bims-ginsta 2025-06-08 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2025–06–08
nineteen papers selected by
Jinrong Hu, National University of Singapore

A Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary.
PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice.
Depletion of aneuploid cells is shaped by cell-to-cell interactions.
RNA Pol I activity maintains chromatin condensation and the H3K4me3 gradient essential for oogenesis, independent of ribosome production.
Control of tissue flows and embryo geometry in avian gastrulation.
Inorganic profiles of preimplantation embryos reveal a role for zinc in blastocyst development.
Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization.
Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
Landscape and regulation of mRNA translation in the early C. elegans embryo.
Establishment of cell size-dependent growth rate via differential scaling of metabolite uptake and release.
Eomesodermin in conjunction with the BAF complex promotes expansion and invasion of the trophectoderm lineage.
Probing condensate microenvironments with a micropeptide killswitch.
Challenges and Opportunities in Spatiotemporal Models of Mammalian Gastrulation.
Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS.
Ubinuclein 2 is essential for mouse development and functions in X chromosome inactivation.
Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.
ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.
Maternal iron deficiency causes male-to-female sex reversal in mouse embryos.
Clearance of protein aggregates during cell division.

Aging Cell. 2025 Jun 01. e70111

A Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary.

Pooja Raj Devrukhkar, Mark A Watson, Bikem Soygur, Fei Wu, Joanna Bons, Hannah Anvari, Tomiris Atazhanova, Nicolas Martin, Tommy Tran, Kevin Schneider, Jacob P Rose, Daniel Winer, Elisheva Shanes, Mary Ellen G Pavone, Judith Campisi, David Furman, Simon Melov, Birgit Schilling, Francesca E Duncan.

  A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary. We thus established a doxorubicin-induced model of cellular senescence to establish a "senotype" (gene/protein signature of a senescence cell state) for ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 h, followed by culture for up to 10 days in a doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins: Lumican, SOD2, MYH9, and Periostin were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging, inform biomarker development to identify, and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.

Keywords:  cellular senescence; explant tissues; ovarian aging; reproductive aging; senescence‐associated secretory phenotype SASP

DOI:  https://doi.org/10.1111/acel.70111
J Clin Invest. 2025 Jun 02. pii: e184158. [Epub ahead of print]135(11):

PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice.

Liran Xu, Ting Li, Yapeng Cao, Yu He, Zehua Shao, Siyu Liu, Bianbian Wang, Ailing Su, Huijing Tian, Yongxin Li, Guozheng Liang, Changhe Wang, John Shyy, Ying Xiong, Fangyuan Chen, Jason Xj Yuan, Junjun Liu, Bin Zhou, Nina Wettschureck, Stefan Offermanns, Yang Yan, Zuyi Yuan, Shengpeng Wang.

  Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the excessive accumulation of activated myofibroblasts that deposit extracellular matrix (ECM) protein, leading to progressive scar formation and mechanical stress. However, the cellular origin and fate of myofibroblasts remain controversial, and the mechanisms by which myofibroblasts sense mechanical cues in the lung are unclear. Here, we report that periostin (Postn) is a reliable and distinctive marker for pulmonary myofibroblasts, while ablation of Postn+ myofibroblasts after injury ameliorated lung fibrosis. PIEZO1 was highly expressed in Postn+ myofibroblast and played a vital role in mechanoactivation of Postn+ myofibroblast and development of lung fibrosis. Conditional deletion of Piezo1 in Postn+ myofibroblasts significantly inhibited lung fibrosis by suppressing myofibroblast activation and proliferation. Loss of Piezo1 led to disruption of actin organization and prevention of Yap/Taz nuclear localization, thus shifting the myofibroblasts from a proliferative state into a stressed and apoptotic state. Furthermore, myofibroblast-specific Yap/Taz deletion fully recapitulated the protective phenotypes of myofibroblast-Piezo1-KO mice. These findings show that periostin marks pulmonary myofibroblasts, and that PIEZO1-mediated mechanosensation is essential for myofibroblast activation in the lung. Targeting PIEZO1 in the periostin-expressing cells is a novel therapeutic option to interfere with fibrotic diseases such as IPF .

