bims-ginsta Biomed News
on Genome instability
Issue of 2025–05–18
23 papers selected by
Jinrong Hu, National University of Singapore
  1. Early coordination of cell migration and cardiac fate determination during mammalian gastrulation.
  2. Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification.
  3. An integrated transcriptomic cell atlas of human endoderm-derived organoids.
  4. KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis.
  5. Phosphorylation by Aurora kinase A facilitates cortical-cytoplasmic dynamics of Par-3 in asymmetric division of radial glia progenitors.
  6. Differential tissue deformability underlies fluid pressure-driven shape divergence of the avian embryonic brain and spinal cord.
  7. Mitochondria-membranous organelle contacts at a glance.
  8. X-linked competition - implications for human development and disease.
  9. E-cadherin mechanotransduction activates EGFR-ERK signaling in epithelial monolayers by inducing ADAM-mediated ligand shedding.
  10. Viscous dissipation in the rupture of cell-cell contacts.
  11. Cardiac regeneration: Unraveling the complex network of intercellular crosstalk.
  12. Ku limits RNA-induced innate immunity to allow Alu-expansion in primates.
  13. RNA transcripts serve as a template for double-strand break repair in human cells.
  14. Proteoform profiling of endogenous single cells from rat hippocampus at scale.
  15. Prediction of protein subcellular localization in single cells.
  16. Establishing dorsal-ventral patterning in human neural tube organoids with synthetic organizers.
  17. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.
  18. Evidence of secondary Notch signaling within the rat small intestine.
  19. Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
  20. Emerging roles for the nucleolus in development and stem cells.
  21. Small molecule and cell contact-inducible systems for controlling expression and differentiation in mouse embryonic stem cells.
  22. Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells.
  23. Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
  1. EMBO J. 2025 May 13.
    Early coordination of cell migration and cardiac fate determination during mammalian gastrulation.
    Shayma Abukar, Peter A Embacher, Alessandro Ciccarelli, Sunita Varsani-Brown, Isabel G W North, Jamie A Dean, James Briscoe, Kenzo Ivanovitch.
      During gastrulation, mesodermal cells derived from distinct regions are destined to acquire specific cardiac fates after undergoing complex migratory movements. Here, we used light-sheet imaging of live mouse embryos between gastrulation and heart tube formation to track mesodermal cells and to reconstruct lineage trees and 3D migration paths for up to five cell divisions. We found independent progenitors emerging at specific times, contributing exclusively to left ventricle/atrioventricular canal (LV/AVC) or atrial myocytes. LV/AVC progenitors differentiated early to form the cardiac crescent, while atrial progenitors later generated the heart tube's Nr2f2+ inflow tract during morphogenesis. We also identified short-lived multipotent progenitors with broad potential, illustrating early developmental plasticity. Descendants of multipotent progenitors displayed greater dispersion and more diverse migratory trajectories within the anterior mesoderm than the progeny of uni-fated progenitors. Progenitors contributing to extraembryonic mesoderm (ExEm) exhibited the fastest and most dispersed migrations. In contrast, those giving rise to endocardial, LV/AVC, and pericardial cells showed a more gradual divergence, with late-stage behavioural shifts: endocardial cells increased in speed, while pericardial cells slowed down in comparison to LV/AVC cells. Together, these data reveal patterns of individual cell directionality and cardiac fate allocation within the seemingly unorganised migratory pattern of mesoderm cells.
    Keywords:  Cardiac Progenitors; Gastrulation; Heart Fields; Light Sheet Microscopy; Live imaging
    DOI:  https://doi.org/10.1038/s44318-025-00441-0
  2. Cell Rep. 2025 May 09. pii: S2211-1247(25)00451-6. [Epub ahead of print]44(5): 115680
    Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification.
    Lindsey N Guerin, Timothy J Scott, Jacqueline A Yap, Annelie Johansson, Fabio Puddu, Tom Charlesworth, Yilin Yang, Alan J Simmons, Ken S Lau, Rebecca A Ihrie, Emily Hodges.
