bims-ginsta Biomed News
on Genome instability
Issue of 2025–01–05
twenty-one papers selected by
Jinrong Hu, National University of Singapore
  1. Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity.
  2. Assembly of tight junction belts by ZO1 surface condensation and local actin polymerization.
  3. Cyclin switch tailors a cell cycle variant to orchestrate multiciliogenesis.
  4. Gliomagenesis mimics an injury response orchestrated by neural crest-like cells.
  5. Measuring age-dependent viscoelasticity of organelles, cells and organisms with time-shared optical tweezer microrheology.
  6. Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
  7. The transcription factor GABPA is a master regulator of naive pluripotency.
  8. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
  9. Direct specification of lymphatic endothelium from mesenchymal progenitors.
  10. Structural diversity of axonemes across mammalian motile cilia.
  11. Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration.
  12. Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains.
  13. Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice.
  14. Decoding aging in the heart via single cell dual omics of non-cardiomyocytes.
  15. Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface.
  16. Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.
  17. FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
  18. Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2.
  19. Intracellular pressure controls the propagation of tension in crumpled cell membranes.
  20. Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy.
  21. The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.
  1. Dev Cell. 2024 Dec 26. pii: S1534-5807(24)00737-8. [Epub ahead of print]
    Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity.
    Alexandra L Nguyen, Eric M Smith, Iain M Cheeseman.
      The cohesin complex is critical for genome organization and regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a mediator of cohesin and genome integrity. We show that PRR12 interacts with NIPBL/MAU2 and the cohesin complex, and that the loss of PRR12 results in reduced cohesin localization and a substantial increase in DNA double-strand breaks in mouse NIH-3T3 cells. Additionally, PRR12 co-localizes with NIPBL to sites of DNA damage in a NIPBL and cohesin-dependent manner. We find that the requirement for PRR12 differs across cell lines, with human HeLa cells exhibiting reduced sensitivity to PRR12 loss compared with mouse NIH-3T3 cells, indicating context-specific roles. Together, our work identifies PRR12 as a regulator of cohesin and provides insight into how genome integrity is maintained across diverse cellular contexts.
    Keywords:  DNA damage; MAU2; NIPBL; PRR12; cohesin; cohesinopathies; differential requirements; genome integrity
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.015
  2. Dev Cell. 2024 Dec 26. pii: S1534-5807(24)00735-4. [Epub ahead of print]
    Assembly of tight junction belts by ZO1 surface condensation and local actin polymerization.
    Daxiao Sun, Xueping Zhao, Tina Wiegand, Cecilie Martin-Lemaitre, Tom Borianne, Lennart Kleinschmidt, Stephan W Grill, Anthony A Hyman, Christoph Weber, Alf Honigmann.
      Tight junctions play an essential role in sealing tissues, by forming belts of adhesion strands around cellular perimeters. Recent work has shown that the condensation of ZO1 scaffold proteins is required for tight junction assembly. However, the mechanisms by which junctional condensates initiate at cell-cell contacts and elongate around cell perimeters remain unknown. Combining biochemical reconstitutions and live-cell imaging of MDCKII tissue, we found that tight junction belt formation is driven by adhesion receptor-mediated ZO1 surface condensation coupled to local actin polymerization. Adhesion receptor oligomerization provides the signal for surface binding and local condensation of ZO1 at the cell membrane. Condensation produces a molecular scaffold that selectively enriches junctional proteins. Finally, ZO1 condensates directly facilitate local actin polymerization and filament bundling, driving the elongation into a continuous tight junction belt. More broadly, our work identifies how cells couple surface condensation with cytoskeleton organization to assemble and structure adhesion complexes.
    Keywords:  condensate shaping; cytoskeleton organization; protein condensation; receptor oligomerization; surface phase separation; tight junction; tissue sealing
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.012
  3. Cell Rep. 2024 Dec 24. pii: S2211-1247(24)01454-2. [Epub ahead of print] 115103
    Cyclin switch tailors a cell cycle variant to orchestrate multiciliogenesis.
    Jacques Serizay, Michella Khoury Damaa, Amélie-Rose Boudjema, Rémi Balagué, Marion Faucourt, Nathalie Delgehyr, Camille Noûs, Laure-Emmanuelle Zaragosi, Pascal Barbry, Nathalie Spassky, Romain Koszul, Alice Meunier.