Keywords:  Cell biology; Fibrosis; Ion channels; Pulmonology

DOI:  https://doi.org/10.1172/JCI184158
Cell Genom. 2025 May 28. pii: S2666-979X(25)00150-8. [Epub ahead of print] 100894

Depletion of aneuploid cells is shaped by cell-to-cell interactions.

Elena Fusari, Mariana Muzzopappa, Juliette Gracia, Marco Milán.

  Aneuploidy is pervasive in early human embryos but robustly dampened during development. Later in life, aneuploidy correlates with pathological conditions, including cancer. Identification of the mechanisms underlying the elimination of aneuploid cells is relevant in development and disease. We characterized the impact on cell proliferation and survival of a large collection of molecularly defined segmental monosomies and trisomies of different sizes and ranges of overlap. Our data reveal signs of outcompetition of cells carrying small monosomies in regions devoid of previously known haploinsufficient genes. Dose-dependent effects of single genes or a discrete number of genes contribute to the phenomenon of cell competition through different mechanisms. By simultaneously inducing cells carrying monosomies and trisomies of the same genomic location, we show that trisomies potentiate or alleviate the negative effects of monosomy on growth, thus revealing a key role of cell interactions in defining the in vivo elimination of aneuploid cells.

Keywords:  TOR; Xrp1; aneuploidy; cell competition; cell death; haploinsufficiency

DOI:  https://doi.org/10.1016/j.xgen.2025.100894
bioRxiv. 2025 May 12. pii: 2025.05.07.652530. [Epub ahead of print]

RNA Pol I activity maintains chromatin condensation and the H3K4me3 gradient essential for oogenesis, independent of ribosome production.

Raquel Mejia-Trujillo, Qiuxia Zhao, Ayesha Rahman, Elif Sarinay Cenik.

Oogenesis requires extensive and dynamic chromatin remodeling that primes gene promoters for later transcriptional activation during embryonic development. Here, we uncover a pivotal, non-canonical role for RNA Polymerase I (Pol I) in driving these chromatin state transitions during Caenorhabditis elegans oogenesis. Using the auxin-inducible degron system to selectively deplete either a Pol I-specific catalytic subunit or a ribosome assembly factor, we disentangle the consequences of impaired nucleolar integrity from reductions in ribosome biogenesis. Strikingly, although disrupting ribosome assembly caused minimal effects on oocyte production, loss of nucleolar structure via Pol I depletion led to severe meiotic chromosome abnormalities, widespread changes in chromatin accessibility, and a dampening of the typical distal-proximal H3K4me3 gradient required for oogenesis, resulting in fewer but significantly larger oocytes. Despite their promoters becoming more accessible, oogenesis genes did not show large changes in steady-state mRNA, consistent with transcriptional repression prior to fertilization. Instead, Pol I depletion prematurely remodeled oogenic chromatin, through a misdirection of H3K4me3 deposition towards promoters normally primed for zygotic genome activation. These findings reveal an epigenetic gating function for nucleolar integrity in oocyte maturation: Pol I preserves three-dimensional chromatin organization and maintains proper spatiotemporal regulation of histone modifications, independent of ribosome production. Given the evolutionary conservation of nucleolar dynamics and histone modifications during gametogenesis, our work suggests that nucleolar stress, whether from environmental factors, aging, or genetic disorders, could broadly compromise fertility by disrupting oogenic chromatin priming.

DOI: https://doi.org/10.1101/2025.05.07.652530
Nat Commun. 2025 Jun 04. 16(1): 5174

Control of tissue flows and embryo geometry in avian gastrulation.

Guillermo Serrano Nájera, Alex M Plum, Ben Steventon, Cornelis J Weijer, Mattia Serra.

