bims-ginsta Biomed News
on Genome instability
Issue of 2024–10–27
thirty-six papers selected by
Jinrong Hu, National University of Singapore
  1. TASOR expression in naive embryonic stem cells safeguards their developmental potential.
  2. Kinetochore dynein is sufficient to biorient chromosomes and remodel the outer kinetochore.
  3. Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
  4. Intercellular fluid dynamics in tissue morphogenesis.
  5. Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
  6. Viscous shear is a key force in Drosophila ventral furrow morphogenesis.
  7. Nuclear release of eIF1 restricts start-codon selection during mitosis.
  8. Chromatin remodelling drives immune cell-fibroblast communication in heart failure.
  9. Changes in DNA repair compartments and cohesin loss promote DNA damage accumulation in aged oocytes.
  10. Transcription-dependent mobility of single genes and genome-wide motions in live human cells.
  11. Targeting immune-fibroblast cell communication in heart failure.
  12. Transcriptomic signatures of WNT-driven pathways and granulosa cell-oocyte interactions during primordial follicle activation.
  13. Regionalized cell and gene signatures govern esophageal epithelial homeostasis.
  14. Metformin slows signs of primate aging.
  15. PCLAF-DREAM drives alveolar cell plasticity for lung regeneration.
  16. DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency.
  17. Generation of human expandable limb-bud-like progenitors via chemically induced dedifferentiation.
  18. Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.
  19. Light-induced targeting enables proteomics on endogenous condensates.
  20. Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
  21. Single-cell multi-modal integrative analyses highlight functional dynamic gene regulatory networks directing human cardiac development.
  22. Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.
  23. Differential stiffness between brain vasculature and parenchyma promotes metastatic infiltration through vessel co-option.
  24. The G1-S transition is promoted by Rb degradation via the E3 ligase UBR5.
  25. Mechanism of actin filament severing and capping by gelsolin.
  26. BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.
  27. Actomyosin clusters as active units shaping living matter.
  28. Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.
  29. Actin dynamics switches two distinct modes of endosomal fusion in yolk sac visceral endoderm cells.
  30. Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.
  31. p53 terminates the regenerative fetal-like state after colitis-associated injury.
  32. Acute contact with profibrotic macrophages mechanically activates fibroblasts via αvβ3 integrin-mediated engagement of Piezo1.
  33. Photo-tunable hydrogels reveal cellular sensing of rapid rigidity changes through the accumulation of mechanical signaling molecules.
  34. Mitochondrial fatty acid oxidation drives senescence.
  35. Don't be so naïve.
  36. Reconstitution of Arp2/3-nucleated actin assembly with proteins CP, V-1, and CARMIL.
  1. Cell Rep. 2024 Oct 24. pii: S2211-1247(24)01238-5. [Epub ahead of print]43(11): 114887
    TASOR expression in naive embryonic stem cells safeguards their developmental potential.
    Carlos A Pinzon-Arteaga, Ryan O'Hara, Alice Mazzagatti, Emily Ballard, Yingying Hu, Alex Pan, Daniel A Schmitz, Yulei Wei, Masahiro Sakurai, Peter Ly, Laura A Banaszynski, Jun Wu.
      The seamless transition through stages of pluripotency relies on a balance between transcription factor networks and epigenetic mechanisms. Here, we reveal the crucial role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in maintaining cell viability during the transition from naive to primed pluripotency. TASOR loss in naive pluripotent stem cells (PSCs) triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 (L1) transposable elements, with more severe effects in primed PSCs. Notably, the survival of Tasor knockout PSCs during this transition can be restored by inhibiting caspase or deleting the mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to cell death specifically in cells exiting naive pluripotency. Our findings highlight the importance of epigenetic programs established in naive pluripotency for normal development.
    Keywords:  5mC; CP: Stem cell research; DNA methylation; H3K9me3; HUSH complex; L1; LINE-1; Stem cells; TASOR; heterochromatin; naive pluripotency; primed pluripotency
    DOI:  https://doi.org/10.1016/j.celrep.2024.114887
  2. Nat Commun. 2024 Oct 21. 15(1): 9085
    Kinetochore dynein is sufficient to biorient chromosomes and remodel the outer kinetochore.
    Bram Prevo, Dhanya K Cheerambathur, William C Earnshaw, Arshad Desai.
      Multiple microtubule-directed activities concentrate on mitotic chromosomes to ensure their faithful segregation. These include couplers and dynamics regulators localized at the kinetochore, the microtubule interface built on centromeric chromatin, as well as motor proteins recruited to kinetochores and chromatin. Here, we describe an in vivo approach in the C. elegans one-cell embryo in which removal of the major microtubule-directed activities on mitotic chromosomes is compared to the selective presence of individual activities. Our approach reveals that the kinetochore dynein module, comprised of cytoplasmic dynein and its kinetochore-specific adapters, is sufficient to biorient chromosomes; by contrast, this module is unable to support congression. In coordination with orientation, the dynein module directs removal of outermost kinetochore components, including dynein itself, independently of the other microtubule-directed activities and kinetochore-localized protein phosphatase 1. These observations indicate that the kinetochore dynein module is sufficient to biorient chromosomes and to direct remodeling of the outer kinetochore in a microtubule attachment state-sensitive manner.