      Meiosis, endoreplication, and asynthetic fissions are variations of the canonical cell cycle where either replication or mitotic divisions are muted. Here, we identify a cell cycle variantconserved across organs and mammals, where both replication and mitosis are muted, and that orchestrates the differentiation of post-mitotic progenitors into multiciliated cells (MCCs). MCC progenitors reactivate most of the cell cycle transcriptional program but replace the temporal expression of cyclins E2 and A2 with non-canonical cyclins O and A1. In addition, the primary APC/C inhibitor Emi1 is silenced. Re-expressing cyclins E2 and A2 and/or Emi1 can induce partial replication or mitosis. This shows that a cell can co-opt the cell cycle genetic program and regulate only certain elements to qualitatively and quantitatively divert CDK activity toward differentiation rather than division. We propose this cell cycle variant to exploit the existence of a cytoplasmic-or centriolar-CDK threshold lower than the S-phase threshold.
    Keywords:  APC/C; CP: Cell biology; CP: Developmental biology; cancer; cell cycle variant; centriole; cilia; ciliopathies; cyclins; meiosis; multiciliated cells; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115103
  4. Nature. 2025 Jan 01.
    Gliomagenesis mimics an injury response orchestrated by neural crest-like cells.
    Akram A Hamed, Kui Hua, Quang M Trinh, Benjamin D Simons, John C Marioni, Lincoln D Stein, Peter B Dirks.
      Glioblastoma is an incurable brain malignancy. By the time of clinical diagnosis, these tumours exhibit a degree of genetic and cellular heterogeneity that provides few clues to the mechanisms that initiate and drive gliomagenesis1,2. Here, to explore the early steps in gliomagenesis, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging, to initiate and then closely track tumour formation. We isolated labelled and unlabelled cells at multiple stages-before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth-and subjected cells of each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogeneous clonal hierarchy that evolves with tumour growth. By exploring the injury response in wounded normal mouse brains, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response program occurs during tumorigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of glioblastoma, identifying a unique cell state and an injury response program tied to early tumour formation. These findings have implications for glioblastoma therapies and raise new possibilities for early diagnosis and prevention of disease.
    DOI:  https://doi.org/10.1038/s41586-024-08356-2
  5. Nat Nanotechnol. 2025 Jan 02.
    Measuring age-dependent viscoelasticity of organelles, cells and organisms with time-shared optical tweezer microrheology.
    Frederic Català-Castro, Santiago Ortiz-Vásquez, Carmen Martínez-Fernández, Fabio Pezzano, Carla Garcia-Cabau, Martín Fernández-Campo, Neus Sanfeliu-Cerdán, Senda Jiménez-Delgado, Xavier Salvatella, Verena Ruprecht, Paolo-Antonio Frigeri, Michael Krieg.
      Quantifying the mechanical response of the biological milieu (such as the cell's interior) and complex fluids (such as biomolecular condensates) would enable a better understanding of cellular differentiation and aging and accelerate drug discovery. Here we present time-shared optical tweezer microrheology to determine the frequency- and age-dependent viscoelastic properties of biological materials. Our approach involves splitting a single laser beam into two near-instantaneous time-shared optical traps to carry out simultaneous force and displacement measurements and quantify the mechanical properties ranging from millipascals to kilopascals across five decades of frequency. To create a practical and robust nanorheometer, we leverage both numerical and analytical models to analyse typical deviations from the ideal behaviour and offer solutions to account for these discrepancies. We demonstrate the versatility of the technique by measuring the liquid-solid phase transitions of MEC-2 stomatin and CPEB4 biomolecular condensates, and quantify the complex viscoelastic properties of intracellular compartments of zebrafish progenitor cells. In Caenorhabditis elegans, we uncover how mutations in the nuclear envelope proteins LMN-1 lamin A, EMR-1 emerin and LEM-2 LEMD2, which cause premature aging disorders in humans, soften the cytosol of intestinal cells during organismal age. We demonstrate that time-shared optical tweezer microrheology offers the rapid phenotyping of material properties inside cells and protein blends, which can be used for biomedical and drug-screening applications.