Embryonic tissues undergo coordinated flows during avian gastrulation to establish the body plan. Here, we elucidate how the interplay between embryonic and extraembryonic tissues affects the chick embryo's size and shape. These two distinct geometric changes are each associated with dynamic curves across which trajectories separate (kinematic repellers). Through physical modeling and experimental manipulations of both embryonic and extraembryonic tissues, we selectively eliminate either or both repellers in model and experiments, revealing their mechanistic origins. We find that embryo size is affected by the competition between extraembryonic epiboly and embryonic myosin-driven contraction-which persists when mesoderm induction is blocked. Instead, the characteristic shape change from circular to pear-shaped arises from myosin-driven cell intercalations in the mesendoderm, irrespective of epiboly. These findings elucidate modular mechanisms controlling avian gastrulation flows and provide a mechanistic basis for the independent control of embryo size and shape during development.

DOI: https://doi.org/10.1038/s41467-025-60249-8
bioRxiv. 2025 May 18. pii: 2025.05.14.654061. [Epub ahead of print]

Inorganic profiles of preimplantation embryos reveal a role for zinc in blastocyst development.

Julia L Balough, Thomas V O'Halloran, Francesca E Duncan, Teresa K Woodruff.

Elements such as iron, copper and zinc play essential roles in the mammalian oocyte, egg, and embryo, however among these metals, zinc plays unique regulatory roles. Temporal fluctuations in zinc concentrations drive reproductive milestones such as meiotic resumption, egg activation, and initiation of the mitotic cell cycle. Roles for zinc in late preimplantation embryo development, have not been well characterized. Using a quantitative element approach we report the inorganic profiles of mouse embryos progressing through the late blastocyst stage. We find that blastocysts, like oocytes and eggs, and distinct to somatic cells, maintain higher levels of zinc than copper and iron. All three of these essential metals are more abundant in the inner cell mass, which contains the population of pluripotent stem cells that give rise to the fetus, relative to the trophectoderm which gives rise to the placenta and extraembryonic tissues. To test whether zinc abundance was associated with mitotic progress and cell fate lineage, we perturbed zinc homeostasis during blastocyst formation by artificially raising intracellular zinc concentrations with zinc pyrithione. This treatment during the morula-to-blastocyst transition when cell fate lineages emerge resulted in an elevation of zinc in the ICM. This treatment did not impact cell number, but did increase expression of the pluripotency and epiblast marker, Nanog , and decreased expression of the primitive endoderm marker, Gata4 . These results demonstrate that the inorganic profiles of the late preimplantation embryo retain elemental hallmarks of earlier developmental stages and perturbation of zinc levels alters pluripotency gene expression in the blastocyst.

DOI: https://doi.org/10.1101/2025.05.14.654061
Science. 2025 Jun 05. 388(6751): eadu9375

Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization.

Oscar J Abilez, Huaxiao Yang, Yuan Guan, Mengcheng Shen, Zehra Yildirim, Yan Zhuge, Ravichandra Venkateshappa, Shane R Zhao, Angello H Gomez, Marcel El-Mokahal, Logan Dunkenberger, Yoshikazu Ono, Masafumi Shibata, Peter N Nwokoye, Lei Tian, Kitchener D Wilson, Evan H Lyall, Fangjun Jia, Hung Ta Wo, Gao Zhou, Bryan Aldana, Ioannis Karakikes, Detlef Obal, Gary Peltz, Christopher K Zarins, Joseph C Wu.

Although model organisms have provided insight into the earliest stages of cardiac and hepatic vascularization, we know very little about this process in humans because of ethical restrictions and the technical difficulty of obtaining embryos during very early development. In this study, we demonstrate that micropatterned human pluripotent stem cell-derived gastruloids enable in vitro modeling of the earliest stages of vascularization. We identify a combination of vascular-inducing factors that give rise to cardiac vascularized organoids with a spatially organized and branched vascular network. To show the broader utility of our vascularization strategy, we use the same vascular-inducing factors to produce hepatic vascularized organoids. Our results suggest that a conserved developmental program generates the vasculature within different types of organs.

DOI: https://doi.org/10.1126/science.adu9375
bioRxiv. 2025 May 15. pii: 2025.05.12.653376. [Epub ahead of print]

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.

Ziyu Lu, Zehao Zhang, Zihan Xu, Abdulraouf Abdulraouf, Wei Zhou, Junyue Cao.