      Chromatin and DNA modifications mediate the transcriptional activity of lineage-specifying enhancers, but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly resolved timeline of their dynamics during neural progenitor cell differentiation. We discovered that, while complete demethylation appears delayed relative to shorter-lived chromatin changes for thousands of enhancers, DNA demethylation actually initiates with 5-hydroxymethylation before appreciable accessibility and transcription factor occupancy is observed. The extended timeline of DNA demethylation creates temporal discordance appearing as heterogeneity in enhancer regulatory states. Few regions ever gain methylation, and resulting enhancer hypomethylation persists long after chromatin activities have dissipated. We demonstrate that the temporal methylation status of CpGs (mC/hmC/C) predicts past, present, and future chromatin accessibility using machine learning models. Thus, chromatin and DNA methylation collaborate on different timescales to shape short- and long-term enhancer regulation during cell fate specification.
    Keywords:  5-hydroxymethylation; 6-base sequencing; ATAC-Me; CP: Developmental biology; CP: Molecular biology; DNA methylation; chromatin accessibility; differentiation; enhancers; epigenetics; machine learning; neural progenitor cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.115680
  3. Nat Genet. 2025 May;57(5): 1201-1212
    An integrated transcriptomic cell atlas of human endoderm-derived organoids.
    Quan Xu, Lennard Halle, Soroor Hediyeh-Zadeh, Merel Kuijs, Rya Riedweg, Umut Kilik, Timothy Recaldin, Qianhui Yu, Isabell Rall, Tristan Frum, Lukas Adam, Shrey Parikh, Raphael Kfuri-Rubens, Manuel Gander, Dominik Klein, Fabiola Curion, Zhisong He, Jonas Simon Fleck, Koen Oost, Maurice Kahnwald, Silvia Barbiero, Olga Mitrofanova, Grzegorz Jerzy Maciag, Kim B Jensen, Matthias Lutolf, Prisca Liberali, Jason R Spence, Nikolche Gjorevski, Joep Beumer, Barbara Treutlein, Fabian J Theis, J Gray Camp.
      Human pluripotent stem cells and tissue-resident fetal and adult stem cells can generate epithelial tissues of endodermal origin in vitro that recapitulate aspects of developing and adult human physiology. Here, we integrate single-cell transcriptomes from 218 samples covering organoids and other models of diverse endoderm-derived tissues to establish an initial version of a human endoderm-derived organoid cell atlas. The integration includes nearly one million cells across diverse conditions, data sources and protocols. We compare cell types and states between organoid models and harmonize cell annotations through mapping to primary tissue counterparts. Focusing on the intestine and lung, we provide examples of mapping data from new protocols and show how the atlas can be used as a diverse cohort to assess perturbations and disease models. The human endoderm-derived organoid cell atlas makes diverse datasets centrally available and will be valuable to assess fidelity, characterize perturbed and diseased states, and streamline protocol development.
    DOI:  https://doi.org/10.1038/s41588-025-02182-6
  4. J Cell Biol. 2025 Jul 07. pii: e202409157. [Epub ahead of print]224(7):
    KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis.
    Lieke Stockmann, Hélène Kabbech, Gert-Jan Kremers, Brent van Herk, Bas Dille, Mirjam van den Hout, Wilfred F J van IJcken, Dick H W Dekkers, Jeroen A A Demmers, Ihor Smal, Danny Huylebroeck, Sreya Basu, Niels Galjart.
      Cytokinesis, the final stage of cell division, serves to physically separate daughter cells. In cultured naïve mouse embryonic stem cells, cytokinesis lasts unusually long. Here, we describe a novel function for the kinesin-13 member KIF2A in this process. In genome-engineered mouse embryonic stem cells, we find that KIF2A localizes to spindle poles during metaphase and regulates spindle length in a manner consistent with its known role as a microtubule minus-end depolymerase. In contrast, during cytokinesis we observe tight binding of KIF2A to intercellular bridge microtubules. At this stage, KIF2A maintains microtubule length and number and controls microtubule acetylation. We propose that the conversion of KIF2A from a depolymerase to a stabilizer is driven by both the inhibition of its ATPase activity, which increases lattice affinity, and a preference for compacted lattices. In turn, KIF2A might maintain the compacted microtubule state at the intercellular bridge, thereby dampening acetylation. As KIF2A depletion causes pluripotency problems and affects mRNA homeostasis, our results furthermore indicate that KIF2A-mediated microtubule stabilization prolongs cytokinesis to maintain pluripotency.
    DOI:  https://doi.org/10.1083/jcb.202409157
  5. Sci Adv. 2025 May 16. 11(20): eadq3858
    Phosphorylation by Aurora kinase A facilitates cortical-cytoplasmic dynamics of Par-3 in asymmetric division of radial glia progenitors.