    DOI:  https://doi.org/10.1038/s41467-024-52964-5
  3. Nat Cell Biol. 2024 Oct 21.
    Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
    Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont.
      Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.
    DOI:  https://doi.org/10.1038/s41556-024-01527-3
  4. Curr Biol. 2024 Oct 21. pii: S0960-9822(24)00738-3. [Epub ahead of print]34(20): R1031-R1044
    Intercellular fluid dynamics in tissue morphogenesis.
    Louise Dagher, Stéphanie Descroix, Jean-Léon Maître.
      During embryonic development, cells shape our body, which is mostly made up of water. It is often forgotten that some of this water is found in intercellular fluid, which, for example, immerses the cells of developing embryos. Intercellular fluid contributes to the properties of tissues and influences cell behaviour, thereby participating in tissue morphogenesis. While our understanding of the role of cells in shaping tissues advances, the exploration of the contribution of intercellular fluid dynamics is just beginning. In this review, we delve into the intricate mechanisms employed by cells to control fluid movements both across and within sealed tissue compartments. These mechanisms encompass sealing by tight junctions and controlled leakage, osmotic pumping, hydraulic fracturing of cell adhesion, cell and tissue contractions, as well as beating cilia. We illustrate key concepts by drawing extensively from the early mouse embryo, which successively forms multiple lumens that play essential roles in its development. Finally, we detail experimental approaches and emerging techniques that allow for the quantitative characterization and the manipulation of intercellular fluids in vivo, as well as theoretical frameworks that are crucial for comprehending their dynamics.
    DOI:  https://doi.org/10.1016/j.cub.2024.05.061
  5. Nat Commun. 2024 Oct 24. 15(1): 9181
    Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
    Leighton H Daigh, Debarya Saha, David L Rosenthal, Katherine R Ferrick, Tobias Meyer.
      DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16INK4 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
    DOI:  https://doi.org/10.1038/s41467-024-52820-6
  6. Development. 2024 Oct 21. pii: dev.202892. [Epub ahead of print]
    Viscous shear is a key force in Drosophila ventral furrow morphogenesis.
    Amanda Nicole Goldner, Mohamad Ibrahim Cheikh, Miriam Osterfield, Konstantin Doubrovinski.
      Ventral furrow (VF) formation in Drosophila melanogaster is an important model of epithelial folding. Previous models of VF formation require cell volume conservation to convert apically localized constriction forces into lateral cell elongation and tissue folding. Here, we investigated embryonic morphogenesis in anillin knockdown (scra RNAi) embryos, where basal cell membranes fail to form and therefore cells can lose cytoplasmic volume through their basal side. Surprisingly, the mesoderm elongation and subsequent folding that comprise VF formation occurred essentially normally. We hypothesized that the effects of viscous shear may be sufficient to drive membrane elongation, providing effective volume conservation, and thus driving tissue folding. Since this hypothesis may not be possible to test experimentally, we turned to a computational approach. To test whether viscous shear is a dominant force for morphogenesis in vivo, we developed a 3D computational model incorporating both accurate cell and tissue geometry and experimentally measured material parameters. Results from this model demonstrate that viscous shear generates sufficient force to drive cell elongation and tissue folding in vivo.
    Keywords:   Drosophila ; Anillin; Gastrulation; Morphogenesis; Shear; Viscosity
    DOI:  https://doi.org/10.1242/dev.202892
  7. Nature. 2024 Oct 23.
    Nuclear release of eIF1 restricts start-codon selection during mitosis.
    Jimmy Ly, Kehui Xiang, Kuan-Chung Su, Gunter B Sissoko, David P Bartel, Iain M Cheeseman.
      Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms1-3. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling4, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1-40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology.
    DOI:  https://doi.org/10.1038/s41586-024-08088-3
  8. Nature. 2024 Oct 23.
    Chromatin remodelling drives immune cell-fibroblast communication in heart failure.
    Michael Alexanian, Arun Padmanabhan, Tomohiro Nishino, Joshua G Travers, Lin Ye, Angelo Pelonero, Clara Youngna Lee, Nandhini Sadagopan, Yu Huang, Kirsten Auclair, Ada Zhu, Yuqian An, Christina A Ekstrand, Cassandra Martinez, Barbara Gonzalez Teran, Will R Flanigan, Charis Kee-Seon Kim, Koya Lumbao-Conradson, Zachary Gardner, Li Li, Mauro W Costa, Rajan Jain, Israel Charo, Alexis J Combes, Saptarsi M Haldar, Katherine S Pollard, Ronald J Vagnozzi, Timothy A McKinsey, Pawel F Przytycki, Deepak Srivastava.
      Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers2, the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1+ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling.
    DOI:  https://doi.org/10.1038/s41586-024-08085-6
  9. Curr Biol. 2024 Oct 17. pii: S0960-9822(24)01281-8. [Epub ahead of print]
    Changes in DNA repair compartments and cohesin loss promote DNA damage accumulation in aged oocytes.
    Ninadini Sharma, Giovanni Coticchio, Andrea Borini, Kikuë Tachibana, Kim A Nasmyth, Melina Schuh.