Aging leads to functional decline across tissues, often accompanied by profound changes in cellular composition and cell-intrinsic molecular states. However, a comprehensive catalog of how the population of individual cell types change with age and the associated epigenomic dynamics is lacking. Here, we constructed a single-cell chromatin accessibility atlas consisting of ∼7 million cells from 21 tissue types spanning three age groups in both sexes. This dataset revealed 536 main cell types and 1,828 finer-grained subtypes, defined by unique chromatin accessibility landscapes at ∼1.3 million cis-regulatory elements. We observed widespread remodeling of immune lineages, with increases in plasma cells and macrophages, and depletion of T and B cell progenitors. Additionally, non-immune cell populations, including kidney podocytes, ovary granulosa cells, muscle tenocytes and lung aerocytes, showed marked reductions with age. Meanwhile, many subtypes changed synchronously across multiple organs, underscoring the potential influence of systemic inflammatory signals or hormonal cues. At the molecular level, aging was marked by thousands of differentially accessible regions, with the most concordant changes shared across cell types linked to genes related to inflammation or development. Putative upstream factors, such as intrinsic shifts in transcription factor usages and extrinsic cytokine signatures, were identified. Notably, around 40% of aging-associated main cell types and subtypes showed sex-dependent differences, with tens of thousands of chromatin accessibility peaks altered exclusively in one sex. Together, these findings present a comprehensive framework of how aging reshapes the chromatin landscape and cellular composition across diverse tissues, offering a comprehensive resource for understanding the molecular and cellular programs underlying aging and supporting the exploration of targeted therapeutic strategies to address age-related dysfunction.

DOI: https://doi.org/10.1101/2025.05.12.653376
Cell Rep. 2025 May 30. pii: S2211-1247(25)00549-2. [Epub ahead of print]44(6): 115778

Landscape and regulation of mRNA translation in the early C. elegans embryo.

Yash Shukla, Vighnesh Ghatpande, Cindy F Hu, Daniel J Dickinson, Can Cenik.

  Animal embryos rely on regulated translation of maternally deposited mRNAs to drive early development. Using low-input ribosome profiling combined with RNA sequencing on precisely staged embryos, we measure mRNA translation during the first four cell cycles of C. elegans development. We uncover stage-specific patterns of developmentally coordinated translational regulation. Our results confirm that mRNA localization correlates with translational efficiency, though initial translational repression in germline precursors occurs before P-granule association. Our analysis suggests that the RNA-binding protein OMA-1 represses the translation of its target mRNAs in a stage-specific manner while indirectly promoting the translational efficiency of other transcripts. These findings illuminate how post-transcriptional mechanisms shape the embryonic proteome to direct cell differentiation, with implications for understanding similar regulation across species where maternal factors guide early development.

Keywords:  C. elegans; CP: Developmental biology; CP: Molecular biology; OMA-1; P granules; Ribo-ITP; cell fate determination; embryogenesis; mRNA translation; maternal transcripts; post-transcriptional control; ribosome profiling; translational regulation

DOI:  https://doi.org/10.1016/j.celrep.2025.115778
Proc Natl Acad Sci U S A. 2025 Jun 10. 122(23): e2425347122

Establishment of cell size-dependent growth rate via differential scaling of metabolite uptake and release.

Ian Meliala, Jingyuan Chen, Jiahang Lyu, Mikael Björklund.

  Metabolism fuels cell growth and functions. While it is well established that cellular growth rate scales with cell size, how cells alter their metabolism as they change size remains largely unexplored. Here, we conducted a systematic analysis of cell size-dependent metabolism across the NCI60 cancer cell line panel comprising a diverse range of cell sizes. We demonstrate that cellular metabolism and growth rate display 2/3 allometric scaling due to differential scaling of overall nutrient uptake and waste metabolite release with respect to cell size, with waste elimination decreasing less rapidly than nutrient uptake rate as cells grow larger. This results in cell size-dependent growth rate and predicts a maximum cell size where net nutrient uptake equals zero and cell enlargement ceases despite active metabolism. We experimentally confirm this prediction and identify that electron acceptor demand constrains cell enlargement as evidenced by depletion of intracellular aspartate and scaling of aspartate uptake, which is more than proportional to cell volume. Overall, these findings may have implications for understanding cell size homeostasis, developmental biology, and the design principles of living organisms.