    DOI:  https://doi.org/10.1038/s41565-024-01830-y
  6. Cell. 2024 Dec 26. pii: S0092-8674(24)01344-8. [Epub ahead of print]
    Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
    Marco Y Hein, Duo Peng, Verina Todorova, Frank McCarthy, Kibeom Kim, Chad Liu, Laura Savy, Camille Januel, Rodrigo Baltazar-Nunez, Madhurya Sekhar, Shivanshi Vaid, Sophie Bax, Madhuri Vangipuram, James Burgess, Leila Njoya, Eileen Wang, Ivan E Ivanov, Janie R Byrum, Soorya Pradeep, Carlos G Gonzalez, Yttria Aniseia, Joseph S Creery, Aidan H McMorrow, Sara Sunshine, Serena Yeung-Levy, Brian C DeFelice, Shalin B Mehta, Daniel N Itzhak, Joshua E Elias, Manuel D Leonetti.
      Defining the subcellular distribution of all human proteins and their remodeling across cellular states remains a central goal in cell biology. Here, we present a high-resolution strategy to map subcellular organization using organelle immunocapture coupled to mass spectrometry. We apply this workflow to a cell-wide collection of membranous and membraneless compartments. A graph-based analysis assigns the subcellular localization of over 7,600 proteins, defines spatial networks, and uncovers interconnections between cellular compartments. Our approach can be deployed to comprehensively profile proteome remodeling during cellular perturbation. By characterizing the cellular landscape following HCoV-OC43 viral infection, we discover that many proteins are regulated by changes in their spatial distribution rather than by changes in abundance. Our results establish that proteome-wide analysis of subcellular remodeling provides key insights for elucidating cellular responses, uncovering an essential role for ferroptosis in OC43 infection. Our dataset can be explored at organelles.czbiohub.org.
    Keywords:  CRISPR; HCoV-OC43 coronavirus; cell biology; ferroptosis; k-NN graph; mass spectrometry; native organelle IP; protein localization; spatial proteomics; subcellular remodeling; viral infection
    DOI:  https://doi.org/10.1016/j.cell.2024.11.028
  7. Nat Cell Biol. 2025 Jan 02.
    The transcription factor GABPA is a master regulator of naive pluripotency.
    Chengjie Zhou, Meng Wang, Chunxia Zhang, Yi Zhang.
      The establishment of naive pluripotency is a continuous process starting with the generation of inner cell mass (ICM) that then differentiates into epiblast (EPI). Recent studies have revealed key transcription factors (TFs) for ICM formation, but which TFs initiate EPI specification remains unknown. Here, using a targeted rapid protein degradation system, we show that GABPA is not only a regulator of major ZGA, but also a master EPI specifier required for naive pluripotency establishment by regulating 47% of EPI genes during E3.5 to E4.5 transition. Chromatin binding dynamics analysis suggests that GABPA controls EPI formation at least partly by binding to the ICM gene promoters occupied by the pluripotency regulators TFAP2C and SOX2 at E3.5 to establish naive pluripotency at E4.5. Our study not only uncovers GABPA as a master pluripotency regulator, but also supports the notion that mammalian pluripotency establishment requires a dynamic and stepwise multi-TF regulatory network.
    DOI:  https://doi.org/10.1038/s41556-024-01554-0
  8. Nat Cell Biol. 2024 Dec 30.
    TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
    TRACERx Consortium
      Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency. FAT1 ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. FAT1 loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of YAP1 partially rescues numerical CIN caused by FAT1 loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP15SA is sufficient to induce numerical CIN. Taken together, we show that FAT1 loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity.
    DOI:  https://doi.org/10.1038/s41556-024-01558-w
  9. Nat Cardiovasc Res. 2025 Jan 02.
    Direct specification of lymphatic endothelium from mesenchymal progenitors.
    Irina-Elena Lupu, David E Grainger, Nils Kirschnick, Sarah Weischer, Erica Zhao, Ines Martinez-Corral, Hans Schoofs, Marie Vanhollebeke, Grace Jones, Jonathan Godwin, Aden Forrow, Ines Lahmann, Paul R Riley, Thomas Zobel, Kari Alitalo, Taija Mäkinen, Friedemann Kiefer, Oliver A Stone.
      During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2+Prox1+ progenitors that directly give rise to LECs. Morphometric analyses of early LEC proliferation and migration, and mutants that disrupt lymphatic development supported these findings. Collectively, this work establishes a cellular blueprint for LEC specification and indicates that discrete pools of mesenchymal progenitors can give rise to specialized subtypes of ECs.
    DOI:  https://doi.org/10.1038/s44161-024-00570-5
  10. Nature. 2025 Jan 01.
    Structural diversity of axonemes across mammalian motile cilia.