      Oocyte loss, a natural process that accelerates as women approach their mid-30s, poses a significant challenge to female reproduction. Recent studies have identified DNA damage as a primary contributor to oocyte loss, but the mechanisms underlying DNA damage accumulation remain unclear. Here, we show that aged oocytes have a lower DNA repair capacity and reduced mobility of DNA damage sites compared to young oocytes. Incomplete DNA repair in aged oocytes results in defective chromosome integrity and partitioning, thereby compromising oocyte quality. We found that DNA repair proteins are arranged in spatially distinct DNA repair compartments that form during the late stages of oocyte growth, accompanied by changes in the activity of DNA repair pathways. We demonstrate alterations in these compartments with age, including substantial changes in the levels of key DNA repair proteins and a shift toward error-prone DNA repair pathways. In addition, we show that reduced cohesin levels make aged oocytes more vulnerable to persistent DNA damage and cause changes in DNA repair compartments. Our study links DNA damage accumulation in aged oocytes, a leading cause of oocyte loss, to cohesin deterioration and changes in the organization, abundance, and response of DNA repair machinery.
    Keywords:  DNA damage; DNA repair; aging; chromosome segregation; cohesin; fertility; meiosis; oocyte
    DOI:  https://doi.org/10.1016/j.cub.2024.09.040
  10. Nat Commun. 2024 Oct 22. 15(1): 8879
    Transcription-dependent mobility of single genes and genome-wide motions in live human cells.
    Fang-Yi Chu, Alexis S Clavijo, Suho Lee, Alexandra Zidovska.
      The human genome is highly dynamic across all scales. At the gene level, chromatin is persistently remodeled and rearranged during active processes such as transcription, replication and DNA repair. At the genome level, chromatin moves in micron-scale domains that break up and re-form over seconds, but the origin of these coherent motions is unknown. Here, we investigate the connection between genomic motions and gene-level activity. Simultaneous mapping of single-gene and genome-wide motions shows that the coupling of gene transcriptional activity to flows of the nearby genome is modulated by chromatin compaction. A motion correlation analysis suggests that a single active gene drives larger-scale motions in low-compaction regions, but high-compaction chromatin drives gene motion regardless of its activity state. By revealing unexpected connections among gene activity, spatial heterogeneities of chromatin and its emergent genome-wide motions, these findings uncover aspects of the genome's spatiotemporal organization that directly impact gene regulation and expression.
    DOI:  https://doi.org/10.1038/s41467-024-51149-4
  11. Nature. 2024 Oct 23.
    Targeting immune-fibroblast cell communication in heart failure.
    Junedh M Amrute, Xin Luo, Vinay Penna, Steven Yang, Tracy Yamawaki, Sikander Hayat, Andrea Bredemeyer, In-Hyuk Jung, Farid F Kadyrov, Gyu Seong Heo, Rajiu Venkatesan, Sally Yu Shi, Alekhya Parvathaneni, Andrew L Koenig, Christoph Kuppe, Candice Baker, Hannah Luehmann, Cameran Jones, Benjamin Kopecky, Xue Zeng, Tore Bleckwehl, Pan Ma, Paul Lee, Yuriko Terada, Angela Fu, Milena Furtado, Daniel Kreisel, Atilla Kovacs, Nathan O Stitziel, Simon Jackson, Chi-Ming Li, Yongjian Liu, Nadia A Rosenthal, Rafael Kramann, Brandon Ason, Kory J Lavine.
      Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2+ monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
    DOI:  https://doi.org/10.1038/s41586-024-08008-5
  12. PLoS One. 2024 ;19(10): e0311978
    Transcriptomic signatures of WNT-driven pathways and granulosa cell-oocyte interactions during primordial follicle activation.
    Hinako M Takase, Tappei Mishina, Tetsutaro Hayashi, Mika Yoshimura, Mariko Kuse, Itoshi Nikaido, Tomoya S Kitajima.
      Primordial follicle activation (PFA) is a pivotal event in female reproductive biology, coordinating the transition from quiescent to growing follicles. This study employed comprehensive single-cell RNA sequencing to gain insights into the detailed regulatory mechanisms governing the synchronized dormancy and activation between granulosa cells (GCs) and oocytes with the progression of the PFA process. Wntless (Wls) conditional knockout (cKO) mice served as a unique model, suppressing the transition from pre-GCs to GCs, and disrupting somatic cell-derived WNT signaling in the ovary. Our data revealed immediate transcriptomic changes in GCs post-PFA in Wls cKO mice, leading to a divergent trajectory, while oocytes exhibited modest transcriptomic alterations. Subpopulation analysis identified the molecular pathways affected by WNT signaling on GC maturation, along with specific gene signatures linked to dormant and activated oocytes. Despite minimal evidence of continuous up-regulation of dormancy-related genes in oocytes, the loss of WNT signaling in (pre-)GCs impacted gene expression in oocytes even before PFA, subsequently influencing them globally. The infertility observed in Wls cKO mice was attributed to compromised GC-oocyte molecular crosstalk and the microenvironment for oocytes. Our study highlights the pivotal role of the WNT-signaling pathway and its molecular signature, emphasizing the importance of intercellular crosstalk between (pre-)GCs and oocytes in orchestrating folliculogenesis.
    DOI:  https://doi.org/10.1371/journal.pone.0311978
  13. Dev Cell. 2024 Oct 15. pii: S1534-5807(24)00575-6. [Epub ahead of print]
    Regionalized cell and gene signatures govern esophageal epithelial homeostasis.