Keywords:  allometry; cell size; growth rate; metabolism; scaling

DOI:  https://doi.org/10.1073/pnas.2425347122
Nat Commun. 2025 May 31. 16(1): 5079

Eomesodermin in conjunction with the BAF complex promotes expansion and invasion of the trophectoderm lineage.

Alexandra Maria Bisia, Maria-Eleni Xypolita, Elizabeth K Bikoff, Elizabeth J Robertson, Ita Costello.

The T-box transcription factor (TF) Eomesodermin/Tbr2 (Eomes) is essential for maintenance of the trophectoderm (TE) lineage, but the molecular mechanisms underlying this critical role remain obscure. Here, we show in trophoblast stem cells (TSCs) that Eomes partners with several TE-specific TFs as well as chromatin remodellers, including Brg1 and other subunits of the BAF complex. Degron-mediated Eomes protein depletion results in genome-wide loss of chromatin accessibility at TSC-specific loci. These overlap with a subset of sites that lose accessibility following Brg1 inhibition, suggesting that Eomes acts as a "doorstop" controlling TSC chromatin accessibility. Eomes depletion also causes transcriptional misregulation of TSC maintenance and early differentiation markers. An additional subset of Eomes-dependent genes encode intercellular/matricellular interaction and cytoskeletal components, likely explaining the implantation defects of Eomes-null embryos. Thus, Eomes promotes TE lineage maintenance by sustaining trophectoderm-specific chromatin accessibility, while promoting the gene regulatory networks that modulate expansion and cell behaviour during implantation.

DOI: https://doi.org/10.1038/s41467-025-60417-w
Nature. 2025 Jun 04.

Probing condensate microenvironments with a micropeptide killswitch.

Yaotian Zhang, Ida Stöppelkamp, Pablo Fernandez-Pernas, Melanie Allram, Matthew Charman, Alexandre P Magalhaes, Melanie Piedavent-Salomon, Gregor Sommer, Yu-Chieh Sung, Katrina Meyer, Nicholas Grams, Edwin Halko, Shivali Dongre, David Meierhofer, Michal Malszycki, Ibrahim A Ilik, Tugce Aktas, Matthew L Kraushar, Nadine Vastenhouw, Matthew D Weitzman, Florian Grebien, Henri Niskanen, Denes Hnisz.

Biomolecular condensates are thought to create subcellular microenvironments that have different physicochemical properties compared with their surrounding nucleoplasm or cytoplasm1-5. However, probing the microenvironments of condensates and their relationship to biological function is a major challenge because tools to selectively manipulate specific condensates in living cells are limited6-9. Here, we develop a non-natural micropeptide (that is, the killswitch) and a nanobody-based recruitment system as a universal approach to probe endogenous condensates, and demonstrate direct links between condensate microenvironments and function in cells. The killswitch is a hydrophobic, aromatic-rich sequence with the ability to self-associate, and has no homology to human proteins. When recruited to endogenous and disease-specific condensates in human cells, the killswitch immobilized condensate-forming proteins, leading to both predicted and unexpected effects. Targeting the killswitch to the nucleolar protein NPM1 altered nucleolar composition and reduced the mobility of a ribosomal protein in nucleoli. Targeting the killswitch to fusion oncoprotein condensates altered condensate compositions and inhibited the proliferation of condensate-driven leukaemia cells. In adenoviral nuclear condensates, the killswitch inhibited partitioning of capsid proteins into condensates and suppressed viral particle assembly. The results suggest that the microenvironment within cellular condensates has an essential contribution to non-stoichiometric enrichment and mobility of effector proteins. The killswitch is a widely applicable tool to alter the material properties of endogenous condensates and, as a consequence, to probe functions of condensates linked to diverse physiological and pathological processes.

DOI: https://doi.org/10.1038/s41586-025-09141-5
Annu Rev Cell Dev Biol. 2025 Jun 04.

Challenges and Opportunities in Spatiotemporal Models of Mammalian Gastrulation.

