Zhang, Ming-Xin Wang, Xiaoxiang Xiang, Shaohong Zhang, Yaru Wang, Huapeng H Yu.

A general mechanism to maintain epithelial integrity during tissue movements is to couple adhesion strength with mechanical force. Mechanosensitive proteins are recruited to cell-cell contacts to reinforce membrane-cortex linkage in response to elevated tension. However, how protein recruitment achieves necessary speed and precision to match the instant nature of force remains unknown. Here we identify a direct "edge-to-vertex" transport mechanism that couples the flow of the adhesion protein Canoe/Afadin to pulsatile actomyosin dynamics, ensuring that adhesion is reinforced precisely where and when force is applied. Genetically, this mechanosensitive transport is gated by kinase-independent activities of Mbt/PAK. In its absence, Canoe/Afadin forms aberrant elliptical condensates at cell edges, becoming unresponsive to mechanical cues. Remarkably, these condensates are dissolved by a simple, physiological increase in temperature, which restores directional protein flow and rescues adhesion-bypassing the genetic requirement of Mbt/PAK. Lastly, we demonstrate that transport efficiency is governed by cortical mobility threshold, fine-tuned through Canoe/Afadin condensation. These results identify a force-coupled transport strategy to ensure adhesion-tension coupling with spatial and temporal precision in living tissues.

DOI: https://doi.org/10.1083/jcb.202601182
EMBO J. 2026 Apr 09.

Global stabilization of the transcriptome in mitotic cells.

Ekaterina Khalizeva, Arash Latifkar, Kehui Xiang, David P Bartel, Jimmy Ly, Iain M Cheeseman.

  In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique aspects of mitosis require substantial adaptations to gene expression. During interphase, homeostatic control of mRNA levels involves a constant balance of transcription and degradation, with a median mRNA half-life of ~2-4 h. If such short half-lives persisted in mitosis, cells would be expected to rapidly deplete their transcriptome without new transcription. Here, we report that the transcriptome is globally stabilized during prolonged mitotic delays. Median mRNA half-lives are increased >4-fold during mitotic arrest compared to interphase, buffering mRNA levels in the absence of new synthesis. Moreover, poly(A) tail-length profiles change during mitotic arrest, strongly suggesting a partial mitotic repression of deadenylation. In contrast, siRNA-directed mRNA degradation machinery remains active. We further show that mitotic mRNA stabilization depends on PABPC1&4. Depletion of PABPC1&4 during mitotic arrest reduces mRNA stability and disrupts the cells' ability to maintain arrest, highlighting the critical physiological role of mitotic transcriptome buffering.

Keywords:  Deadenylation; Gene Regulation; Mitosis; mRNA Stability

DOI:  https://doi.org/10.1038/s44318-026-00765-5
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2531899123

Maternal IntS11 primes embryonic totipotency by organizing early zygotic transcription initiation.

Liangliang Wang, Yiru Wang, Yaqi Miao, Yuan Song, Jialiang Zhou, Yuanxiang Zhu, Ying Cheng, Wenxin Zhang, Qinmiao Sun, Fan Lai, Guoqiang Zhang, Dahua Chen.

  Zygotic genome activation (ZGA) marks the first transcriptional milestone and establishes embryonic totipotency. Although pioneer factors have been reported to initiate this process, how chromatin is primed for the totipotent state, allowing the binding of pioneer factors for successful ZGA, remains unclear. Here, we identify IntS11, the catalytic subunit of the Integrator complex, as a totipotent determinant of embryonic chromatin governing ZGA in Drosophila. We show that IntS11 functions upstream of pioneer factors in early embryos: Maternal IntS11 depletion substantially impairs RNA polymerase II (Pol II) recruitment, thereby preventing pioneer factors Zelda and GAGA factor (GAF) from accessing regulatory elements and initiating genome-wide zygotic transcription. Mechanistically, IntS11 exerts dual roles: its canonical endonuclease activity is required to sustain major-wave zygotic transcription, while a distinct enzyme-independent function drives de novo Pol II loading and pioneer factor engagement. These findings uncover a fundamental maternal-specific mechanism whereby IntS11 establishes transcriptional competence, ensuring totipotent chromatin states and successful ZGA.

Keywords:  Drosophila; Integrator complex; early embryo; zygotic genome activation

DOI:  https://doi.org/10.1073/pnas.2531899123
Mol Cell. 2026 Apr 03. pii: S1097-2765(26)00168-1. [Epub ahead of print]

BRCA2-dependent maturation of nascent strands during DNA replication.

Larissa Milano, Sophie Wells, Alina Vaitsiankova, Lylah Drummond-Clarke, Xiaoxuan Zhu, Aura Carreira, Masato T Kanemaki, Keith W Caldecott.

  A major source of poly(ADP-ribose) polymerase (PARP) activity in proliferating cells is unligated Okazaki fragments. Consequently, the anti-cancer PARP inhibitor olaparib impedes the maturation of nascent DNA strand fragments during DNA replication. Here, we show that wild-type human cells overcome this impediment by triggering a process that facilitates nascent strand maturation in the presence of olaparib. We show that this process operates on very large nascent strand fragments and repairs thousands of olaparib-induced DNA single-strand breaks/gaps per genome. Critically, this process is dependent on the tumor suppressors BRCA1 and BRCA2 and is associated with the BRCA2-dependent accumulation of RAD51 recombinase in chromatin. Our data identify nascent strand gaps that are induced by olaparib independently of replication fork reversal and/or PRIMPOL-mediated repriming and that are repaired by a BRCA2-dependent process that we propose is daughter-strand gap protection and/or repair occurring hundreds of kilobases behind DNA replication forks.

Keywords:  BRCA1; BRCA2; DNA replication; Okazaki fragment; PARP1; RAD51; gap protection; gap repair; homologous recombination; single-strand gaps

DOI:  https://doi.org/10.1016/j.molcel.2026.03.012
bioRxiv. 2026 Apr 01. pii: 2026.03.30.715371. [Epub ahead of print]

NFYA regulates two sequential genome-wide transcriptional activation events during oocyte to embryo transition.

Qianying Yang, Shan Jiang, Boyan Wang, Yi Zhang.

Primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA) represent two major waves of transcription activation respectively required for oocyte growth and preimplantation embryo development. Although many shared molecular hallmarks between PFA and ZGA suggest potential common factors and mechanisms driving both waves of transcriptional activation, such factors are yet to be identified. Here we demonstrate that the pioneer factor NFYA belongs to such regulators. Oocyte-specific Nfya deletion impairs open chromatin establishment and transcriptional activation during PFA, which triggers non-canonical ferroptosis leading to early folliculogenesis failure. Moreover, acute NFYA depletion in zygotes causes defective ZGA and predominantly two-cell embryo arrest. Mechanistically, although NFYA exhibits distinct chromatin-binding preferences predominantly targeting promoters during PFA and enhancers during ZGA, pre-occupied NFYA regulates chaperones and histone genes in both PFA and ZGA through conserved promoter binding. Together, our studies establish NFYA as a multifaceted regulator of genome activation during both PFA and ZGA.
Highlights: NFYA deficiency impairs primordial follicle oocyte activation (PFA) and triggers non-canonical ferroptosis resulting in early folliculogenesis failureNFYA depletion impairs zygotic genome activation (ZGA) and causes predominantly 2-cell embryo arrestConserved and distinct NFYA-chromatin interactions drive both PFA and ZGAChaperones are pre-occupied and regulated by NFYA and their inhibition impairs both PFA and ZGA.

DOI: https://doi.org/10.64898/2026.03.30.715371
Nat Phys. 2026 ;22(3): 461-473

Boundary-guided cell alignment drives mouse epiblast maturation.

Takafumi Ichikawa, Pamela C Guruciaga, Shuchang Hu, Steffen Plunder, Mei Makino, Marina Hamaji, Anniek Stokkermans, Shinjiro Yoshida, Takashi Hiiragi, Anna Erzberger.