    Jason Q Garcia, Vincent Mouilleau, Henry Ng, Xiang Zhao, David O Morgan, Su Guo.
      During asymmetric cell division (ACD) of radial glia progenitors (RGPs), the cortical polarity regulator Par-3 is detected in the cytoplasm colocalizing with dynein and Notch ligand DeltaD (Dld). What drives Par-3 to the cytoplasm and its impact on RGP ACD remain unknown. Here, we visualize cytoplasmic Par-3 using in vivo time-lapse imaging and find that Ser954 of zebrafish Par-3 is phosphorylated by Aurora kinase A (AurkA) in vitro. Expression of the nonphosphorylated mutant Par-3S954A dominant negatively affects embryonic development, reduces cytoplasmic Par-3, and disrupts the anteroposterior asymmetry of cortical Par-3 and Dld endosomes and, in turn, daughter cell fate. AurkA in mitotic RGPs shows dynamic pericentrosomal distribution that transiently colocalizes with cortical Par-3 preferentially on the posterior side. AurkA is both necessary and sufficient to increase cytoplasmic while decreasing cortical Par-3, disrupts Par-3 cortical asymmetry, and perturbs polarized Dld endosome dynamics. These findings suggest that AurkA regulates Par-3 cortical-cytoplasmic dynamics that is critical for ACD and daughter cell fate.
    DOI:  https://doi.org/10.1126/sciadv.adq3858
  6. Dev Cell. 2025 May 06. pii: S1534-5807(25)00248-5. [Epub ahead of print]
    Differential tissue deformability underlies fluid pressure-driven shape divergence of the avian embryonic brain and spinal cord.
    Susannah B P McLaren, Shi-Lei Xue, Siyuan Ding, Alexander K Winkel, Oscar Baldwin, Shreya Dwarakacherla, Kristian Franze, Edouard Hannezo, Fengzhu Xiong.
      An enlarged brain underlies the complex central nervous system of vertebrates. The dramatic expansion of the brain that diverges its shape from the spinal cord follows neural tube closure during embryonic development. Here, we show that this differential deformation is encoded by a pre-pattern of tissue material properties in chicken embryos. Using magnetic droplets and atomic force microscopy, we demonstrate that the dorsal hindbrain is more fluid than the dorsal spinal cord, resulting in a thinning versus a resisting response to increasing lumen pressure, respectively. The dorsal hindbrain exhibits reduced apical actin and a disorganized laminin matrix consistent with tissue fluidization. Blocking the activity of neural-crest-associated matrix metalloproteinases inhibits hindbrain expansion. Transplanting dorsal hindbrain cells to the spinal cord can locally create an expanded brain-like morphology in some cases. Our findings raise questions in vertebrate head evolution and suggest a general role of mechanical pre-patterning in sculpting epithelial tubes.
    Keywords:  ECM; brain; development; extracellular matrix; lumen; morphogenesis; neural tube; pressure; spinal cord; tissue fluidity; tissue mechanics
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.010
  7. J Cell Sci. 2025 May 01. pii: jcs263895. [Epub ahead of print]138(9):
    Mitochondria-membranous organelle contacts at a glance.
    Antigoni Diokmetzidou, Luca Scorrano.
      Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined by unique proteomic and lipidomic profiles, these sites enable direct interorganellar communication and functional coordination, playing crucial roles in cellular physiology and homeostasis. Recent advances have expanded our knowledge of contact site-resident proteins, illuminated the dynamic and adaptive nature of these interfaces, and clarified their contribution to pathophysiology. In this Cell Science at a Glance article and the accompanying poster, we summarize the mitochondrial contacts that have been characterized in mammals, the molecular mechanisms underlying their formation, and their principal functions.
    Keywords:  Contact sites; Mitochondria; Organelles
    DOI:  https://doi.org/10.1242/jcs.263895
  8. Nat Rev Genet. 2025 May 12.
    X-linked competition - implications for human development and disease.
    Philip M Boone, Teresa Buenaventura, James W D King, Matthias Merkenschlager.