    David Grommisch, Harald Lund, Evelien Eenjes, Anais Julien, Christian Göritz, Robert A Harris, Rickard Sandberg, Michael Hagemann-Jensen, Maria Genander.
      Regionalized disease prevalence is a common feature of the gastrointestinal tract. Herein, we employed regionally resolved Smart-seq3 single-cell sequencing, generating a comprehensive cell atlas of the adult mouse esophagus. Characterizing the esophageal axis, we identify non-uniform distribution of epithelial basal cells, fibroblasts, and immune cells. In addition, we demonstrate a position-dependent, but cell subpopulation-independent, transcriptional signature, collectively generating a regionalized esophageal landscape. Combining in vivo models with organoid co-cultures, we demonstrate that proximal and distal basal progenitor cell states are functionally distinct. We find that proximal fibroblasts are more permissive for organoid growth compared with distal fibroblasts and that the immune cell profile is regionalized in two dimensions, where proximal-distal and epithelial-stromal gradients impact epithelial maintenance. Finally, we predict and verify how WNT, BMP, insulin growth factor (IGF), and neuregulin (NRG) signaling are differentially engaged along the esophageal axis. We establish a cellular and transcriptional framework for understanding esophageal regionalization, providing a functional basis for epithelial disease susceptibility.
    Keywords:  epithelial stem cells; esophagus; fibroblast heterogeneity; intra-epithelial immune cells; progenitor cell niches; regional cell architecture; regionalization; single-cell atlas
    DOI:  https://doi.org/10.1016/j.devcel.2024.09.025
  14. Nat Aging. 2024 Oct 22.
    Metformin slows signs of primate aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00748-3
  15. Nat Commun. 2024 Oct 24. 15(1): 9169
    PCLAF-DREAM drives alveolar cell plasticity for lung regeneration.
    Bongjun Kim, Yuanjian Huang, Kyung-Pil Ko, Shengzhe Zhang, Gengyi Zou, Jie Zhang, Moon Jong Kim, Danielle Little, Lisandra Vila Ellis, Margherita Paschini, Sohee Jun, Kwon-Sik Park, Jichao Chen, Carla Kim, Jae-Il Park.
      Cell plasticity, changes in cell fate, is crucial for tissue regeneration. In the lung, failure of regeneration leads to diseases, including fibrosis. However, the mechanisms governing alveolar cell plasticity during lung repair remain elusive. We previously showed that PCLAF remodels the DREAM complex, shifting the balance from cell quiescence towards cell proliferation. Here, we find that PCLAF expression is specific to proliferating lung progenitor cells, along with the DREAM target genes transactivated by lung injury. Genetic ablation of Pclaf impairs AT1 cell repopulation from AT2 cells, leading to lung fibrosis. Mechanistically, the PCLAF-DREAM complex transactivates CLIC4, triggering TGF-β signaling activation, which promotes AT1 cell generation from AT2 cells. Furthermore, phenelzine that mimics the PCLAF-DREAM transcriptional signature increases AT2 cell plasticity, preventing lung fibrosis in organoids and mice. Our study reveals the unexpected role of the PCLAF-DREAM axis in promoting alveolar cell plasticity, beyond cell proliferation control, proposing a potential therapeutic avenue for lung fibrosis prevention.
    DOI:  https://doi.org/10.1038/s41467-024-53330-1
  16. Nat Struct Mol Biol. 2024 Oct 24.
    DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency.
    Julien Richard Albert, Teresa Urli, Ana Monteagudo-Sánchez, Anna Le Breton, Amina Sultanova, Angélique David, Margherita Scarpa, Mathieu Schulz, Maxim V C Greenberg.
      In mammals, 5-methylcytosine (5mC) and Polycomb repressive complex 2 (PRC2)-deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naive pluripotent state, there is massive gain of 5mC concomitantly with restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naive and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. Instead, this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonist Ezhip (encoding EZH inhibitory protein). At the subset of regions where 5mC appears to genuinely supplant H3K27me3, we identified 163 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Using site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. Our study also implies a noncanonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa.
    DOI:  https://doi.org/10.1038/s41594-024-01405-4
  17. Cell Stem Cell. 2024 Oct 16. pii: S1934-5909(24)00363-1. [Epub ahead of print]
    Generation of human expandable limb-bud-like progenitors via chemically induced dedifferentiation.
    Jialiang Zhu, Xinxing Zhong, Huanjing He, Jingxiao Cao, Zhengyang Zhou, Jiebin Dong, Honggang Li, Anqi Zhang, Yulin Lyu, Cheng Li, Jingyang Guan, Hongkui Deng.
      In certain highly regenerative animals, cellular dedifferentiation occurs after injury, allowing specialized cells to become progenitor cells for regeneration. However, this capacity is restricted in human cells due to reduced plasticity. Here, we introduce a chemical-induced dedifferentiation approach that reverts the differentiated cells to a progenitor-like state, conferring the features of human limb bud cells from human adult somatic cells. These chemically induced human limb-bud-like progenitors (hCiLBP cells) show a high degree of transcriptomic similarity to human embryonic limb bud progenitors. Importantly, we established culture conditions that allow hCiLBP cells to undergo extensive expansion while maintaining population homogeneity and long-term self-renewal capacity. Moreover, hCiLBP cells exhibit increased osteochondrogenic differentiation ability, providing an innovative platform for generation of skeletal lineage cell types. These results highlight a potential therapeutic approach for repairing damaged human tissues through reversal of developmental pathways from mature cells to expandable progenitor cells.