  Symmetry breaking and pattern formation occur throughout embryonic development. In early mouse development, a mass of non-polarized epiblast cells in the blastocyst forms the egg cylinder, while cells become apico-basally polarized and build a radial configuration. However, it remains unclear what drives the formation of this tissue architecture. Here we demonstrate that the orientational patterning of epiblast cells is dictated by heterogeneous tissue boundaries, which then defines central lumen positioning. We show that epiblast cells progressively orient perpendicular to the visceral endoderm boundary-which is enriched with the basement membrane protein laminin and the cell surface receptor active integrin β1-but parallel to the extraembryonic ectoderm interface. These orientation dynamics are consistent with general boundary-induced alignment effects in polar materials, with a topological defect predicting the position at which the proamniotic cavity nucleates. The knockout of laminin γ1 and integrin β1 confirms the essential role of adhesion at the epiblast and visceral endoderm boundary. The established epiblast pattern, in turn, facilitates ERK activation-a key cell signalling pathway-to ensure proper epiblast maturation. Together, these findings present the mechanistic basis and functional significance of epiblast tissue patterning.

Keywords:  Biological physics; Biophysics

DOI:  https://doi.org/10.1038/s41567-026-03176-9
Science. 2026 Apr 09. 392(6794): eady3136

Hyaluronic acid and tissue mechanics orchestrate mammalian digit tip regeneration.

Byron W H Mui, Joseph J Y Wong, Camille E Dumas, Jia Hua Wang, Toni Bray, Kentaro Hirose, Lauren Connolly, Alexander Winkel, Sebastian Timmler, Nicholas A Bright, Evelina Sliauteryte, Ragnhildur Thóra Káradóttir, Pamela G Robey, Kristian Franze, Kevin J Chalut, Mekayla A Storer.

Tissue regeneration is rare in mammals, but the digit tip can regrow after amputation, whereas injuries beyond the nail do not. How the microenvironment drives divergent outcomes remains unclear. In this study, we found that the extracellular matrix (ECM) and tissue mechanics govern the amputation response in mouse digits. Nonregenerative regions were stiffer and contained dense, organized collagen, whereas regenerative regions were soft and enriched in hyaluronic acid (HA). Depleting HA inhibited regeneration and promoted fibrosis, demonstrating that the HA-collagen balance shaped tissue mechanics and repair signaling. Stabilization of HA with hyaluronan and proteoglycan link protein 1 (HAPLN1) after nonregenerative amputations tuned ECM mechanics, reduced scarring, and enhanced bone repair. Thus, ECM composition and mechanics influence cell behavior and ECM-targeted strategies could help unlock mammalian regeneration.

DOI: https://doi.org/10.1126/science.ady3136
EMBO J. 2026 Apr 10.

The H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation.

Christina Ambrosi, Ramon Pfaendler, Kristeli Eleftheriou, Stefan Butz, Davide Recchia, Xue Bao, Richard Cardoso da Silva, Niklas Kupfer, Ilse M Lagerwaard, Hanneke Vlaming, Nina Schmolka, Vivek Bhardwaj, Tuncay Baubec.

  Chromatin modifications are essential for mammalian development, and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove histone modifications have been largely elucidated, their roles in regulating gene activity during cellular differentiation are yet to be fully understood. Here, we performed a deletion screen to identify stage-specific requirements of chromatin regulators during neuronal differentiation of mouse embryonic stem cells. We show that the H3K36me3 methyltransferase SETD2 is required for the establishment of neuronal gene expression during late stages of differentiation but is dispensable in mature neurons. Notably, this function is independent of its histone methyltransferase activity. Instead, SETD2 promotes interactions between the PAF1 complex and elongating RNA Pol II, suggesting a role in supporting efficient transcription of neuronal genes.

Keywords:  Chromatin; H3K36me3; SETD2

DOI:  https://doi.org/10.1038/s44318-026-00768-2
Cell Rep. 2026 Apr 08. pii: S2211-1247(26)00314-1. [Epub ahead of print]45(4): 117236

RNA polymerase II drives FUS and EWSR1 exclusion from damaged chromatin.

Sylvia Varhoshkova, Christopher Chin Sang, Liana Antonova, Sonya Uzunova, Dilyana Kirova, Radoslav Aleksandrov, Masato T Kanemaki, Hyun O Lee, Stoyno Stoynov.

  FUS and EWSR1 are RNA-binding proteins that accumulate at DNA lesions in a poly(ADP-ribose)-dependent manner. Notably, upon foci formation, both proteins are gradually excluded from sites of complex DNA damage, yet the mechanism and significance of this exclusion remain unclear. Here, we show that inhibition of the transcription-associated cyclin-dependent kinases CDK7, CDK9, and CDK12/13, or degron-mediated depletion of RPB1, the catalytic subunit of RNA polymerase II, prevents the exclusion of FUS and EWSR1. RPB1 itself is also excluded from sites of DNA damage with kinetics similar to those of FUS. Furthermore, we demonstrate that CDK7 inhibition leads to reduced 53BP1 accumulation at DNA lesions in vivo. Our findings clarify a mechanism by which RPB1 and FUS/EWSR1 are excluded from damaged chromatin and highlight its importance in DNA repair coordination.

Keywords:  53BP1; CDKs; CP: molecular biology; DNA repair; EWSR1; FET proteins; FUS; RNAPII; complex DNA lesions; exclusion; live-cell imaging

DOI:  https://doi.org/10.1016/j.celrep.2026.117236
Curr Opin Genet Dev. 2026 Apr 08. pii: S0959-437X(26)00036-5. [Epub ahead of print]98 102469

Regulation of DNA replication and 3D genome organization during early embryogenesis.

Ichiro Hiratani.

Three-dimensional (3D) genome organization underlies virtually all DNA-based transactions. To fully appreciate its functional impact, we must first elucidate how it is established. DNA replication in early embryos offers a unique window into this process, as replication timing (RT) closely mirrors 3D genome architecture, which is absent at fertilization but progressively acquired during development. Here, recent single-cell studies of mouse embryos are synthesized, with a particular focus on how RT emerges during early post-fertilization development. The emerging picture suggests that a somatic-cell-like RT program arises shortly after zygotic genome activation (ZGA). This transition likely unfolds as a series of events, offering a valuable entry point for exploring the biological significance of 3D genome organization and understanding how diverse DNA-based processes are coordinated.

DOI: https://doi.org/10.1016/j.gde.2026.102469
Mol Biol Cell. 2026 Apr 08. mbcE25120606

Asymmetric branched F-actin networks at apical clathrin coated pits support microvillar biogenesis.

Olivia Perkins, Malcom Díaz García, Matthew J Tyska.

Microvilli are conserved actin-based protrusions that expand surface area and absorptive capacity in epithelial tissues. In humans, the intestinal tract grows three-hundred trillion microvilli per day, yet the molecular mechanisms defining where and when microvilli grow remain unclear. Using a combination of live-cell confocal and super-resolution N-SPARC microscopy to investigate native intestinal tissues and epithelial cell culture models, we found that microvilli grow from Arp2/3-generated branched actin networks that form on the surface of clathrin coated pits. These transient networks are stabilized by cortactin and localize to the apical plasma membrane minutes before reorganizing into the linear core actin bundles that support microvilli. Moreover, subpixel precision localization of coated pit and microvilli markers revealed that F-actin asymmetrically localizes to one side of a nascent clathrin coated pit, and that microvilli grow from the side with the highest F-actin density. These findings support a model where the asymmetric accumulation of F-actin and growing barbed ends on the surface of a clathrin coated pit offer a filament source to support microvilli formation. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-12-0606
Nature. 2026 Apr 08.

Multiomics and deep learning dissect regulatory syntax in human development.

Betty B Liu, Selin Jessa, Samuel H Kim, Yan Ting Ng, Soon Il Higashino, Georgi K Marinov, Derek C Chen, Benjamin E Parks, Li Li, Tri C Nguyen, Austin T Wang, Sean K Wang, Meng How Tan, Serena Y Tan, Michael Kosicki, Len A Pennacchio, Eyal Ben-David, Anca M Pasca, Anshul Kundaje, Kyle K H Farh, William J Greenleaf.

