EMBO Reports最新文献

Folliculogenesis is a process that requires accurate interpretation of female physiological cues and elaborate coordination between the growing oocyte and its surrounding follicle cells, each being capable of responding to external signals. Here, we investigate the role of insulin signaling in Drosophila follicle cells. Using a phase separation-based reporter system, we observe a surge of insulin receptor activity in follicle cells during vitellogenic stages, a surge that is disrupted by a maternal high-sucrose diet. Single-cell RNA-seq reveals a diet-sensitive subpopulation of stage-8 follicle cells, which exhibits a reduction in CrebA-mediated transcription of genes for yolk and vitelline membrane proteins. Our results suggest a critical role of CrebA in implementing the stage-specific effect of insulin signaling to boost the secretory capacity of follicle cells. Mechanistically, CrebA is directly repressed by nuclear FoxO that is subject to insulin control, a regulatory axis that we show is conserved in human granulosa cells. This study delineates a mechanism through which insulin and nutrient cues act on a developmental transition via modulating the biosynthetic and secretory functions of the ovary.

Effective visualization of 3D microscopy data is essential for communicating biological results. While scientific 3D rendering software is specifically designed for this purpose, it often lacks the flexibility found in non-scientific software like Blender, which is a free and open-source 3D graphics platform. However, loading microscopy data in Blender is not trivial. To bridge this gap, we introduce Microscopy Nodes, an extension for Blender that enables the seamless integration of large microscopy data. Microscopy Nodes provides efficient loading and visualization of up to 5D microscopy data from Tif and OME-Zarr files. Microscopy Nodes supports various visualization modes including volumetric, isosurface, and label-mask representations, and offers additional tools for slicing, annotation, and dynamic adjustments. By leveraging Blender's advanced rendering capabilities, users can create high-quality visualizations that accommodate both light and electron microscopy. Microscopy Nodes makes powerful, clear data visualization available to all researchers, regardless of their computational experience, and is available through the Blender extensions platform with comprehensive tutorials.

Functional traits shape ecological niches, yet the interplay between nanoscale structural modifications, sexual dimorphism, and habitat range remains poorly understood. In fireflies, cuticular nanostructures that enhance bioluminescent signaling efficiency also impose ecological constraints. Anti-reflective nanocoatings improve cuticle transparency and optical performance but typically increase surface adhesion, reducing fitness. In Luciola lusitanica, this trade-off is mitigated by temperature-sensitive nanocoatings that form only within a narrow thermal range, limiting habitat expansion. This study presents the first thermodynamic analysis of environmentally constrained nanocoating formation, demonstrating how small temperature fluctuations can destabilize protein-lipid self-assembly. These findings link nanoscale biophysics to ecological resilience, providing a framework to understand how the environmental sensitivity of structural self-organization shapes adaptation, species distribution, and evolutionary potential.

Muscle stem cells (MuSCs) are essential for skeletal muscle repair. Following injury, MuSCs reside in low oxygen environments until muscle fibers and vascularization are restablished. The dynamics of oxygen levels during the regenerative process and its impact on muscle repair has been underappreciated. We confirm that muscle repair is initiated in a low oxygen environment followed by gradual reoxygenation. Strikingly, when muscle reoxygenation is limited by keeping mice under systemic hypoxia, muscle repair is impaired and leads to the formation of hypotrophic myofibers. Sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1α or HIF-2α. Prolonged hypoxia specifically affects the circadian clock by increasing Rev-erbα expression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERBα negatively regulates myogenesis by reducing late myogenic cell fusion under prolonged hypoxia. Our results underscore the critical role of progressive muscle reoxygenation after transient hypoxia in coordinating proper myogenesis through Rev-ERBα.

5'-Azacitidine (Aza) and 5-Aza-2'-deoxycytidine (Dac) are widely used demethylating drugs that directly integrate into nucleic acids. They are frequently used interchangeably, surprisingly as their selectivity is unique from the other, with no predictors of response or clinical biomarkers to indicate drug preference. Using these drugs to induce demethylation, we combine DRIPc-Seq, Immunostaining, RNA-Seq and Mass spectrometry to uncover unique cellular responses. Activation of p53, exclusively by Aza, sustains accumulation of R-loops in CpG islands of p53 target genes. This effect is abolished by the removal of p53, compounded by destabilisation of heterochromatin marks. Dac treatment induces global chromatin modification, sustaining DNA damage, which is heightened in the absence of p53. Rescue experiments reverse the changes observed in the epigenome, demonstrating a direct role for p53 in preserving H3K9me3 and H3K27me3. These insights further our knowledge of how cells recognize and respond to methylation changes and uncover novel roles for p53 in modulation of the epigenome. Further to this, we determine a first in kind biomarker in p53 status that may be relevant for clinical settings.

Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.

Myocardial ischemia-reperfusion (I/R) injury remains a significant challenge in cardiovascular medicine, with its molecular mechanisms still not fully understood. Screening the GEO and Comparative Toxicogenomics Database as well as spatial multi-omics data, we identify Cdkn2a, encoding p16^INK4a, as a determinant in I/R injury. Cdkn2a expression is elevated in the myocardium of ischemic cardiomyopathy patients and p16^INK4a protein is enriched in cardiomyocytes within ischemic zones of myocardial infarction tissues. We find that p16^INK4a is consistently upregulated in both in vivo and in vitro I/R models, promoting apoptosis in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). p16^INK4a inhibition confers cellular protection, an effect also observed in in vivo I/R injury models. Mechanistically, p16^INK4a promotes binding of the RNA-binding protein CUGBP1 to the GRE sequence of Npas2 mRNA reducing its stability and translation, likely by inhibiting CDK4. This regulation impairs transcription of the Nasp2 target Slco1a4 and consequently bile acid transport, resulting in accumulation of intracellular bile acids and apoptosis. These findings identify p16^INK4a-regulated bile acid transport as a driver of cardiac I/R injury.

The activation of PLK1 in late G2 is critical for mitotic entry, requiring its phosphorylation by Aurora-A, facilitated by the intrinsically disordered protein Bora. The structural basis of this mechanism has remained unresolved. Here, we present models of the Aurora-A/Bora complex and the Aurora-A/Bora/PLK1 complex, validated with site-specific mutagenesis, biochemical assays and NMR spectroscopy. Bora wraps around the N-lobe of Aurora-A, occupying the pockets used by its other activators. A CDK1 phosphorylation site on Bora (Ser112) mimics the structural role of Aurora-A activation loop phosphorylation within a TPX2-like binding motif. In the ternary complex, Bora bridges the two kinases, orienting the activation loop of PLK1 towards the active site of Aurora-A. Bora residues 56-66 form a critical interface with a conserved pocket on the PLK1 C-helix that is analogous to the TPX2-binding Y-pocket of Aurora-A. Aurora-A phosphorylation of Bora Ser59 creates an additional interaction that increases the efficiency of PLK1 phosphorylation. These findings deepen our understanding of Aurora-A regulation by its disordered binding partners and establish a mechanistic framework for Bora-dependent activation of PLK1.

The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.