      During early mammalian female development, X chromosome inactivation leads to random transcriptional silencing of one of the two X chromosomes. This inactivation is maintained through subsequent cell divisions, leading to intra-individual diversity, whereby cells express either the maternal or paternal X chromosome. Differences in X chromosome sequence content can trigger competitive interactions between clones that may alter organismal development and skew the representation of X-linked sequence variants in a cell-type-specific manner - a recently described phenomenon termed X-linked competition in analogy to existing cell competition paradigms. Skewed representation can define the phenotypic impact of X-linked variants, for example, the manifestation of disease in female carriers of X-linked disease alleles. Here, we review what is currently known about X-linked competition, reflect on what remains to be learnt and map out the implications for X-linked human disease.
    DOI:  https://doi.org/10.1038/s41576-025-00840-3
  9. Sci Signal. 2025 May 13. 18(886): eadr7926
    E-cadherin mechanotransduction activates EGFR-ERK signaling in epithelial monolayers by inducing ADAM-mediated ligand shedding.
    Ronja M Houtekamer, Mirjam C van der Net, Marjolein J Vliem, Tomas E J C Noordzij, Lisa van Uden, Robert M van Es, Joo Yong Sim, Eriko Deguchi, Kenta Terai, Matthew A Hopcroft, Harmjan R Vos, Beth L Pruitt, Michiyuki Matsuda, Willem-Jan Pannekoek, Martijn Gloerich.
      The behavior of cells is governed by signals originating from their local environment, including mechanical forces exerted on the cells. Forces are transduced by mechanosensitive proteins, which can impinge on signaling cascades that are also activated by growth factors. We investigated the cross-talk between mechanical and biochemical signals in the regulation of intracellular signaling networks in epithelial monolayers. Phosphoproteomic and transcriptomic analyses on epithelial monolayers subjected to mechanical strain revealed the activation of extracellular signal-regulated kinase (ERK) downstream of the epidermal growth factor receptor (EGFR) as a predominant strain-induced signaling event. Strain-induced EGFR-ERK signaling depended on mechanosensitive E-cadherin adhesions. Proximity labeling showed that the metalloproteinase ADAM17, an enzyme that mediates shedding of soluble EGFR ligands, was closely associated with E-cadherin. A probe that we developed to monitor ADAM-mediated shedding demonstrated that mechanical strain induced ADAM activation. Mechanically induced ADAM activation was essential for mechanosensitive, E-cadherin-dependent EGFR-ERK signaling. Together, our data demonstrate that mechanical strain transduced by E-cadherin adhesion triggers the shedding of EGFR ligands that stimulate downstream ERK activity. Our findings illustrate how mechanical signals and biochemical ligands can operate within a linear signaling cascade.
    DOI:  https://doi.org/10.1126/scisignal.adr7926
  10. Nat Mater. 2025 May 12.
    Viscous dissipation in the rupture of cell-cell contacts.
    Aditya Arora, Mohd Suhail Rizvi, Gianluca Grenci, Florian Dilasser, Chaoyu Fu, Modhura Ganguly, Sree Vaishnavi, Kathirvel Paramsivam, Srikanth Budnar, Ivar Noordstra, Alpha S Yap, Virgile Viasnoff.
      Cell-cell adhesions mediated by adherens junctions, structures connecting cells to each other and to the cortical cytoskeleton, are essential for epithelial physical and biological integrity. Nonetheless, how such structures resist mechanical stimuli that prompt cell-cell rupture is still not fully understood. Here we challenge the conventional views on cell-cell adhesion stability, highlighting the importance of viscous dissipation at the cellular level. Using microdevices to measure the rupture energy of cell-cell junctions and synthetic cadherins to discriminate cadherin binding energy from downstream cytoskeletal regulation, we demonstrate that the balance between cortical tension and cell shape recovery time determines a transition from ductile to brittle fracture in cell-cell contact. These findings suggest that junction toughness, defined as the junction disruption energy, is a more accurate measure of junctional stability, challenging the current emphasis on bond energy and tension. Overall, our results highlight the role and the regulation of energy dissipation through the cytoskeleton during junction deformation for epithelial integrity.
    DOI:  https://doi.org/10.1038/s41563-025-02232-8
  11. Semin Cell Dev Biol. 2025 May 13. pii: S1084-9521(25)00029-1. [Epub ahead of print]171 103619
    Cardiac regeneration: Unraveling the complex network of intercellular crosstalk.
    Bailin Wu, Florian Constanty, Arica Beisaw.