Transcription factors establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility and regulating gene expression1. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs or single modalities2. Here we present the Human Development Multiomic Atlas, a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and more than 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs that influence accessibility, including composite motifs exhibiting distinct syntactic constraints that are predicted to mediate transcription factor cooperativity. We identify 'hard' syntactic rules requiring precise motif spacing and orientation, 'soft' rules allowing flexible motif arrangements, and ubiquitous motifs inhibiting accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell-type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.

DOI: https://doi.org/10.1038/s41586-026-10326-9
Science. 2026 Apr 09. 392(6794): eadw8526

Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration.

Georgios Tsissios, Marion Leleu, Kelly Hu, Alp Eren Demirtas, Hanrong Hu, Sabrina Vinzens, Toru Kawanishi, Evangelia Skoufa, Atharva Valanju, Alessandro Valente, Lorenzo Noseda, Haruki Ochi, Antonio Herrera, Selman Sakar, Mikiko Tanaka, Sara A Wickström, Fides Zenk, Can Aztekin.

Why mammals cannot regenerate limbs like amphibians do presents a long-standing puzzle in biology. To uncover the underlying differences, we compared amputation responses of embryonic mouse (Mus musculus) and Xenopus laevis tadpole limbs. Lowering environmental oxygen or stabilizing the oxygen-sensitive hypoxia-inducible factor 1A (HIF1A) induced rapid wound healing in mouse limbs. This response was accompanied by altered cellular mechanics, metabolism, and a histone landscape that primed regenerative cell states. Conversely, Xenopus tadpole limbs retained these features even under high oxygen levels. Their reduced oxygen-sensing capacity was associated with decreased HIF1A-regulating gene expression. Our results thus identify species-specific oxygen-sensing capacity as a fundamental, targetable mechanism that can unlock latent regenerative programs in mammals.

DOI: https://doi.org/10.1126/science.adw8526
Curr Biol. 2026 Apr 06. pii: S0960-9822(26)00316-7. [Epub ahead of print]

The DNA damage response pathway is required for multiciliated cell differentiation.

Cayla E Jewett, Andrew J Holland, Chad G Pearson.

  Multiciliated cells (MCCs) lining the airways, reproductive tracts, and brain ventricles construct hundreds of motile cilia, each anchored by a centriole.1 This necessitates the production of hundreds of centrioles in a post-mitotic state, yet centriole duplication is normally restricted to the S and G2 phases of the cell cycle.2 During their differentiation, MCCs utilize an alternative cell cycle repurposing many of the Cyclin-CDKs used in a canonical cell cycle,3,4 yet how this alternative cell cycle bypasses the numerical and temporal constraints governing centriole duplication remains unclear. DNA damage can result from external sources or occur during programmed genome rearrangements in processes like immunity or meiosis.5 To maintain genomic integrity, cells activate the DNA repair pathways that alter the cell cycle to prevent harmful outcomes such as cancer or immune dysfunction.6 Here, we uncover an unexpected role for DNA damage during the terminal differentiation of MCCs. We show that differentiating MCCs accumulate extensive double-strand DNA breaks during centriole amplification, with DNA damage levels scaling with centriole number. DNA damage response (DDR) kinases are required to support centriole biogenesis and ciliogenesis. Moreover, we find that the high transcriptional output needed to express centriole and cilia genes generates RNA-DNA hybrids (R-loops) that co-localize with the sites of DNA damage. These findings suggest that transcription-coupled DNA damage engages DDR signaling to permit centriole amplification in MCCs. Together, our findings reveal a developmental program that harnesses physiological DNA damage and DDR signaling to adaptively rewire the canonical cell cycle.

Keywords:  ATM; DNA damage; DNA-PK; H2AX; R-loop; cell cycle; centriole amplification; cilia

DOI:  https://doi.org/10.1016/j.cub.2026.03.027
Nat Commun. 2026 Apr 08. pii: 3404. [Epub ahead of print]17(1):

Cell loss disrupts mechanical homeostasis to drive retinal pigment epithelium ageing-like phenotype in vitro.

Teodora Piskova, Aleksandra N Kozyrina, Giedrė Astrauskaitė, Mohamed Elsafi Mabrouk, Sebastian Schepl, Stacy Lok Sze Yam, Ragul Ravithas, Wolfgang Wagner, Massimo Vassalli, Jacopo Di Russo.

Tissue homeostasis emerges from mechanical feedback loops balanced by cell loss and proliferation, a balance that in postmitotic tissues must be maintained without compensatory proliferation. Yet how these tissues preserve mechanical homeostasis and how this challenges function in ageing remains unclear. To establish the relationship between cell density, mechanical homeostasis, and function, we induced age-mimicking cell loss in a postmitotic retinal pigment epithelium (RPE) in vitro. This model recapitulates key structural hallmarks of RPE ageing, including reduced cell height, shortened microvilli and cytoskeletal reorganisation. The density-reduced RPE establishes a new mechanical equilibrium characterised by tissue stiffening and increased junctional contractility. Functionally, these monolayers exhibit impaired phagocytosis of photoreceptor outer segments due to compromised apicolateral plasticity, which is mechanistically linked to the modulation of actin nucleators, Arp2/3 and formins. Altogether, our findings show that a cell loss-induced shift in mechanical homeostasis drives age-related RPE dysfunction, demonstrating that structural remodelling and mechanics alone can compromise tissue function in ageing.

DOI: https://doi.org/10.1038/s41467-026-71493-x
Trends Cell Biol. 2026 Apr 09. pii: S0962-8924(26)00039-5. [Epub ahead of print]

Ferroptosis as an approach to leverage cancer metabolism.

Jenny Jin, Jiachen Hu, Mingyue Li, Wei Gu, Xuejun Jiang, Brent R Stockwell.

  Ferroptosis is a cell death process defined by the iron-mediated peroxidation of membrane phospholipids that overwhelms the cell's innate antioxidant capabilities. Sitting at the nexus of iron, lipid, reactive oxygen species stress responses, and cellular metabolism, ferroptosis is intricately tied to these pathways. The burgeoning field of cancer metabolism has revealed that cancer cells exhibit changes in ferroptosis-relevant metabolic pathways, thereby opening an important avenue of investigation into whether tumors can have characteristic metabolic alterations that render them exquisitely sensitive to ferroptotic cell death. In this review, we highlight recent findings in the metabolic pathways linking ferroptosis and oncogenesis, as well as implications for future cancer therapeutic strategies.

Keywords:  cancer metabolism; ferroptosis; lipid metabolism; lipidomics; metabolomics; oncogenic signaling

DOI:  https://doi.org/10.1016/j.tcb.2026.03.008
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2533973123

Niche-dependent modular regulation of the stem cell transcriptome separates cell identity and potential.

Amelie Raz, Hafidh Hassan, Yukiko M Yamashita.

  Adult stem cells maintain tissue homeostasis, yet are themselves vulnerable to loss. One common mechanism to replace lost stem cells is dedifferentiation, in which progeny revert to stem cell identity. It is a paradox how stem cells and progeny retain the same stem cell potential while exhibiting distinct current identities of self-renewal, differentiation, and dedifferentiation. Here, we show that the Drosophila male germline lineage solves this paradox via two parallel and complementary mechanisms to separate potential and identity. First, differentiating progeny maintain stem cell potency by inheriting perdurant stem cell mRNAs without actively transcribing them. Second, two known niche signals (Bmp and Jak-Stat) activate distinct sets of targets, defining three identities (self-renewal, differentiation, and dedifferentiation) based on the combination of their on/off states. Together, this study reveals how a pool of dedifferentiation-competent progeny is maintained to regenerate stem cells as needed without resulting in stem cell overproduction and resolves the puzzle of why most stem cell systems require multiple independent niche signals.

Keywords:  dedifferentiation; stem cell niche; stem cells

DOI:  https://doi.org/10.1073/pnas.2533973123
Sci Signal. 2026 Apr 07. 19(932): eaec0204

Wnt-dependent Frizzled clustering is required for Dishevelled phosphorylation but insufficient for β-catenin stabilization.

Sarah Moldaver, Pierre E Thibeault, Mélanie Robitaille, Aaron Au, Sichun Lin, Graham MacLeod, Harald J Junge, Melissa V Gammons, Christopher M Yip, Stephane Angers.