Hernan Rubinstein, Yoav Mayshar, Yonatan Stelzer.

How cells diversify to form an embryo represents a profound interdisciplinary challenge. Decades of innovative research using model organisms have uncovered principles of lineage specification, morphogenesis, epigenetic mechanisms, and gene regulation that underlie this fundamental process. As biology enters the genomic era, marked by rapid convergence of technological and computational advances, construction of quantitative and heuristic models of development becomes increasingly feasible. In gastrulation, a founding population of equipotent stem cells rapidly diversifies in a highly canonical manner to form the basic body plan. This review discusses considerations required to establish a time-resolved model that reflects the cellular and molecular aspects involved in this process. Building on insights from recent studies and the transformative potential of evolving technologies and experimental frameworks, we discuss how to devise such a model by integrating multiple molecular modalities at the single-cell level within the spatial context as a benchmark for studying cell specification.

DOI: https://doi.org/10.1146/annurev-cellbio-101323-125216
Cell. 2025 May 29. pii: S0092-8674(25)00556-2. [Epub ahead of print]

Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS.

Xavier Lahaye, Patrick Tran Van, Camellia Chakraborty, Anna Shmakova, Ngoc Tran Bich Cao, Hermine Ferran, Ouardia Ait-Mohamed, Mathieu Maurin, Joshua J Waterfall, Benedikt B Kaufer, Patrick Fischer, Thomas Hennig, Lars Dölken, Patrick Lomonte, Daniele Fachinetti, Nicolas Manel.

  The cGAS-cGAMP-STING pathway is crucial for antiviral immunity. While cytosolic cGAS detects viral DNA, most DNA viruses shield their genome and invade the nucleus, where chromatin restricts cGAS activation. How viruses may activate nuclear cGAS is not well understood. Here, we show that several herpesvirus proteins trigger nuclear cGAS activation by perturbing centromeres, where cGAS is enriched. The herpes simplex virus type 1 (HSV-1) ubiquitin ligase infected cell protein 0 (ICP0), which degrades centromeric proteins, promotes centromeric DNA amplification through the translesion DNA synthesis (TLS) pathway in quiescent monocyte-derived cells, thereby activating nuclear cGAS. During infection, HSV-1 evades this detection by also expressing UL36USP, a suppressor of TLS. Similarly to ICP0, the cytomegalovirus IE1 protein causes centromeric DNA amplification and cGAS activation. We define this mechanism as viral-induced centromeric DNA amplification and recognition (VICAR), uncovering a non-mitotic, immune-activating role of centromeres.

Keywords:  CMV; HSV-1; ICP0; UL36USP; VICAR; cGAS; centromeres; innate sensing; translesion DNA synthesis

DOI:  https://doi.org/10.1016/j.cell.2025.05.008
PLoS Genet. 2025 Jun 02. 21(6): e1011711

Ubinuclein 2 is essential for mouse development and functions in X chromosome inactivation.

Asun Monfort, Giulio Di Minin, Sarah Sting, Charles Etienne Dumeau, Peter Scambler, Anton Wutz.

The HIRA complex mediates deposition of histone H3.3 independent of replication. Its functions in gene regulation in mice remain to be fully understood. Here we analyze mutations of the HIRA complex genes Ubn1 and Ubn2. We observe that Ubn1 mutant mice of both sexes are viable and fertile. In contrast, mutation of Ubn2 causes embryonic lethality with variable penetrance and skewed sex ratio in favor of males. Combined Ubn1 and Ubn2 mutations cause embryonic lethality with complete penetrance, variable developmental arrest before turning, and reduced recovery of female embryos. Consistent with a female specific function of the HIRA complex, reanalysis of the Hira mutation during embryogenesis reveals that previously observed severe and mild phenotypic classes correspond to female and male sex. Mechanistically, we show that mutations of Ubn1, Ubn2, and Hira in mouse embryonic stem cells affect the initiation of X inactivation. Xist mediated gene silencing is impaired to increasing extent by Ubn1, Ubn2, Hira, and combined Ubn1 and Ubn2 mutations. We identify a failure of establishing histone H3 tri-methyl lysine 27 over X-linked genes after induction of Xist expression as earliest molecular defect, whereas deacetylation of lysine 27 by Xist remains largely unaffected by the loss of Ubinucleins. Our study thereby identifies a switch from histone H3 acetyl to tri-methyl lysine 27 at the initiation of X inactivation that depends on HIRA complex function.