      The heart is composed of multiple cell types, including cardiomyocytes, endothelial/endocardial cells, fibroblasts, resident immune cells and epicardium and crosstalk between these cell types is crucial for proper cardiac function and homeostasis. In response to cardiac injury or disease, cell-cell interactions and intercellular crosstalk contribute to remodeling to compensate reduced heart function. In some vertebrates, the heart can regenerate following cardiac injury. While cardiomyocytes play a crucial role in this process, additional cell types are necessary to create a pro-regenerative microenvironment in the injured heart. Here, we review recent literature regarding the importance of cellular crosstalk in promoting cardiac regeneration and provide insight into emerging technologies to investigate cell-cell interactions in vivo. Lastly, we explore recent studies highlighting the importance of inter-organ communication in response to injury and promotion of cardiac regeneration. Importantly, understanding how intercellular and inter-organ crosstalk promote cardiac regeneration is essential for the development of therapeutic strategies to stimulate regeneration in the human heart.
    Keywords:  Cardiac regeneration; Cell-cell interaction; Inter-organ communication; Intercellular crosstalk; Mouse; Zebrafish
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103619
  12. Nature. 2025 May 15.
    Ku limits RNA-induced innate immunity to allow Alu-expansion in primates.
    Yimeng Zhu, Angelina Li, Suvrajit Maji, Brian J Lee, Sophie M Korn, Jake A Gertie, Tyler J Dorrity, Jianhua Wang, Kyle J Wang, Amandine Pelletier, Daniel F Moakley, Rachel D Kelly, Antony B Holmes, Raul Rabadan, David R Edgell, Caroline Schild Poulter, Mauro Modesti, Anna-Lena Steckelberg, Eric A Hendrickson, Hachung Chung, Chaolin Zhang, Shan Zha.
      Ku70 and Ku80 form Ku, a ring-shaped complex that initiates the non-homologous end-joining (NHEJ) DNA repair pathway.1 Ku binds to double-stranded DNA (dsDNA) ends and recruits other NHEJ factors (e.g., LIG4, DNA-PKcs). While Ku can bind to double-stranded RNA (dsRNA)2 and trap mutated-DNA-PKcs on ribosomal RNA (rRNA),3,4 the physiological role on Ku-RNA interaction in otherwise wildtype cells remains unclear. Intriguingly, Ku is dispensable for murine development5,6 but essential in human cells.7 Despite similar genome sizes, human cells express ~100-fold more Ku than mouse cells, implying functions beyond NHEJ - possibly through a dose-sensitive interaction with dsRNA, which binds Ku 10~100 times weaker than dsDNA.2,8 Investigating Ku's essentiality in human cells, we found that Ku-depletion - unlike LIG4 - induces profound interferon (IFN) and NF-kB signaling via dsRNA-sensor MDA5/RIG-I and MAVS. Prolonged Ku-degradation further activates other dsRNA sensors, especially PKR (suppressing translation) and OAS/RNaseL (cleaving rRNA), leading to growth arrest and cell death. MAVS, RIG-I, or MDA5 knockouts suppressed IFN signaling and, like PKR knockouts, all partially rescued Ku-depleted human cells. Ku-irCLIP analyses revealed Ku binding to diverse dsRNA, predominantly stem-loops in primate-specific antisense Alu elements9 in introns and 3'-UTRs. Ku expression rose sharply in higher primates, correlating tightly with Alu-expansion (r = 0.94/0.95). Thus, Ku plays a vital role in accommodating Alu-expansion in primates by limiting dsRNA-induced innate immunity, explaining both Ku's elevated expression and its essentiality in human cells.
    DOI:  https://doi.org/10.1038/s41586-025-09104-w
  13. Nat Commun. 2025 May 10. 16(1): 4349
    RNA transcripts serve as a template for double-strand break repair in human cells.
    Manisha Jalan, Alessandra Brambati, Hina Shah, Niamh McDermott, Juber Patel, Yingjie Zhu, Ahmet Doymaz, Julius Wu, Kyrie S Anderson, Andrea Gazzo, Fresia Pareja, Takafumi N Yamaguchi, Theodore Vougiouklakis, Sana Ahmed-Seghir, Philippa Steinberg, Anna Neiman-Golden, Benura Azeroglu, Joan Gomez-Aguilar, Edaise M da Silva, Suleman Hussain, Daniel Higginson, Paul C Boutros, Nadeem Riaz, Jorge S Reis-Filho, Simon N Powell, Agnel Sfeir.