Wnt-β-catenin signaling begins when Wnt ligands engage the receptors Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6), leading to the recruitment and phosphorylation of the intracellular protein Dishevelled (Dvl), which is necessary for stabilization of the transcriptional coactivator β-catenin. Understanding the mechanisms by which ligand binding to Fzd activates Wnt-β-catenin signaling is crucial for rational ligand design to selectively modulate Wnt responses in the context of diseases and tissue regeneration. Here, we determined that ligand-induced Fzd clustering was the initiating event for the recruitment and phosphorylation of the downstream signaling mediator Dvl. Using synthetic, bivalent antibodies and single-molecule microscopy, we found that Wnts and bivalent Fzd-binding antibodies, but not monovalent antibodies, clustered Fzd at the plasma membrane in cells, activating Dvl independently of LRP5/6. However, β-catenin-mediated signaling required LRP5/6 recruitment as an additional step to enable inhibition of the kinase GSK3α or GSK3β and stabilization of β-catenin. This two-step mechanism may separate Fzd activation from β-catenin pathway output, underlying a mechanism by which Wnts encode signaling specificity and may inform the design of selective Wnt pathway modulators.

DOI: https://doi.org/10.1126/scisignal.aec0204
Genome Biol. 2026 Apr 06. pii: 126. [Epub ahead of print]27(1):

An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease.

William Gao, Peng Hu, Brittney Wick, Qi Qiu, Hongjie Zhang, Ying Li, Xiangjin Kang, Kenneth Bedi, Maximilian Haeussler, Kotaro Sasaki, Kenneth Margulies, Hao Wu.

   BACKGROUND: As the first organ to develop in utero, the human heart undergoes extensive molecular, structural and metabolic remodeling during development and must sustain its function throughout life.
RESULTS: We generate an integrated multiomic atlas of human cardiac cells, combining newly generated and publicly available single-nucleus RNA sequencing datasets from 299 donors and single nucleus ATAC-seq datasets from 106 donors. Developmental and disease-associated processes drive far more extensive molecular remodeling than sex-associated or aging-dependent effects. Across nearly all cardiac cell types, developmental and disease-driven changes exhibit strong overlap at both the transcriptomic and epigenomic levels, revealing widespread reactivation of fetal-associated gene programs beyond cardiomyocytes. Both cardiac development and disease show convergent shifts in intercellular communication, including increased TGFβ signaling. Integration of gene expression and chromatin accessibility data reveals putative cell-type-specific transcriptional factors driving fetal reactivation in major cardiac diseases. Spatial transcriptomics data orthogonally identifies localization of this fetal reactivation signature within spatially distinct niches in ischemic and fibrotic zones of acute myocardial infarction. Finally, we construct a cell-type-resolved enhancer-to-gene linkage map that refines the association of dilated and hypertrophic cardiomyopathy genetic risk loci to downstream target genes.
CONCLUSIONS: This study presents a comprehensive multimodal, cell-type-resolved atlas of the human heart, providing a foundation for understanding human cardiac gene regulation across the human lifespan and in cardiac diseases.

Keywords:  Cardiovascular disease; Epigenomics; Multiomics; Single cell biology; Single-cell atlas integration; Transcriptomics

DOI:  https://doi.org/10.1186/s13059-026-04061-7
Cell. 2026 Apr 03. pii: S0092-8674(26)00272-2. [Epub ahead of print]

Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.

Clemens Hinterleitner, Hailey V Goldberg, Domhnall McHugh, Valentin J A Barthet, Aveline Filliol, Scott W Lowe.

Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially described as a barrier to unlimited cell division, senescence is now recognized as a pleiotropic and heterogeneous biological process with roles in development, tissue repair, immune surveillance, tumor suppression, aging, fibrosis, and cancer progression. Despite its broad relevance, senescence remains challenging to define operationally, as its molecular features, functional outputs, and physiological consequences vary across cell types, tissues, and stimuli. This review summarizes core hallmarks of senescence while synthesizing how these features are differentially engaged, diversified, and repurposed across biological contexts. Focusing on cancer, we discuss how senescence influences tumor initiation, evolution, and therapeutic response through both cell-intrinsic and microenvironmental mechanisms. We further evaluate emerging strategies to therapeutically modulate senescence, highlighting both opportunities and unresolved challenges for precision intervention.

DOI: https://doi.org/10.1016/j.cell.2026.03.005
Cell Rep. 2026 Apr 04. pii: S2211-1247(26)00281-0. [Epub ahead of print]45(4): 117203

Systematic profiling of cytosolic membraneless organelles reveals enrichment of oncogenic mRNA upon oxidative stress.

Savannah O'Connell, Helen E King, Peter Kjer-Hansen, Karina Pazaky, Gabriela Santos Rodriguez, Daisy Kavanagh, Helaine Graziele S Vieira, Javier Fernandez-Chamorro, Robert J Weatheritt.

  Cytosolic mRNA regulation during and after stress is driven by distinct membraneless organelles. However, their compositional and functional dynamics throughout the stress response remain unclear. We combine APEX2-mediated proximity labeling, RNA sequencing, and high-content imaging to map the human P-body and stress granule transcriptomes during oxidative stress and recovery. Our findings reveal that P-bodies undergo extensive compositional remodeling during stress and that these changes persist during stress recovery. P-body-associated mRNAs during stress exhibit increased AU-rich elements and oncogenic content relative to the cytosol. In contrast, stress granule-associated mRNAs closely resemble the cytosol. These results uncover critical differences between P-bodies and stress granules, shedding light on their functional specialization. Our study provides a valuable resource of cytosolic membraneless organelle-associated transcripts and suggests a specialized role for P-bodies in stress adaptation and recovery.

Keywords:  APEX-sequencing; CP: cell biology; CP: molecular biology; P-bodies; bioinformatics; membraneless organelles; stress granules; stress response

DOI:  https://doi.org/10.1016/j.celrep.2026.117203
Nat Genet. 2026 Apr 09.

Histone acetylation-dependent clustering of BRD2 instructs transcription dynamics.

Niyazi Umut Erdogdu, Sukanya Guhathakurta, Ronald Oellers, Maria Shvedunova, Jose A Morin, Eric M Patrick, Janine Seyfferth, Ward Deboutte, Alejandro Gomez-Auli, Gerhard Mittler, Ibrahim I Cissé, Asifa Akhtar.

Bromodomain (BD) and extra-terminal domain (BET) proteins are key regulators of RNA polymerase II (Pol II)-mediated transcription and their BDs represent promising drug targets. Yet, the interplay between histone acetylation and the chromatin dynamics of individual BET proteins with respect to transcriptional regulation is not fully understood. Here in mouse embryonic stem cells, we uncover an essential role of BRD2 in maintaining Pol II recruitment at promoters through its interaction with TFIID, which becomes particularly critical under the conditions of impaired pause release. Combining rapid protein degradation, chemogenomics and super-resolution microscopy, we show that MOF-mediated histone H4 acetylation promotes BRD2 chromatin association, which in turn enables BRD2 clustering. Accordingly, MOF depletion or deletion of the BRD2's intrinsically disordered region largely recapitulates defects in promoter enrichment and clustering of the transcription machinery observed upon BRD2 loss. Thus, these findings support a model in which histone acetylation-dependent spatiotemporal dynamics of BRD2 coordinate the transcription machinery to regulate transcription initiation.

DOI: https://doi.org/10.1038/s41588-026-02533-x
Nat Chem Biol. 2026 Apr 06.

Charged molecular glue discovery enabled by targeted degron display.

Zhe Zhuang, Woong Sub Byun, Jakub Chrustowicz, Zuzanna Kozicka, Veronica L Li, Dinah M Abeja, Katherine A Donovan, Sara Sepic, Inchul You, Mikołaj Słabicki, Eric S Fischer, Stephen M Hinshaw, Benjamin L Ebert, Brenda A Schulman, Nathanael S Gray.

Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity-inducing molecules, especially molecular glue degraders (MGDs). These compounds catalyze the destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. MGD discovery for predefined targets is a major challenge in contemporary drug discovery. Here, we solve this important chemical challenge through 'chemocentric' MGD discovery of ZZ1, a BET-family protein degrader and a prodrug of a negatively charged glue. ZZ1 activation unmasks a sulfinic acid that binds the modular CTLH ubiquitin ligase complex through a basic pocket in its YPEL5 subunit. These findings demonstrate a previously unrecognized capacity of YPEL5 to recruit CTLH substrates and enable the discovery of MGDs for exceedingly common acidic and basic degrons.