    Keywords:  chemical reprogramming; dedifferentiation; human limb-bud-like progenitors; large-scale expansion; progenitor maintenance; regeneration
    DOI:  https://doi.org/10.1016/j.stem.2024.10.001
  18. Nat Commun. 2024 Oct 24. 15(1): 9095
    Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.
    Suvra Nath, Jose C Martínez Santamaría, Yu-Hsuan Chu, James S Choi, Pasquale Conforti, Jia-Di Lin, Roman Sankowski, Lukas Amann, Christos Galanis, Kexin Wu, Sachin S Deshpande, Andreas Vlachos, Marco Prinz, Jae K Lee, Christian Schachtrup.
      After a stroke, the neurogenic response from the subventricular zone (SVZ) to repair the brain is limited. Microglia, as an integral part of the distinctive SVZ microenvironment, control neural stem / precursor cell (NSPC) behavior. Here, we show that discrete stroke-associated SVZ microglial clusters negatively impact the innate neurogenic response, and we propose a repository of relevant microglia-NSPC ligand-receptor pairs. After photothrombosis, a mouse model of ischemic stroke, the altered SVZ niche environment leads to immediate activation of microglia in the niche and an abnormal neurogenic response, with cell-cycle arrest of neural stem cells and neuroblast cell death. Pharmacological restoration of the niche environment increases the SVZ-derived neurogenic repair and microglial depletion increases the formation and survival of newborn neuroblasts in the SVZ. Therefore, we propose that altered cross-communication between microglial subclusters and NSPCs regulates the extent of the innate neurogenic repair response in the SVZ after stroke.
    DOI:  https://doi.org/10.1038/s41467-024-53217-1
  19. Cell. 2024 Oct 15. pii: S0092-8674(24)01140-1. [Epub ahead of print]
    Light-induced targeting enables proteomics on endogenous condensates.
    Choongman Lee, Andrea Quintana, Ida Suppanz, Alejandro Gomez-Auli, Gerhard Mittler, Ibrahim I Cissé.
      Endogenous condensates with transient constituents are notoriously difficult to study with common biological assays like mass spectrometry and other proteomics profiling. Here, we report a method for light-induced targeting of endogenous condensates (LiTEC) in living cells. LiTEC combines the identification of molecular zip codes that target the endogenous condensates with optogenetics to enable controlled and reversible partitioning of an arbitrary cargo, such as enzymes commonly used in proteomics, into the condensate in a blue light-dependent manner. We demonstrate a proof of concept by combining LiTEC with proximity-based biotinylation (BioID) and uncover putative components of transcriptional condensates in mouse embryonic stem cells. Our approach opens the road to genome-wide functional studies of endogenous condensates.
    Keywords:  IDR; LiTEC; composition; endogenous condensate; intrinsically disordered; mass spectrometry; optogenetics; proteomics; targeting; transcriptional cluster
    DOI:  https://doi.org/10.1016/j.cell.2024.09.040
  20. Nat Cardiovasc Res. 2024 Oct 21.
    Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
    Farid F Kadyrov, Andrew L Koenig, Junedh M Amrute, Hao Dun, Wenjun Li, Carla J Weinheimer, Jessica M Nigro, Attila Kovacs, Andrea L Bredemeyer, Steven Yang, Shibali Das, Vinay R Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J Kopecky, Daniel Kreisel, Kory J Lavine.
      Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.
    DOI:  https://doi.org/10.1038/s44161-024-00553-6
  21. Cell Genom. 2024 Oct 16. pii: S2666-979X(24)00299-4. [Epub ahead of print] 100680
    Single-cell multi-modal integrative analyses highlight functional dynamic gene regulatory networks directing human cardiac development.
    Alyssa R Holman, Shaina Tran, Eugin Destici, Elie N Farah, Ting Li, Aileena C Nelson, Adam J Engler, Neil C Chi.
      Illuminating the precise stepwise genetic programs directing cardiac development provides insights into the mechanisms of congenital heart disease and strategies for cardiac regenerative therapies. Here, we integrate in vitro and in vivo human single-cell multi-omic studies with high-throughput functional genomic screening to reveal dynamic, cardiac-specific gene regulatory networks (GRNs) and transcriptional regulators during human cardiomyocyte development. Interrogating developmental trajectories reconstructed from single-cell data unexpectedly reveal divergent cardiomyocyte lineages with distinct gene programs based on developmental signaling pathways. High-throughput functional genomic screens identify key transcription factors from inferred GRNs that are functionally relevant for cardiomyocyte lineages derived from each pathway. Notably, we discover a critical heat shock transcription factor 1 (HSF1)-mediated cardiometabolic GRN controlling cardiac mitochondrial/metabolic function and cell survival, also observed in fetal human cardiomyocytes. Overall, these multi-modal genomic studies enable the systematic discovery and validation of coordinated GRNs and transcriptional regulators controlling the development of distinct human cardiomyocyte populations.