      Double-strand breaks (DSBs) are toxic lesions that lead to genome instability. While canonical DSB repair pathways typically operate independently of RNA, growing evidence suggests that RNA:DNA hybrids and nearby transcripts can influence repair outcomes. However, whether transcript RNA can directly serve as a template for DSB repair in human cells remains unclear. In this study, we develop fluorescence and sequencing-based assays to show that RNA-containing oligonucleotides and messenger RNA can serve as templates during DSB repair. We conduct a CRISPR/Cas9-based genetic screen to identify factors that promote RNA-templated DSB repair (RT-DSBR). Of the candidate polymerases, we identify DNA polymerase zeta (Polζ) as a potential reverse transcriptase that facilitates RT-DSBR. Furthermore, analysis of cancer genome sequencing data reveals whole intron deletions - a distinct genomic signature of RT-DSBR that occurs when spliced mRNA guides repair. Altogether, our findings highlight RT-DSBR as an alternative pathway for repairing DSBs in transcribed genes, with potential mutagenic consequences.
    DOI:  https://doi.org/10.1038/s41467-025-59510-x
  14. Nat Biotechnol. 2025 May 15.
    Proteoform profiling of endogenous single cells from rat hippocampus at scale.
    Pei Su, Michael A R Hollas, Indira Pla, Stanislav Rubakhin, Fatma Ayaloglu Butun, Joseph B Greer, Bryan P Early, Ryan T Fellers, Michael A Caldwell, Jonathan V Sweedler, Jared O Kafader, Neil L Kelleher.
      We perform intact proteoform profiling of 10,809 endogenous single cells from the rat hippocampus using single-cell proteoform imaging mass spectrometry (scPiMS). scPiMS directly extracts whole proteins and demonstrates high throughput for MS-based single-cell proteomics compared with existing approaches. We develop an informatics workflow dedicated to this datatype and use it to assign neurons, astrocytes or microglia cell types according to their proteoform signatures.
    DOI:  https://doi.org/10.1038/s41587-025-02669-x
  15. Nat Methods. 2025 May 13.
    Prediction of protein subcellular localization in single cells.
    Xinyi Zhang, Yitong Tseo, Yunhao Bai, Fei Chen, Caroline Uhler.
      The subcellular localization of a protein is important for its function, and its mislocalization is linked to numerous diseases. Existing datasets capture limited pairs of proteins and cell lines, and existing protein localization prediction models either miss cell-type specificity or cannot generalize to unseen proteins. Here we present a method for Prediction of Unseen Proteins' Subcellular localization (PUPS). PUPS combines a protein language model and an image inpainting model to utilize both protein sequence and cellular images. We demonstrate that the protein sequence input enables generalization to unseen proteins, and the cellular image input captures single-cell variability, enabling cell-type-specific predictions. Experimental validation shows that PUPS can predict protein localization in newly performed experiments outside the Human Protein Atlas used for training. Collectively, PUPS provides a framework for predicting differential protein localization across cell lines and single cells within a cell line, including changes in protein localization driven by mutations.
    DOI:  https://doi.org/10.1038/s41592-025-02696-1
  16. Cell Stem Cell. 2025 May 07. pii: S1934-5909(25)00178-X. [Epub ahead of print]
    Establishing dorsal-ventral patterning in human neural tube organoids with synthetic organizers.
    Tao Luo, Cong Liu, Tao Cheng, Guo-Qin Zhao, Ying Huang, Jing-Yun Luan, Junyu Guo, Xiang Liu, Yi-Fan Wang, Yang Dong, Yu Xiao, Enhui He, Rui-Zhen Sun, Xiuyu Chen, Jiekai Chen, Jun Ma, Sean Megason, Junfeng Ji, Peng-Fei Xu.
      Precise dorsal-ventral (D-V) patterning of the neural tube (NT) is essential for the development and function of the central nervous system. However, existing models for studying NT D-V patterning and related human diseases remain inadequate. Here, we present organizers derived from pluripotent stem cell aggregate fusion ("ORDER"), a method that establishes opposing BMP and SHH gradients within neural ectodermal cell aggregates. Using this approach, we generated NT organoids with ordered D-V patterning from both zebrafish and human pluripotent stem cells (hPSCs). Single-cell transcriptomic analysis revealed that the synthetic human NT organoids (hNTOs) closely resemble the human embryonic spinal cord at Carnegie stage 12 (CS12) and exhibit greater similarity to human NT than to mouse models. Furthermore, using the hNTO model, we demonstrated the critical role of WNT signaling in regulating intermediate progenitors, modeled TCTN2-related D-V patterning defects, and identified a rescue strategy.