DOI: https://doi.org/10.1038/s41589-026-02182-5
Nat Cardiovasc Res. 2026 Apr 07.

Spastin-mediated severing of glutamylated microtubules controls cardiomyocyte coupling.

Jiayin Zhang, Xiaozhi Huang, Zhichao Wu, Jinxiu Liang, Shuo Chen, Chen Xu, Xinjian Wang, Ranran Cao, Xue Ji, Zijian Feng, Tao Lin, Xuyun Li, Xinyang Hu, Wei Zhu, Peidong Han.

Cardiac ischemia-reperfusion injury frequently induces malignant arrhythmias because of connexin 43 (Cx43) mislocalization and impaired cardiomyocyte coupling; yet, effective therapies targeting this mechanism remain scarce. Here we show that ischemic cardiomyopathy in humans and ischemia-reperfusion in mice promote the accumulation and stabilization of glutamylated microtubules, disrupting targeted Cx43 trafficking. This remodeling of the glutamylated microtubule network is mediated by the microtubule-severing enzyme spastin. Spastin overexpression in cardiomyocytes reduced microtubule density, whereas its deficiency caused accumulation of glutamylated, stabilized microtubules. Although cardiomyocyte-specific spastin knockout mice displayed normal cardiac structure and function at baseline, they were highly susceptible to stress-induced malignant arrhythmias. Mechanistically, spastin deficiency impaired microtubule plus end dynamics and Cx43 transport. Notably, genetic or pharmacological reduction of microtubule glutamylation before ischemia-reperfusion preserved Cx43 localization and mitigated oxidative stress-induced injury. Together, these findings identify microtubule glutamylation as a key regulator of cardiac electrical stability and a promising therapeutic target in ischemia-reperfusion injury.

DOI: https://doi.org/10.1038/s44161-026-00800-y
J Cell Biol. 2026 Jun 01. pii: e202508040. [Epub ahead of print]225(6):

PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.

Shan Zhao, Jie Zhang, Tengfei Ma, Jinglin Li, Mei Duan, Xin Wang, Meijiao Li, Chonglin Yang.

Mitochondria form highly complex and dynamic networks to maintain their homeostasis. However, the underlying mechanisms remain elusive. Here we report a PI(3)P-dependent mechanism that regulates the mitochondrial dynamics required for formation of mitochondrial networks. Using genetic screening, we reveal that mutations of Caenorhabditis elegans EXC-5/FGD lead to formation of spherical and unconnected mitochondria. EXC-5 binds to endosomal PI(3)P generated by the PI 3-kinase VPS-34 and is recruited to endosome-mitochondrion contacts, where it acts as the guanine nucleotide exchange factor to activate the CDC-42 GTPase. Loss of exc-5 or vps-34 similarly disrupts mitochondrial and actin networks as well as mitochondrial recruitment of DRP-1, leading to failure of mitochondrial fission, branching, and elongation. In contrast, expression of constitutively activated CDC-42 ameliorates the defective mitochondrial networks in an actin-dependent manner. Together, these findings suggest a PI(3)P-EXC-5-CDC-42 axis that acts at endosome-mitochondrion contacts to regulate actin organization for maintenance of mitochondrial dynamics and networks.

DOI: https://doi.org/10.1083/jcb.202508040
Nat Commun. 2026 Apr 10.

PGC-derived migrasomes couple PGC proliferation with migration.

Boqi Liu, Zheng Jiang, Wenhao Song, Zhaocheng Zhai, Yaqi Li, Weiying Zhang, Anming Meng, Li Yu.

The coordination of cell migration and proliferation is essential for embryogenesis and tissue homeostasis. However, the classical gradient signaling model is insufficient to explain how stable mitogenic signaling is maintained within migratory cells. Here, we reveal that primordial germ cells (PGCs) in zebrafish employ migrasomes-vesicular organelles formed during migration-to couple their proliferation with migration, ensuring germline expansion. Migrasomes, generated at retraction fibers via tspan7-dependent biogenesis, deliver the growth factor GDF3 specifically to neighboring PGCs through contact-dependent interactions. GDF3 activates the TGF-β receptor acvr1ba, driving proliferation in a spatiotemporally restricted manner. This homocrine signaling mechanism allows migrating PGCs to autonomously sustain proliferation, circumventing signal dilution in embryonic environments. This work uncovers migrasomes as a bridge linking migration and proliferation, with implications for understanding collective cell behaviors in development and disease.

DOI: https://doi.org/10.1038/s41467-026-71616-4
bioRxiv. 2026 Mar 31. pii: 2026.03.27.714900. [Epub ahead of print]

Haplotype-resolved centromeric chromatin organization from a complete diploid human genome.

Yuan Xu, Hailey Loucks, Julian Menendez, Fedor Ryabov, Julian K Lucas, Monika Cechova, Luke Morina, Emily Xu, Danilo Dubocanin, Cy Chittenden, Mobin Asri, Ivo Violich, Christian Ortiz, Joshua M V Gardner, Todd Hillaker, Sara O'Rourke, Brandy McNulty, Tamara A Potapova, Matthew W Mitchell, Jacob P Schwartz, Aaron F Straight, Jennifer L Gerton, Winston Timp, Ivan A Alexandrov, Nicolas Altemose, Karen H Miga.

Centromeres ensure proper chromosome segregation during cell division, yet the organization and regulation of centromeric chromatin within satellite DNA arrays remain incompletely understood. Here, we leverage the complete diploid human genome benchmark (T2T-HG002) to provide a detailed study of centromeric sequence and chromatin architecture on individual haplotypes. Using adaptive-sampling-enriched, ultra-long-read DiMeLo-seq, we achieve single-molecule chromatin profiling across all centromeres, revealing that along single chromatin fibers, CENP-A, the histone variant specifying centromere identity, forms multiple discrete subdomains within hypomethylated centromere dip regions (CDRs) that are flanked by H3K9me3-enriched heterochromatin. Despite underlying sequence variation, CDRs localize to sequence-homogeneous domains and maintain relatively balanced CENP-A dosage and aggregate length across all chromosomes and between haplotypes. Further, we show that bidirectional changes to centromeric and pericentromeric DNA methylation are accompanied by changes to centromeric chromatin architecture. In passaged cells with centromeric hypomethylation, subdomain boundaries are eroded, and adjacent CENP-A domains tend to merge and expand. Conversely, in pluripotent stem cells with centromeric hypermethylation, CDRs are fundamentally reorganized, such that discrete hypomethylated domains are frequently consolidated into broader contiguous tracts. These methylation-associated CDR restructuring events suggest that DNA methylation acts as a principal regulator of human centromere organization, with implications for understanding centromere plasticity, epigenetic inheritance, and chromosomal instability in development and disease.

DOI: https://doi.org/10.64898/2026.03.27.714900
bioRxiv. 2026 Mar 30. pii: 2026.03.26.714557. [Epub ahead of print]

Comparative single-cell atlases reveal injury-driven tubal epithelial regeneration as a window for ovarian carcinoma initiation.

Coulter Q Ralston, Andrea Flesken-Nikitin, Dah-Jiun Fu, Christopher S Ashe, Blaine A Harlan, Md Mozammal Hossain, Derek K Wang, Anna Yemelyanova, Elisa Schmoeckel, Andrew K Godwin, Doris Mayr, Benjamin D Cosgrove, Alexander Yu Nikitin.