    Keywords:  CRISPR-based functional genomics screening; cardiac development; directed differentiation; gene regulatory networks; multi-omics
    DOI:  https://doi.org/10.1016/j.xgen.2024.100680
  22. Cell Stem Cell. 2024 Oct 18. pii: S1934-5909(24)00329-1. [Epub ahead of print]
    Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.
    Yawen Li, Yalin He, Qi Zheng, Jiazhu Zhang, Xinwen Pan, Xi Zhang, Huairui Yuan, Guangchuan Wang, Xin Liu, Xiaolong Zhou, Xueliang Zhu, Tao Ren, Pengfei Sui.
      Basal cells (BCs) are the progenitor cells responsible for tracheal epithelium integrity. Here, we demonstrate that mitochondrial pyruvate carriers (MPCs) act as metabolic checkpoints that are essential for BC fate decision. Inhibition of MPCs enables long-term expansion of BCs from both mice and humans. Genetic inactivation of Mpc2 in mice leads to BC hyperplasia and reduced ciliated cells during homeostasis, as well as delayed epithelial regeneration and accumulation of intermediate cells following injury. Mechanistically, MPC2 links glycolysis to ATP citrate lyase (ACLY)-dependent cytosolic acetyl-coenzyme A (CoA) generation, which is required for the epigenetic control of differentiation-related gene transcription. Modulating this metabolic-epigenetic axis partially rescues Yes-associated protein (YAP)-dysfunction-induced changes in BCs. Importantly, exogenous citrate promotes the differentiation of BCs from chronic obstructive lung disease (COPD) patients. Thus, beyond demonstrating the role of pyruvate metabolism in BC fate decision, our study suggests that targeting pyruvate-citrate metabolism may serve as a potential strategy to rectify abnormal BC behavior in lung diseases.
    Keywords:  airway; cell fate decision; injury repair; lung basal progenitor cell; lung epithelium homeostasis; lung progenitor cell metabolism; mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1016/j.stem.2024.09.015
  23. Nat Cell Biol. 2024 Oct 24.
    Differential stiffness between brain vasculature and parenchyma promotes metastatic infiltration through vessel co-option.
    Marina Uroz, Amy E Stoddard, Bryan P Sutherland, Olivia Courbot, Roger Oria, Linqing Li, Cara R Ravasio, Mai T Ngo, Jinling Yang, Juliann B Tefft, Jeroen Eyckmans, Xue Han, Alberto Elosegui-Artola, Valerie M Weaver, Christopher S Chen.
      In brain metastasis, cancer cells remain in close contact with the existing vasculature and can use vessels as migratory paths-a process known as vessel co-option. However, the mechanisms regulating this form of migration are poorly understood. Here we use ex vivo brain slices and an organotypic in vitro model for vessel co-option to show that cancer cell invasion along brain vasculature is driven by the difference in stiffness between vessels and the brain parenchyma. Imaging analysis indicated that cells move along the basal surface of vessels by adhering to the basement membrane extracellular matrix. We further show that vessel co-option is enhanced by both the stiffness of brain vasculature, which reinforces focal adhesions through a talin-dependent mechanism, and the softness of the surrounding environment that permits cellular movement. Our work reveals a mechanosensing mechanism that guides cell migration in response to the tissue's intrinsic mechanical heterogeneity, with implications in cancer invasion and metastasis.
    DOI:  https://doi.org/10.1038/s41556-024-01532-6
  24. Sci Adv. 2024 Oct 25. 10(43): eadq6858
    The G1-S transition is promoted by Rb degradation via the E3 ligase UBR5.
    Shuyuan Zhang, Lucas Fuentes Valenzuela, Evgeny Zatulovskiy, Lise Mangiante, Christina Curtis, Jan M Skotheim.
      Mammalian cells make the decision to divide at the G1-S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Passage through the G1-S transition is initially driven by Rb inactivation via phosphorylation and by Rb's decreasing concentration in G1. While many studies have identified the mechanisms of Rb phosphorylation, the mechanism underlying Rb's decreasing concentration in G1 was unknown. Here, we found that Rb's concentration decrease in G1 requires the E3 ubiquitin ligase UBR5. UBR5 knockout cells have increased Rb concentration in early G1, exhibited a lower G1-S transition rate, and are more sensitive to inhibition of cyclin-dependent kinase 4/6 (Cdk4/6). This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.
    DOI:  https://doi.org/10.1126/sciadv.adq6858
  25. Nat Struct Mol Biol. 2024 Oct 24.
    Mechanism of actin filament severing and capping by gelsolin.
    Kyle R Barrie, Grzegorz Rebowski, Roberto Dominguez.
      Gelsolin is the prototypical member of a family of Ca2+-activated F-actin severing and capping proteins. Here we report structures of Ca2+-bound human gelsolin at the barbed end of F-actin. One structure reveals gelsolin's six domains (G1G6) and interdomain linkers wrapping around F-actin, while another shows domains G1G3-a fragment observed during apoptosis-binding on both sides of F-actin. Conformational changes that trigger severing occur on one side of F-actin with G1G6 and on both sides with G1G3. Gelsolin remains bound after severing, blocking subunit exchange.
    DOI:  https://doi.org/10.1038/s41594-024-01412-5
  26. EMBO J. 2024 Oct 21.
    BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.