    Keywords:  BMP; SHH; neural tube; organoid; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.04.011
  17. Nat Aging. 2025 May 12.
    Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.
    Seyed Soheil Saeedi Saravi, Benoit Pugin, Florentin Constancias, Khatereh Shabanian, Marianne Spalinger, Aurélien Thomas, Sylvain Le Gludic, Taraneh Shabanian, Gergely Karsai, Manuel Colucci, Cristina Menni, Ilias Attaye, Xinyuan Zhang, Meret Sarah Allemann, Pratintip Lee, Alessia Visconti, Mario Falchi, Andrea Alimonti, Frank Ruschitzka, Francesco Paneni, Jürg H Beer.
      Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 (Clos). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H2O2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut-vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.
    DOI:  https://doi.org/10.1038/s43587-025-00864-8
  18. Development. 2025 May 15. pii: dev.204277. [Epub ahead of print]
    Evidence of secondary Notch signaling within the rat small intestine.
    Eleanor Zagoren, Nicolas Dias, Anderson K Santos, Zachary D Smith, Nadia A Ameen, Kaelyn Sumigray.
      The small intestine is well known for its nutrient-absorbing enterocytes; yet equally critical for homeostasis is a diverse set of secretory cells, all presumed to originate from the same intestinal stem cell. Despite their major roles in intestinal function and health, understanding how the full spectrum of secretory cell types arises remains a longstanding challenge, largely due to their comparative rarity. Here, we investigate the specification of a rare population of small intestinal epithelial cells found in rats and humans but not mice: CFTR High Expressers (CHEs). Using pseudotime trajectory analysis of single-cell RNA-seq data from rat jejunum, we provide evidence that CHEs are specified along the secretory lineage and appear to employ a second wave of Notch-based signaling to distinguish themselves from other secretory cells. We validate the transcription factors directing these cells from crypt progenitors and demonstrate that Notch signaling is necessary to induce CHE fate in vivo and in vitro. Our findings suggest that Notch reactivation along the secretory lineage specifies CHEs, which may help regulate luminal pH and have direct relevance in cystic fibrosis pathophysiology.
    Keywords:  CFTR High Expressers Cells (CHEs); Notch signaling; Secretory cells; Single-cell RNA-seq; Small intestine
    DOI:  https://doi.org/10.1242/dev.204277
  19. Nat Chem Biol. 2025 May 14.
    Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
    Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, António M de Jesus Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric Nathaniel Anderson, Frank Stein, Hyun O Lee, Xiaojie Zhang, Anatol W Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C Murthy, Simon Alberti, Marc Bickle, Nicolas L Fawzi, André Nadler, Della C David, Udai B Pandey, Andreas Hermann, Florian Stengel, Benjamin G Davis, Andrew J Baldwin, Mikhail M Savitski, Anthony A Hyman, Richard J Wheeler.
      Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.
    DOI:  https://doi.org/10.1038/s41589-025-01893-5
  20. Development. 2025 May 01. pii: dev204696. [Epub ahead of print]152(9):
    Emerging roles for the nucleolus in development and stem cells.
    Bryony J Leeke, Imke Staffhorst, Michelle Percharde.
      The nucleolus is a membrane-less subnuclear compartment known for its role in ribosome biogenesis. However, emerging evidence suggests that nucleolar function extends beyond ribosome production and is particularly important during mammalian development. Nucleoli are dynamically reprogrammed post-fertilisation: totipotent early mouse embryos display non-canonical, immature nucleolar precursor bodies, and their remodelling to mature nucleoli is essential for the totipotency-to-pluripotency transition. Mounting evidence also links nucleolar disruption to various pathologies, including embryonic lethality in mouse mutants for nucleolar factors, human developmental disorders and observations of nucleolar changes in disease states. As well as its role in ribogenesis, new findings point to the nucleolus as an essential regulator of genome organisation and heterochromatin formation. This Review summarises the varied roles of nucleoli in development, primarily in mammals, highlighting the importance of nucleolar chromatin for genome regulation, and introduces new techniques for exploring nucleolar function.