High-grade serous carcinoma (HGSC), the most lethal form of ovarian cancer, preferentially originates in the tubal epithelium (TE) of the distal uterine tube (also known as Fallopian tube or oviduct). Mouse models are widely used to study how HGSC initiates in humans; however, the extent to which mouse and human uterine tubes are comparable remains unclear. Here, we conduct cross-species single-cell transcriptomic comparative analyses and organoid assay validations to reveal conserved differentiation trajectories from bipotent progenitors to secretory or ciliated cell fates. Regional analyses of both datasets reveal enriched injury repair features in the distal human TE, where mice lack such a trend. Experimentally inducing mechanical injury to the mouse TE yields significant expansion of pre-ciliated cells compared to uninjured counterparts. Furthermore, inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, in regenerating pre-ciliated cells leads to rapid neoplastic transformation, implicating post-traumatic repair as a permissive window for malignant transformation. Together, our findings establish a comparative atlas of cell states between mice and humans, show that injury-associated regeneration may contribute to the known vulnerability of the fimbrial region, and raise potential concerns regarding procedures or conditions that mechanically perturb the tubal epithelium.

DOI: https://doi.org/10.64898/2026.03.26.714557
Aging Cell. 2026 Apr;25(4): e70484

Human cGAS Drives LINE-1 Transcriptional Activation to Trigger MAVS-Dependent Cellular Senescence.

Zhixi Chen, Lingjiang Chen, Xinyu Chen, Hao Wang, Huanyin Tang, Zhengyi Zhen, Ying Jiang, Zhiyong Mao, Yu Chen.

  Long interspersed nuclear element 1 (LINE-1 or L1) retrotransposons pose a significant threat to somatic genomic integrity and are a source of sterile inflammation. Consequently, L1 activity is stringently controlled by multiple regulatory layers to ensure silencing, while its transcriptional derepression is linked to aging and age-related diseases. Recent studies have revealed complex interrelationships between L1 and cGAS, but whether cGAS regulates L1 transcription and its biological significance remains unclear. Here, we demonstrate that human cGAS activates L1 transcription by upregulating the transcriptional regulators CTCF and RUNX3. This cGAS-mediated promotion of L1 transcription is absent in mice due to functional divergence in CTCF and RUNX3. Furthermore, cGAS-mediated elevation of L1 mRNA promotes cellular senescence via MAVS, a key RNA-sensing pathway component. Together, our findings reveal a novel role of cGAS in activating L1 transcription and define a cGAS-L1-MAVS senescence pathway, thereby bridging the noncanonical function of cGAS and the RNA-sensing signaling.

Keywords:  LINE‐1 retrotransposon; MAVS; cGAS; cellular senescence; comparative biology

DOI:  https://doi.org/10.1111/acel.70484
Nature. 2026 Apr 08.

Single-cell spatiotemporal dissection of the human maternal-fetal interface.

Cheng Wang, Yan Zhou, Yuejun Wang, Tuhin Kumar Guha, Zhida Luo, Anxhela Mustafaraj, Tara I McIntyre, Marisa E Schwab, Brittany R Davidson, Gabriella C Reeder, Ronald J Wong, Sarah K England, Juan M Gonzalez, Robert Blelloch, Alexis J Combes, Linda C Giudice, Adrian Erlebacher, Tippi C MacKenzie, David K Stevenson, Gary M Shaw, Michael P Snyder, Xiaofei Sun, Virginia D Winn, Susan J Fisher, Jingjing Li.

The human maternal-fetal interface is characterized by mosaic intermingling of maternal and fetal cells1. Yet the underlying cellular, molecular and spatial programmes remain incompletely defined. Here we generate a comprehensive atlas of the human maternal-fetal interface across normal pregnancies from early gestation to term by integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometre-resolution spatial transcriptomics and CODEX multiplex protein imaging2, substantially boosting the spatiotemporal resolution of prior research3. This framework delineates common and transient cell types, states and spatial niches across the fetal and maternal compartments, reconstructs transcriptional programmes that guide cytotrophoblast and decidual stromal cell differentiation, and resolves recurrent architecture structural units that build this interface. We identify previously unrecognized arterial endothelial state transitions during cytotrophoblast-mediated spiral artery remodelling and develop a machine learning model that predicts cytotrophoblast invasiveness from transcriptomic signatures. We further discover a decidual stromal cell subtype that suppresses cytotrophoblast invasion via endocannabinoid signalling at the human maternal-fetal interface. By integrating the atlas with genome-wide association data, we pinpoint maternal and fetal cells that are most vulnerable to pre-eclampsia, preterm birth or miscarriage. This resource provides a comprehensive spatially resolved single-cell multiomic reference of the human placenta and decidua and offers a framework for decoding their normal and disordered development.

DOI: https://doi.org/10.1038/s41586-026-10316-x
J Cell Sci. 2026 Apr 08. pii: jcs.264421. [Epub ahead of print]

The molecular basis of tricalbin-mediated membrane contact site organization in cells.

Lazar Ivanović, Anne-Laure Boinet, Andrea Picco, Eliane Zinn, Daniela Ross-Kaschitza, Marko Kaksonen, Wanda Kukulski.

  Membrane contact sites facilitate molecular exchanges through physical interactions between organelles, connected by specific protein tethers. Among these tethers are the tricalbins, which mediate contacts between endoplasmic reticulum (ER) and plasma membrane in yeast. Tricalbins are integral to the ER, have a cytosolic lipid binding domain and bind the plasma membrane through C2 domains. Here, we combine fluorescence recovery after photobleaching with correlative light and 3D electron microscopy to dissect how tricalbins control their localization, dynamic distribution and contact site organization. We find that heteromerization via lipid binding domains is a prerequisite for tricalbin accumulation at contact sites, membrane curvature sensing and restrained mobility in the ER. By altering tricalbin protein domains, we show that intermembrane distances and intrinsically disordered regions interdependently control distribution and dynamics of contact site tethers. Our study reveals principles of contact site architecture that are fine-tuned by tricalbin domain organization.

Keywords:  Correlative light and electron microscopy; FRAP; Live imaging; Membrane contact sites; Tricalbins; Yeast

DOI:  https://doi.org/10.1242/jcs.264421
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00199-1. [Epub ahead of print]

Multivalent 28S rRNA expansion segments enable reconstitution of multilayered nucleolar architecture.

Jieli Wei, Yize Zhang, Jiaxin Wu, Bingcheng Ye, Xueyuan Fan, Yucen Hu, Zhonghuai Hou, ShengQi Xiang, Weirui Ma.

  Eukaryotic 28S rRNA contains expansion segments (ESs) that increase dramatically in length during evolution, yet their functions remain elusive. The nucleolus, where rRNA is transcribed, exhibits divergent architectures: three-layered (tripartite) in amniotes but two-layered (bipartite) in other eukaryotes. Here, we identified distinct rRNA localization patterns within nucleolar compartments. Through in vitro reconstitution and simulations, we demonstrated that 28S rRNA induces layered nucleolar-like structures via multivalent RNA-RNA interactions. This structure-forming capacity correlates with the evolutionary expansion of ESs. 28S rRNAs from tripartite-nucleolus organisms possess longer ESs and exhibit enhanced multivalency compared with those from bipartite-nucleolus species. Deletion of specific ESs abolishes human 28S rRNA's ability to induce nucleolar-like structures, whereas transferring these segments to C. elegans 26S rRNA confers this capability in vitro. We conclude that rRNA ESs function as architectural elements that promote nucleolar complexity, providing mechanistic insight into how genomic expansion drives sophisticated cellular organization through enhanced intermolecular interactions.

Keywords:  RNA multivalency; biomolecular condensates; dense fibrillar component; in vitro reconstitution; multivalent RNA-RNA interactions; nucleolar architecture; nucleolus; phase separation; rRNA expansion segments; ribosomal RNA

DOI:  https://doi.org/10.1016/j.molcel.2026.03.023
Nat Commun. 2026 Apr 10.

Translation in proximity to forming autophagosomes during sustained autophagy.

Yunping Xue, Kaela O'Connor, Karsten Nalbach, Alexandre Savard, Karyn E King, Ryan C Russell, Christian Behrends, Derrick Gibbings.