    Miguel Ricardo Leung, Chen Sun, Jianwei Zeng, Jacob R Anderson, Qingwei Niu, Wei Huang, Willem E M Noteborn, Alan Brown, Tzviya Zeev-Ben-Mordehai, Rui Zhang.
      Reproduction, development and homeostasis depend on motile cilia, whose rhythmic beating is powered by a microtubule-based molecular machine called the axoneme. Although an atomic model of the axoneme is available for the alga Chlamydomonas reinhardtii1, structures of mammalian axonemes are incomplete1-5. Furthermore, we do not fully understand how molecular structures of axonemes vary across motile-ciliated cell types in the body. Here we use cryoelectron microscopy, cryoelectron tomography and proteomics to resolve the 96-nm modular repeat of axonemal doublet microtubules (DMTs) from both sperm flagella and epithelial cilia of the oviduct, brain ventricles and respiratory tract. We find that sperm DMTs are the most specialized, with epithelial cilia having only minor differences across tissues. We build a model of the mammalian sperm DMT, defining the positions and interactions of 181 proteins including 34 newly identified proteins. We elucidate the composition of radial spoke 3 and uncover binding sites of kinases associated with regeneration of ATP and regulation of ciliary motility. We discover a sperm-specific, axoneme-tethered T-complex protein ring complex (TRiC) chaperone that may contribute to construction or maintenance of the long flagella of mammalian sperm. We resolve axonemal dyneins in their prestroke states, illuminating conformational changes that occur during ciliary movement. Our results illustrate how elements of chemical and mechanical regulation are embedded within the axoneme, providing valuable resources for understanding the aetiology of ciliopathy and infertility, and exemplifying the discovery power of modern structural biology.
    DOI:  https://doi.org/10.1038/s41586-024-08337-5
  11. Nat Cardiovasc Res. 2025 Jan 02.
    Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration.
    Mara Bouwman, Dennis E M de Bakker, Hessel Honkoop, Alexandra E Giovou, Danielle Versteeg, Arie R Boender, Phong D Nguyen, Merel Slotboom, Daniel Colquhoun, Marta Vigil-Garcia, Lieneke Kooijman, Rob Janssen, Ingeborg B Hooijkaas, Marie Günthel, Kimberly J Visser, Mischa Klerk, Lorena Zentilin, Mauro Giacca, Jan Kaslin, Gerard J J Boink, Eva van Rooij, Vincent M Christoffels, Jeroen Bakkers.
      In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program. Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.
    DOI:  https://doi.org/10.1038/s44161-024-00588-9
  12. Mol Cell. 2024 Dec 20. pii: S1097-2765(24)00997-3. [Epub ahead of print]
    Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains.
    Elana Bryan, Devisree Valsakumar, Nwamaka J Idigo, Marie Warburton, Kimberly M Webb, Katy A McLaughlin, Christos Spanos, Simone Lenci, Viktoria Major, Christina Ambrosi, Simon Andrews, Tuncay Baubec, Juri Rappsilber, Philipp Voigt.
      Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state. Strikingly, the bivalent mark combination further promotes recruitment of specific chromatin proteins that are not recruited by each mark individually, including the lysine acetyltransferase (KAT) complex KAT6B. Knockout of KAT6B blocks neuronal differentiation, demonstrating that KAT6B is critical for proper bivalent gene expression during ESC differentiation. These findings reveal how readout of the bivalent histone marks directly promotes a poised state at developmental genes while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.
    Keywords:  Polycomb; bivalent domains; chromatin; differentiation; embryonic stem cells; histone acetylation; histone methylation; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2024.12.002
  13. Nat Commun. 2025 Jan 02. 16(1): 72
    Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice.
    Lu Mu, Ge Wang, Xuebing Yang, Jing Liang, Huan Tong, Lingyu Li, Kaiying Geng, Yingnan Bo, Xindi Hu, Ruobing Yang, Xueqiang Xu, Yan Zhang, Hua Zhang.