    Keywords:  Development; ESCs; Heterochromatin; NADs; Nuclear architecture; Nucleoli
    DOI:  https://doi.org/10.1242/dev.204696
  21. Development. 2025 May 16. pii: dev.204505. [Epub ahead of print]
    Small molecule and cell contact-inducible systems for controlling expression and differentiation in mouse embryonic stem cells.
    Sarah S Soliman, Devan H Shah, Hana El-Samad, Zara Y Weinberg.
      Synthetic developmental biology uses engineering approaches to understand multicellularity with goals ranging from recapitulating development to building synthetic organisms. Current approaches include engineering multicellular patterning, controlling differentiation, and implementing cooperative cellular behaviors in model systems. Synthetic biology enables these pursuits by providing tools to control cell behavior. Mouse embryonic stem cells (mESCs) offer a well-studied and genetically tractable pluripotent model for pursuing synthetic development questions. However, there is minimal characterization of existing synthetic biology tools in mESCs. Here, we characterize three small molecule and two cell contact-inducible systems for gene expression in and differentiation of mESCs. We show that small molecule and cell-contact inducible systems work reliably and efficiently for controlling expression of arbitrary genetic payloads. We identify how these systems function differently across model differentiations. Furthermore, we show that these systems can drive direct differentiation of mESCs into neurons. Each of these systems can be used on their own or in combination, opening many possibilities for studying developmental principles with high precision.
    Keywords:  Cell engineering; Differentiation; Gene expression; Inducible systems; Stem cells; Synthetic development
    DOI:  https://doi.org/10.1242/dev.204505
  22. EMBO J. 2025 May 12.
    Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells.
    Esteban Quezada, Klaus-Peter Knoch, Jovana Vasiljevic, Annika Seiler, Akshaye Pal, Abishek Gunasekaran, Carla Münster, Daniela Friedland, Eyke Schöniger, Anke Sönmez, Pascal Roch, Carolin Wegbrod, Katharina Ganß, Nicole Kipke, Simon Alberti, Rita Nano, Lorenzo Piemonti, Daniela Aust, Jürgen Weitz, Marius Distler, Michele Solimena.
      Upregulation of insulin mRNA translation upon hyperglycemia in pancreatic islet β-cells involves several RNA-binding proteins. Here, we found that G3BP1, a stress granule marker downregulated in islets of subjects with type 2 diabetes, binds to insulin mRNA in glucose concentration-dependent manner. We show in mouse insulinoma MIN6-K8 cells exposed to fasting glucose levels that G3BP1 and its paralog G3BP2 colocalize to cytosolic condensates with eIF3b, phospho-AMPKαThr172 and Ins1/2 mRNA. Glucose stimulation dissolves G3BP1+/2+ condensates with cytosolic redistribution of their components. The aldolase inhibitor aldometanib prevents the glucose- and pyruvate-induced dissolution of G3BP1+/2+ condensates, increases phospho-AMPKαThr172 levels and reduces those of phospho-mTORSer2448. G3BP1 or G3BP2 depletion precludes condensate assembly. KO of G3BP1 decreases Ins1/2 mRNA abundance and translation as well as proinsulin levels, and impaires glucose-stimulated insulin secretion. Further, other insulin secretagogues such as exendin-4 and palmitate, but not high KCl, prompts the dissolution of G3BP1+/2+ condensates. G3BP1+/2+/Ins mRNA+ condensates are also found in primary mouse and human β-cells. Hence, G3BP1+/2+ condensates represent a conserved glycolysis/aldolase-regulated compartment for the physiological storage and protection of insulin mRNA in resting β-cells.
    Keywords:  Diabetes; Insulin; Islet; Stress Granules; Translation
    DOI:  https://doi.org/10.1038/s44318-025-00448-7
  23. Cell Metab. 2025 May 08. pii: S1550-4131(25)00253-0. [Epub ahead of print]
    Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
    Jessica W Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J Coon, James A Shayman, Monther Abu-Remaileh, Judith A Simcox.
      Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.
    Keywords:  BMP; LC-MS; Pla2g15; TFEB; bis(monoacylglycero)phosphate; cold exposure; lipidomics; liquid chromatography-mass spectrometry; liver; lysosome; phospholipase A2 G15; transcription factor EB
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.015
This page is being maintained by Thomas Krichel. It was last updated on 2025‒05‒27 at 4:28.