Autophagy is an evolutionarily conserved catabolic process. In a process requiring a cascade of over 35 autophagy-related genes (Atg), a cupped phagophore membrane expands to surround cytoplasmic material, and seals itself to form an autophagosome, which finally fuses with lysosomes. Large numbers of autophagosomes form during stress responses, while simultaneously cells drastically reduce translation to conserve energy. Here, using proximity-labeling and Fluorescence in situ Hybridization we demonstrate that multiple mRNAs encoding proteins required for autophagy preferentially localize in proximity to forming autophagosomes. Polysome fractionation and proteomics of nascent proteins in proximity to forming autophagosomes provides evidence for the local translation of these mRNAs. Translation and the ribosome-binding protein RACK1 were required for the localization of these mRNAs to forming autophagosomes. Inhibition of translation or knockdown of RACK1 caused depletion of several proteins required for autophagy and a reduction in the number of autophagosomes. Local translation may enable a rapid, energy-efficient supply of proteins for autophagy to enable cells to massively induce autophagy while conserving energy during cell stress.

DOI: https://doi.org/10.1038/s41467-026-71551-4
Nature. 2026 Apr 08.

Engineered immunosuppressive dendritic cells protect against cardiac remodelling.

Xiaoying Li, Jiamin Li, Guohua Li, Lisheng Zhu, Guo Cheng, Huanqiang Li, Hao Lin, Ningqing Jia, Xiaoqian Hong, Ye Liu, Zhiwei Zhong, Yize Chen, Biqing Wang, Jing Zhao, Zhenqi Hua, Lingjun Wang, Qiming Chen, Peijie Zheng, Shuyuan Sheng, Songting Gu, Cheng Ni, Shuchang Ye, Changle Ke, Feimu Zhang, Mo Li, Shaohui Shi, Junhua He, Yan Wu, Yinghui Xu, Minjian Kong, Qi Chen, Huajun Li, Yu Zhang, Jianzhong Sun, Guanhua Hu, Chengchen Zhao, Yiping Dong, Lili Yu, Yang Xu, Xinyang Hu.

Heart failure remains a leading cause of morbidity and mortality, yet no approved therapies effectively prevent or reverse pathological cardiac fibrosis and the associated decline in cardiac function1-4. Chronic inflammation is a central driver of pathological fibrosis after ischaemic or haemodynamic stress, but strategies that locally rebalance injurious and reparative immune responses without systemic immunosuppression are lacking5,6. Dendritic cells (DCs) are key regulators of immune activation and tolerance, providing an opportunity for therapeutic immune reprogramming in cardiac diseases7,8. Here we show that engineered immunosuppressive and fibrosis-targeted DCs (iCDCs) effectively protect against pathological cardiac remodelling. In mouse models of ischaemia-reperfusion injury, myocardial infarction and pressure overload, iCDC therapy reduced inflammatory cardiac fibrosis, improved cardiac perfusion and preserved contractility. Mechanistically, iCDCs conferred sustained cardioprotection directly by suppressing immune and stromal cell activation or indirectly through promoting clonal expansion of regulatory T cells. Importantly, in a non-human primate model of myocardial infarction, iCDC therapy also reduced cardiac fibrosis, improved cardiac perfusion and contractile function without inducing systemic toxicity. These findings establish lesion-targeted immune modulation as a feasible strategy to control cardiac fibrosis and identify engineered dendritic cells as a promising therapeutic platform for treating cardiac remodelling and heart failure.

DOI: https://doi.org/10.1038/s41586-026-10346-5
Nat Struct Mol Biol. 2026 Apr 08.

Microtubules in the axon are GDP bound but adopt a stable GTP-like expanded state.

Elena A Zehr, Shufeng Sun, Stephanie L Sarbanes, Antonina Roll-Mecak.

Microtubules scaffold cells, supporting signaling and cargo transport. They assemble from GTP-tubulin, which hydrolyzes to GDP-tubulin during polymerization. GTP-microtubule lattices are stable; GDP lattices depolymerize rapidly. In vitro, hydrolysis triggers lattice compaction. Lattice spacing regulates motors and microtubule-associated proteins; however, the conformation of tubulin in microtubules in cells is unknown. Here, we present the atomic-resolution cryo-electron microscopy structure of human microtubules in situ, in the axons of human cortical neurons derived from induced pluripotent stem cells (iPS cells). Our 2.7-Å-resolution reconstruction delineates bound water molecules and reveals that axonal microtubules adopt an expanded GTP-like lattice, despite being GDP bound. Using cryo-electron tomography and power spectrum analysis, we find that, unlike in axons, microtubules in undifferentiated iPS cells are compacted. Therefore, lattice expansion is part of neuronal differentiation. Our work provides molecular insights into neurogenesis and has implications for understanding microtubule stability and effector recruitment in neurons.

DOI: https://doi.org/10.1038/s41594-026-01787-7
J Cell Biol. 2026 Jun 01. pii: e202511004. [Epub ahead of print]225(6):

Spatial inhibition of RhoA by RhoGAP15B promotes protrusive activity during collective migration.

Vítor Yang, Cristian Marchant, Bing Liu, Mariana Osswald, Jesus Lopez-Gay, Yohanns Bellaïche, Xiaobo Wang, Eurico Morais-de-Sá.

The Rho family GTPases RhoA, Rac1, and Cdc42 are well-established regulators of collective migration by driving the formation of cellular protrusions and by regulating actomyosin contraction and adhesion. However, how their activation and inhibition are spatially and temporally coordinated remains unclear. Using GFP knock-in lines, we systematically characterized the localization patterns of all Drosophila RhoGEFs (activators) and RhoGAPs (inhibitors) in border cells, an in vivo model of collective migration. We have further combined RNAi screening with GFP-based validation of depletion efficiency to assess the functional significance of those RhoGEFs/GAPs expressed in border cells. This identified RhoGAP15B as a localized inhibitor of RhoA activity at the border cell cortex. RhoGAP15B regulates cluster morphology and is enriched at the leading cell front, where it restrains actomyosin contractility to promote protrusive behavior. Our findings reveal RhoGAP15B as a key spatial RhoA regulator and highlight that patterned RhoGAP and RhoGEF activities are essential for coordinating cortical contraction and protrusion dynamics during collective migration.

DOI: https://doi.org/10.1083/jcb.202511004
bioRxiv. 2026 Apr 02. pii: 2026.03.31.713900. [Epub ahead of print]

Mapping the mammalian dark metabolome by in vivo isotope tracing.

Michael R MacArthur, Justine Raeber, Wenyun Lu, Hantao Qiang, Amelia V Schueppert, Lucas B Ayres, Ricardo A Cordova, Michael D Neinast, Edmundo Leiva, Vanha N Pham, Jenna E AbuSalim, Connor S R Jankowski, Laith Z Samarah, Asael Roichman, Christian G Peace, Daniil G Ivanov, Gianna L Renzo, Anna M Oschmann, Julien F Ayroles, Sarah J Mitchell, Xi Xing, Kellen Olszewski, Hahn Kim, Joshua D Rabinowitz, Michael A Skinnider.

Despite decades of biochemical study, a comprehensive map of the mammalian metabolome remains elusive. Mass spectrometry-based metabolomics detects thousands of small molecule-associated signals in mammalian tissues, but it is currently unclear how many of these reflect products of endogenous metabolism. Here, we leverage systematic in vivo isotope tracing to infer the biosynthetic origins of unidentified metabolites. We administered 26 different isotopically labelled nutrients to mice, measured circulating and tissue metabolite labelling by mass spectrometry, and developed a statistical framework to infer the number of carbon atoms incorporated from each of these precursors into more than 4,000 putative metabolites. We show this information can be harnessed for biosynthesis-aware structure elucidation using a multimodal AI model that co-embeds isotopic labelling patterns with chemical structures. This approach revealed several previously unrecognized families of mammalian metabolites, including cysteine-derived alkylthiazolidines, dithioacetal mercapturic acid derivatives, short-chain N-acyltaurines, acylglycyltaurines, and N-oxidized taurines. It further uncovered a family of mevalonate-derived isoprenoid metabolites that includes 2,3-dihydrofarnesoic acid, which is markedly depleted in both mouse and human aging. Age-related depletion of these isoprenoids is driven by impaired coenzyme A synthesis. Our work establishes the biosynthetic precursors for thousands of unidentified metabolites and reveals multiple previously unrecognized branches of mammalian metabolism.

DOI: https://doi.org/10.64898/2026.03.31.713900
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00189-9. [Epub ahead of print]

Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF.