    Yehua Li, Xiaodan Wang, Meimei Huang, Xu Wang, Chunlin Li, Siqi Li, Yuhui Tang, Shicheng Yu, Yalong Wang, Wanglu Song, Wei Wu, Yuan Liu, Ye-Guang Chen.
      Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.
    Keywords:  BMP Signaling; Bcl11b; Colorectal Cancer; Intestinal Stem Cells; Wnt Signaling
    DOI:  https://doi.org/10.1038/s44318-024-00276-1
  27. Curr Biol. 2024 Oct 21. pii: S0960-9822(24)01158-8. [Epub ahead of print]34(20): R1045-R1058
    Actomyosin clusters as active units shaping living matter.
    Karsten Kruse, Rémi Berthoz, Luca Barberi, Anne-Cécile Reymann, Daniel Riveline.
      Stress generation by the actin cytoskeleton shapes cells and tissues. Despite impressive progress in live imaging and quantitative physical descriptions of cytoskeletal network dynamics, the connection between processes at molecular scales and spatiotemporal patterns at the cellular scale is still unclear. Here, we review studies reporting actomyosin clusters of micrometre size and with lifetimes of several minutes in a large number of organisms, ranging from fission yeast to humans. Such structures have also been found in reconstituted systems in vitro and in theoretical analyses of cytoskeletal dynamics. We propose that tracking these clusters could provide a simple readout for characterising living matter. Spatiotemporal patterns of clusters could serve as determinants of morphogenetic processes that have similar roles in diverse organisms.
    DOI:  https://doi.org/10.1016/j.cub.2024.08.043
  28. Science. 2024 Oct 24. eado6836
    Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.
    Julia Phan, Brandon Chen, Zhiyu Zhao, Gabriele Allies, Antonella Iannaccone, Animesh Paul, Feyza Cansiz, Alberto Spina, Anna-Sophia Leven, Alexandra Gellhaus, Dirk Schadendorf, Rainer Kimmig, Marcel Mettlen, Alpaslan Tasdogan, Sean J Morrison.
      Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and LINE elements. Retrotransposon transcription activates the innate immune sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in non-pregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN regulated genes were also induced in mouse HSCs after serial bleeding and in human HSCs during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant, but not non-pregnant, people suggesting conservation of these mechanisms from mice to humans.
    DOI:  https://doi.org/10.1126/science.ado6836
  29. Elife. 2024 Oct 23. pii: RP95999. [Epub ahead of print]13
    Actin dynamics switches two distinct modes of endosomal fusion in yolk sac visceral endoderm cells.
    Seiichi Koike, Masashi Tachikawa, Motosuke Tsutsumi, Takuya Okada, Tomomi Nemoto, Kazuko Keino-Masu, Masayuki Masu.
      Membranes undergo various patterns of deformation during vesicle fusion, but how this membrane deformation is regulated and contributes to fusion remains unknown. In this study, we developed a new method of observing the fusion of individual late endosomes and lysosomes by using mouse yolk sac visceral endoderm cells that have huge endocytic vesicles. We found that there were two distinct fusion modes that were differently regulated. In homotypic fusion, two late endosomes fused quickly, whereas in heterotypic fusion they fused to lysosomes slowly. Mathematical modeling showed that vesicle size is a critical determinant of these fusion types and that membrane fluctuation forces can overcome the vesicle size effects. We found that actin filaments were bound to late endosomes and forces derived from dynamic actin remodeling were necessary for quick fusion during homotypic fusion. Furthermore, cofilin played a role in endocytic fusion by regulating actin turnover. These data suggest that actin promotes vesicle fusion for efficient membrane trafficking in visceral endoderm cells.
    Keywords:  actin; cell biology; fusion; late endosome; lysosome; mouse; mouse embryo; yolk sac visceral endoderm
    DOI:  https://doi.org/10.7554/eLife.95999
  30. Nat Commun. 2024 Oct 23. 15(1): 9117
    Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.
    Yeongjun Jang, Livia Tomasini, Taejeong Bae, Anna Szekely, Flora M Vaccarino, Alexej Abyzov.
      Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyze the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We find that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyzes of public data from several multi-children families and from 1934 familial quads confirm this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in mutation transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyzes of all the data consistently suggest that the germline has a balanced 50:50 lineage allocation from the first two blastomeres.
    DOI:  https://doi.org/10.1038/s41467-024-53485-x
  31. Sci Adv. 2024 Oct 25. 10(43): eadp8783
    p53 terminates the regenerative fetal-like state after colitis-associated injury.
    Kimberly Hartl, Şafak Bayram, Alexandra Wetzel, Christine Harnack, Manqiang Lin, Anne-Sophie Fischer, Lichao Liu, Giulia Beccaceci, Guido Mastrobuoni, Sabrina Geisberger, Martin Forbes, Benedict J E Monteiro, Martina Macino, Roberto E Flores, Cornelius Engelmann, Hans-Joachim Mollenkopf, Michael Schupp, Frank Tacke, Ashley D Sanders, Stefan Kempa, Hilmar Berger, Michael Sigal.
      Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.
    DOI:  https://doi.org/10.1126/sciadv.adp8783
  32. Sci Adv. 2024 Oct 25. 10(43): eadp4726
    Acute contact with profibrotic macrophages mechanically activates fibroblasts via αvβ3 integrin-mediated engagement of Piezo1.