      Ovarian function declines significantly as females enter middle-age, but the mechanisms underlying this decline remain unclear. Here, we utilize whole-organ imaging to observe a notable decrease in ovarian blood vessel (oBV) density and angiogenesis intensity of middle-aged mice. This leads to a diminished blood supply to the ovaries, resulting in inadequate development and maturation of ovarian follicles. Utilizing genetic-modified mouse models, we demonstrate that granulosa cell secreted VEGFA governs ovarian angiogenesis, but the physiological decline in oBV is not attributed to VEGFA insufficiency. Instead, through single-cell sequencing, we identify the aging of the ovarian vascular endothelium as the primary factor contributing to oBV decline. Consequently, the administration of salidroside, a natural compound that is functional to reverse oBV aging and promote ovarian angiogenesis, significantly enhances ovarian blood supply and improve fertility in older females. Our findings highlight that enhancing oBV function is a promising strategy to boost fertility in females.
    DOI:  https://doi.org/10.1038/s41467-024-55509-y
  14. iScience. 2024 Dec 20. 27(12): 111469
    Decoding aging in the heart via single cell dual omics of non-cardiomyocytes.
    Yiran Song, Li Wang, Haofei Wang, Hong Ma, Jun Xu, Jiandong Liu, Li Qian.
      To understand heart aging at the single-cell level, we employed single-cell dual omics (scRNA-seq and scATAC-seq) in profiling non-myocytes (non-CMs) from young, middle-aged, and elderly mice. Non-CMs, vital in heart development, physiology, and pathology, are understudied compared to cardiomyocytes. Our analysis revealed aging response heterogeneity and its dynamics over time. Immune cells, notably macrophages and neutrophils, showed significant aging alterations, while endothelial cells displayed moderate changes. We identified distinct aging signatures within the cell type, including differential gene expression, transcription factor activity, and motif variation. Sub-cluster analysis revealed intra-cell type heterogeneity, characterized by diverse aging patterns. The senescence-associated secretory phenotype emerged as a key aging-related phenotype. Moreover, aging significantly influenced cell-cell communication, especially impacting a fibroblast sub-cluster with high expression of ERBB4. This study elucidates the complex cellular and molecular landscape of cardiac aging and offers guidance for potential therapeutic avenues to treat aging-related heart diseases.
    Keywords:  Biological sciences; Cell biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111469
  15. Nat Commun. 2025 Jan 02. 16(1): 142
    Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface.
    Dafina M Angelova, Aleksandra Tsolova, Malwina Prater, Noura Ballasy, Wendi Bacon, Russell S Hamilton, Danielle Blackwell, Ziyi Yu, Xin Li, Xin Liu, Myriam Hemberger, D Stephen Charnock-Jones.
      The placenta is the critical interface between mother and fetus, and consequently, placental dysfunction underlies many pregnancy complications. Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell RNA sequencing of mouse trophoblast stem cells during the earliest phases of differentiation, we identify gatekeepers of the stem cell state, notably Nicol1, and uncover unsuspected trajectories of cell lineage diversification as well as regulators of lineage entry points. We show that junctional zone precursors and precursors of one of the two syncytial layers of the mouse placental labyrinth, the Syncytiotrophoblast-I lineage, initially share similar trajectories. Importantly, our functional analysis of one such lineage precursor marker, CXADR, demonstrates that this cell surface protein regulates the differentiation dynamics between the two syncytial layers of the mouse labyrinth, ensuring the correct establishment of the placental exchange surface. Deciphering the mechanisms underlying trophoblast lineage specification will inform our understanding of human pregnancy in health and disease.
    DOI:  https://doi.org/10.1038/s41467-024-55597-w
  16. Nat Cardiovasc Res. 2025 Jan 02.
    Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.
    Matthew DeBerge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P Sullivan, Swapna Patil, Bo Ryung Lee, Minori I Thorp, Adam Mullick, Steve Yeh, Shuling Han, Anja M van der Laan, Hans W M Niessen, Xunrong Luo, Nicholas E S Sibinga, Edward B Thorp.
      Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species-dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.
    DOI:  https://doi.org/10.1038/s44161-024-00585-y
  17. Nature. 2025 Jan 01.
    FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
    Liver Cancer Collaborative
      Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)1. While increasing HCC risk2, MASH triggers p53-dependent hepatocyte senescence3, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells4,5, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2-FBP1-AKT-p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.
    DOI:  https://doi.org/10.1038/s41586-024-08317-9
  18. Nat Commun. 2025 Jan 02. 16(1): 272
    Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2.