DOI: https://doi.org/10.1371/journal.pgen.1011711
Nat Neurosci. 2025 Jun 02.

Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.

Kevin Rhine, Rachel Li, Hema M Kopalle, Katherine Rothamel, Xuezhen Ge, Elle Epstein, Orel Mizrahi, Assael A Madrigal, Hsuan-Lin Her, Trent A Gomberg, Anita Hermann, Joshua L Schwartz, Amanda J Daniels, Uri Manor, John Ravits, Robert A J Signer, Eric J Bennett, Gene W Yeo.

Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.

DOI: https://doi.org/10.1038/s41593-025-01952-z
Dev Cell. 2025 May 27. pii: S1534-5807(25)00318-1. [Epub ahead of print]

ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.

Stefano De Tito, Eugenia Almacellas, Daniel Dai Yu, Emily Millard, Wenxin Zhang, Cecilia de Heus, Christophe Queval, Javier H Hervás, Enrica Pellegrino, Ioanna Panagi, Ditte Fogde, Teresa L M Thurston, Judith Klumperman, Maximiliano Gutierrez, Sharon A Tooze.

  Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving endoplasmic reticulum (ER)-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P), and oxysterol-binding protein-like proteins (OSBPLs) lipid transfer proteins. PI4K2A localizes to the trans-Golgi network and endosomes, yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing OSBPL-dependent lipid transfer and promoting the retrieval of ATG9A vesicles through the recruitment of the adaptor protein complex-3 (AP-3). Our results identify a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.

Keywords:  AP-3; ARFIP2; ATG9A; PI4K2A; PI4P; autophagy; lysosomal damage; lysosome; membrane trafficking

DOI:  https://doi.org/10.1016/j.devcel.2025.05.007
Nature. 2025 Jun 04.

Maternal iron deficiency causes male-to-female sex reversal in mouse embryos.

Naoki Okashita, Ryo Maeda, Shunsuke Kuroki, Kyona Sasaki, Yoko Uno, Peter Koopman, Makoto Tachibana.

Ferrous iron (Fe2+) is essential in all eukaryotic cells for various oxidoreductase reactions, including the demethylation of DNA and proteins. Histone demethylation is required for normal epigenetic regulation of the Y-chromosomal sex-determining gene Sry in developing gonads during male sex determination1,2. Here we investigate the potential connection between iron metabolism, histone demethylation and sex determination in mammals. We found that Fe2+-producing pathways are substantially activated in mouse embryonic gonads during the sex-determining period. Chelation of iron in cultured XY gonads reduced the level of KDM3A-mediated H3K9 demethylation of Sry, mostly abolished Sry expression and caused the gonads to express ovarian markers. In vivo, conditional deletion of the gene Tfrc-which is required for iron incorporation-in fetal XY gonadal somatic cells, or acute pharmaceutical suppression of available iron in pregnant mice, resulted in male-to-female gonadal sex reversal in a proportion of offspring, highlighting the pivotal role of iron metabolism in male sex determination. Finally, long-term feeding of pregnant mice with a low-iron diet, when combined with a heterozygous variant of Kdm3a that by itself has no observable effect, suppressed Sry expression and caused male-to-female sex reversal in some of the progeny, revealing a connection between maternal dietary iron and fetal developmental outcomes.

DOI: https://doi.org/10.1038/s41586-025-09063-2
Elife. 2025 Jun 06. pii: RP96675. [Epub ahead of print]13

Clearance of protein aggregates during cell division.

Shoukang Du, Yuhan Wang, Bowen Chen, Shuangshuang Xie, Kuan Yoow Chan, David C Hay, Ting Gang Chew.

  Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.

Keywords:  ER reorganization; aggregates; cell biology; chaperone; human; mitosis; proteostasis

DOI:  https://doi.org/10.7554/eLife.96675