    Maya Ezzo, Katrin Spindler, Jun Bo Wang, Dahea Lee, Gilbert Pecoraro, Justin Cowen, Pardis Pakshir, Boris Hinz.
      Fibrosis-excessive scarring after injury-causes >40% of disease-related deaths worldwide. In this misguided repair process, activated fibroblasts drive the destruction of organ architecture by accumulating and contracting extracellular matrix. The resulting stiff scar tissue, in turn, enhances fibroblast contraction-bearing the question of how this positive feedback loop begins. We show that direct contact with profibrotic but not proinflammatory macrophages triggers acute fibroblast contractions. The contractile response depends on αvβ3 integrin expression on macrophages and Piezo1 expression on fibroblasts. The touch of macrophages elevates fibroblast cytosolic calcium within seconds, followed by translocation of the transcription cofactors nuclear factor of activated T cells 1 and Yes-associated protein, which drive fibroblast activation within hours. Intriguingly, macrophages induce mechanical stress in fibroblasts on soft matrix that alone suppresses their spontaneous activation. We propose that acute contact with suitable macrophages mechanically kick-starts fibroblast activation in an otherwise nonpermissive soft environment. The molecular components mediating macrophage-fibroblast mechanotransduction are potential targets for antifibrosis strategies.
    DOI:  https://doi.org/10.1126/sciadv.adp4726
  33. Cell Stem Cell. 2024 Oct 18. pii: S1934-5909(24)00359-X. [Epub ahead of print]
    Photo-tunable hydrogels reveal cellular sensing of rapid rigidity changes through the accumulation of mechanical signaling molecules.
    Jiapeng Yang, Peng Wang, Yu Zhang, Man Zhang, Qian Sun, Huiyan Chen, Liang Dong, Zhiqin Chu, Bin Xue, Wouter David Hoff, Changsheng Zhao, Wei Wang, Qiang Wei, Yi Cao.
      Cells use traction forces to sense mechanical cues in their environment. While the molecular clutch model effectively explains how cells exert more forces on stiffer substrates, it falls short in addressing their adaptation to dynamic mechanical fluctuations prevalent in tissues and organs. Here, using hydrogel with photo-responsive rigidity, we show that cells' response to rigidity changes is frequency dependent. Strikingly, at certain frequencies, cellular traction forces exceed those on static substrates 4-fold stiffer, challenging the established molecular clutch model. We discover that the discrepancy between the rapid adaptation of traction forces and the slower deactivation of mechanotransduction signaling proteins results in their accumulation, thereby enhancing long-term cellular traction in dynamic settings. Consequently, we propose a new model that melds immediate mechanosensing with extended mechanical signaling. Our study underscores the significance of dynamic rigidity in the development of synthetic biomaterials, emphasizing the importance of considering both immediate and prolonged cellular responses.
    Keywords:  cell; cell migration; cellular force; cyclic mechanical stimulation; focal adhesion; focal adhesion kinase; mechanotransduction; photoactive yellow protein; switchable hydrogel
    DOI:  https://doi.org/10.1016/j.stem.2024.09.016
  34. Sci Adv. 2024 Oct 25. 10(43): eado5887
    Mitochondrial fatty acid oxidation drives senescence.
    Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.
      Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
    DOI:  https://doi.org/10.1126/sciadv.ado5887
  35. Elife. 2024 Oct 25. pii: e103292. [Epub ahead of print]13
    Don't be so naïve.
    Valerie Horsley, Aya Nasserdine.
      New evidence sheds light on actin regulation of pluripotency in human embryonic stem cells.
    Keywords:  YAP; actin; cell biology; cytoskeleton; human; human embryonic stem cells; naive pluripotency; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.103292
  36. Curr Biol. 2024 Oct 16. pii: S0960-9822(24)01292-2. [Epub ahead of print]
    Reconstitution of Arp2/3-nucleated actin assembly with proteins CP, V-1, and CARMIL.
    Olivia L Mooren, Patrick McConnell, James D DeBrecht, Anshuman Jaysingh, John A Cooper.
      Actin polymerization is often associated with membrane proteins containing capping-protein-interacting (CPI) motifs, such as capping protein, Arp2/3, myosin I linker (CARMIL), CD2AP, and WASHCAP/Fam21. CPI motifs bind directly to actin-capping protein (CP), and this interaction weakens the binding of CP to barbed ends of actin filaments, lessening the ability of CP to functionally cap those ends. The protein V-1/myotrophin binds to the F-actin-binding site on CP and sterically blocks CP from binding barbed ends. CPI-motif proteins also weaken the binding between V-1 and CP, which decreases the inhibitory effects of V-1, thereby freeing CP to cap barbed ends. Here, we address the question of whether CPI-motif proteins on a surface analogous to a membrane lead to net activation or inhibition of actin assembly nucleated by Arp2/3 complex. Using reconstitution with purified components, we discovered that CARMIL at the surface promotes and enhances actin assembly, countering the inhibitory effects of V-1 and thus activating CP. The reconstitution involves the presence of an Arp2/3 activator on the surface, along with Arp2/3 complex, V-1, CP, profilin, and actin monomers in solution, recreating key features of cell physiology.
    Keywords:  CARMIL; CPI-motif proteins; V-1; WASHCAP; myotrophin; protein conformation
    DOI:  https://doi.org/10.1016/j.cub.2024.09.051
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