Christoph Nössing, Olga Troitskaya, Jaclyn S Long, Andrew Craxton, Martina Brucoli, Eve Anderson, Sergio Lilla, David G McEwan, Annabel R Minton, Valentin J A Barthet, Jim O'Prey, Gemma Thomson, Colin Nixon, Sara Zanivan, Douglas Strathdee, Marion MacFarlane, Kevin M Ryan.

  Inflammation can affect many diseases. We report here that inflammatory cytokines invoke caspase-8-mediated cleavage of the autophagy adaptor p62/SQSTM1 at aspartic acid 329 in human cells, producing a previously described truncated form, which we term tr-p62. We show that TNF-driven cell death is tr-p62 dependent and that autophagy inhibition promotes death via tr-p62 accumulation. Mechanistically, p62 cleavage is receptor-interacting serine/threonine-protein kinase 1 (RIPK1) dependent, and tr-p62 stabilizes caspase-8 activating complex-IIb. tr-p62-driven cell death downstream of TNF is also RIPK1 and caspase dependent, promoting feedforward caspase-8 activation. p62 cleavage does not, however, affect necroptosis. Surprisingly, this caspase-8 cleavage site in p62 is absent in mice, and introduction of cleavable forms of p62 into mouse cells causes sensitization to TNF-induced death. Moreover, mice with CRISPR-Cas9-generated cleavable p62 exhibit TNF hypersensitivity and intestinal inflammation in vivo. These findings provide significant insights into TNF-induced cell death and introduce a mouse model that may provide better clarity for human-related studies of inflammatory disease.

Keywords:  TNF; autophagy; caspase; cell death; mice; p62

DOI:  https://doi.org/10.1016/j.molcel.2026.03.013
Nat Aging. 2026 Apr 06.

Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.

Huilong Li, Ruzhou Zhao, Luming Wan, Yang Yuan, Enhao Ma, Yingang Li, Zhuangzhuang Chen, Binbin Liu, Yurong Song, Ziwei Cao, Xinxin Jiao, Yue Wang, Peng Wu, Hao Jin, Jiatong Li, Xiaopan Yang, Linfei Huang, Yanhong Zhang, Ke Yang, Jiang Huo, Haoran Jin, Hui Zhong, Min Min, Shaohua Zhang, Yuan Cao, Wenlong Li, Rui Zhang, Congwen Wei.

Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7 (P2RX7), which is associated with increased EV biogenesis. We identify EV-encapsulated miRNAs (miR-25, miR-92a, miR-30c and miR-30d) that reach primary tumors through the circulation and enhance tumor invasiveness and metastatic potential. Similarly, clinical samples from older patients show reduced expression of the miRNA target genes PTEN and LATS2, as well as enhanced epithelial-mesenchymal transition in metastatic tumors. Therapeutically, targeting senescence with dasatinib and quercetin (D + Q), inhibiting P2RX7, or silencing EV-associated miRNAs considerably reduces metastasis in aged mice. Together, our study uncovers a mechanism by which senescent hepatocyte-derived EVs drive tumor metastasis during aging and highlights potential strategies to mitigate this process.

DOI: https://doi.org/10.1038/s43587-026-01102-5
Nat Cardiovasc Res. 2026 Apr 08.

Fetal-restricted hematopoietic progenitors arise from hemogenic endothelium in vitelline and umbilical arteries.

Cristiana Barone, Giulia Quattrini, Alessandro Muratore, Giorgio Anselmi, Yurim Park, Naeema T Mehmood, Elena Morganti, Roberto Orsenigo, Filipa Timóteo-Ferreira, Anna Cazzola, Arianna Patelli, Thea Milanesi, Bianca Nesti, Francisca Soares-da-Silva, Matthew Nicholls, Gloria Zambelli, Mario Mauri, Silvia Bombelli, Sofia De Marco, Deborah D'Aliberti, Silvia Spinelli, Veronica Bonalume, Alison Domingues, Mahdieh Naghavi Alhosseini, Gianluca Sala, Arianna Colonna, Elisabetta D'Errico, Cristina D'Orlando, Cristina Bianchi, Roberto A Perego, Raffaella Meneveri, Ana Cumano, Silvia Brunelli, Marella F T R De Bruijn, Andrea Ditadi, Alessandro Fantin, Rocco Piazza, Emanuele Azzoni.

Embryonic hematopoiesis involves successive waves of progenitors from distinct anatomical sites, but the origins and contributions of early hematopoietic stem and progenitor cells (HSPCs) remain incompletely defined. Here we use genetic fate mapping in mice to temporally label hemogenic endothelium (HE) subsets and track their progeny. We show that a wave of fetal-restricted HSPCs arises from HE in the vitelline and umbilical arteries between embryonic days 8.5 and 9.5, preceding the emergence of definitive hematopoietic stem cells. Lineage tracing, single-cell transcriptomic analyses and functional assays revealed that these progenitors are transient and distinct from erythro-myeloid progenitors, contribute extensively to fetal lympho-myelopoiesis but decline postnatally. Our findings reveal a previously unrecognized early HE wave as a key source of fetal-restricted HSPCs, refining the spatial-temporal understanding of layered hematopoiesis and informing developmental origins of blood cell diversity.

DOI: https://doi.org/10.1038/s44161-026-00793-8
J Cell Biol. 2026 May 04. pii: e202507146. [Epub ahead of print]225(5):

Ring canals in the larval adipose of Drosophila buffer stress response.

Shyama Nandakumar, Deepika Vasudevan.

Cells in metabolically active tissues with high biosynthetic and secretory demands often use robust stress-responsive mechanisms to maintain homeostasis. Coordinating such stress response mechanisms requires intercellular communication and coordination. Such modalities of intercellular communication have been relatively understudied in the context of stress tolerance. Here, we use the Drosophila melanogaster third instar fat body to demonstrate that adipocytes communicate with each other through intercellular bridges called ring canals to buffer endoplasmic reticulum (ER) stress. The fat body supports the exponential growth from embryo to late larval stage over a short period of time through its energy storage and secretory functions, enduring a high basal level of stress in the process. We discovered that individual cells in the fat body are paired to one neighboring cell through ring canals. We further demonstrate that ring canals mediate rapid and highly specific intercellular cargo and organellar trafficking, and allow the transport of cytoplasmic, ER-bound, and Golgi vesicular proteins. Disrupting fat body ring canals resulted in higher levels of stress response markers, aberrant cell size, and increased cell sensitivity and lethality in response to various exogenous stressors. We also find that animals with disrupted fat body ring canals display an overall delay in larval development, likely due to reduced secretion of larval serum proteins from the fat body. In sum, our work reveals a novel feature of intercellular communication in adipose tissue that serves to buffer stress across cells, which is required for both homeostatic secretory function and maintaining tissue viability under exogenous stress.

DOI: https://doi.org/10.1083/jcb.202507146
Nat Commun. 2026 Apr 07.

Recruitment of Mre11 to recombination sites during meiosis.

Priyanka Priyadarshini, Mahesh Survi, Wael El Yazidi Mouloud, Regina Bohn, Steven Ballet, Neil Hunter, Alexander N Volkov, Corentin Claeys Bouuaert.

The Mre11 nuclease is part of the conserved MRX complex involved in DNA double-strand break (DSB) repair. During meiosis in budding yeast, MRX is also required for Spo11-mediated programmed DSB formation to initiate homologous recombination. Recruitment of Mre11 to meiotic DSB sites depends on Rec114-Mei4 and Mer2, proposed to organize the DSB machinery via biomolecular condensation. Here, we show that Mre11 and MRX complexes form DNA-dependent, hexanediol-sensitive condensates in vitro. In vivo, Mre11 assembles into DNA damage-dependent foci during mitosis and DSB-independent foci during meiosis. Both in vitro condensates and in vivo foci require Mre11 C-terminal intrinsically-disordered region (IDR). While dispensable for vegetative DNA repair, Mre11 IDR is essential during meiosis, where it mediates interaction with Mer2 via a short α-helix and contains a SUMO-interacting motif that enhances Mre11 recruitment and DSB formation. Together, these findings provide insights into the biophysical properties of Mre11 and its role in initiating meiotic recombination.

DOI: https://doi.org/10.1038/s41467-026-71310-5