    Chrystian Junqueira Alves, Theodore Hannah, Sita Sadia, Christy Kolsteeg, Angela Dixon, Robert J Wiener, Ha Nguyen, Murray J Tipping, Júlia Silva Ladeira, Paula Fernandes da Costa Franklin, Nathália de Paula Dutra de Nigro, Rodrigo Alves Dias, Priscila V Zabala Capriles, José P Rodrigues Furtado de Mendonça, Paul A Slesinger, Kevin D Costa, Hongyan Zou, Roland H Friedel.
      Glioblastoma (GBM) is a malignant brain tumor with diffuse infiltration. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 for confined migration through restricted space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal endocytic vesicle accumulation at cell front and filamentous actin assembly at cell rear in a polarized manner. These processes are interconnected and require Plexin-B2 signaling. We further show that Plexin-B2 governs membrane tension and other membrane features such as endocytosis, phospholipid composition, and inner leaflet surface charge, thus providing biophysical mechanisms by which Plexin-B2 promotes GBM invasion. Together, our studies unveil how GBM cells regulate membrane tension and mechano-electrical coupling to adapt to physical constraints and achieve polarized confined migration.
    DOI:  https://doi.org/10.1038/s41467-024-55056-6
  19. Nat Commun. 2025 Jan 02. 16(1): 91
    Intracellular pressure controls the propagation of tension in crumpled cell membranes.
    Raviv Dharan, Avishai Barnoy, Andrey K Tsaturyan, Alon Grossman, Shahar Goren, Inbar Yosibash, Dikla Nachmias, Natalie Elia, Raya Sorkin, Michael M Kozlov.
      Propagation of membrane tension mediates mechanical signal transduction along surfaces of live cells and sets the time scale of mechanical equilibration of cell membranes. Recent studies in several cell types and under different conditions revealed a strikingly wide variation range of the tension propagation speeds including extremely low ones. The latter suggests a possibility of long-living inhomogeneities of membrane tension crucially affecting mechano-sensitive membrane processes. Here, we propose, analyze theoretically, and support experimentally a mechanism of tension propagation in membranes crumpled by the contractile cortical cytoskeleton. The tension spreading is mediated by the membrane flow between the crumples. We predict the pace of the tension propagation to be controlled by the intra-cellular pressure and the degree of the membrane crumpling. We provide experimental support for the suggested mechanism by monitoring the rate of tension propagation in cells exposed to external media of different osmolarities.
    DOI:  https://doi.org/10.1038/s41467-024-55398-1
  20. J Clin Invest. 2025 Jan 02. pii: e181630. [Epub ahead of print]135(1):
    Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy.
    Bryan Z Wang, Margaretha Aj Morsink, Seong Won Kim, Lori J Luo, Xiaokan Zhang, Rajesh Kumar Soni, Roberta I Lock, Jenny Rao, Youngbin Kim, Anran Zhang, Meraj Neyazi, Joshua M Gorham, Yuri Kim, Kemar Brown, Daniel M DeLaughter, Qi Zhang, Barbara McDonough, Josephine M Watkins, Katherine M Cunningham, Gavin Y Oudit, Barry M Fine, Christine E Seidman, Jonathan G Seidman, Gordana Vunjak-Novakovic.
      Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Analysis of cell type-specific conditional knockout engineered heart tissues revealed an essential contribution of CF BAG3 to contractility and cardiac fibrosis, recapitulating the phenotype of DCM. In BAG3-/- CFs, we observed an increased sensitivity to TGF-β signaling and activation of a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, we showed that loss of BAG3 increased transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 and mediating its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nucleus RNA sequencing of cardiac tissue from DCM patients carrying pathogenic BAG3 variants. BAG3 pathogenic variants increased fibrotic gene expression in CFs. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view and highlight the ability of tissue-engineered hiPSC models to elucidate cell type-specific aspects of cardiac disease.
    Keywords:  Cardiology; Cardiovascular disease; Fibrosis; Human stem cells
    DOI:  https://doi.org/10.1172/JCI181630
  21. Nat Commun. 2025 Jan 02. 16(1): 232
    The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.
    Peilu She, Bangjun Gao, Dongliang Li, Chen Wu, Xuejiao Zhu, Yuan He, Fei Mo, Yao Qi, Daqing Jin, Yewei Chen, Xin Zhao, Jinzhong Lin, Hairong Hu, Jia Li, Bing Zhang, Peng Xie, Chengqi Lin, Vincent M Christoffels, Yueheng Wu, Ping Zhu, Tao P Zhong.
      Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function.
    DOI:  https://doi.org/10.1038/s41467-024-55557-4
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