EMBO Reports最新文献

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.

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 potential role of small interfering RNAs (siRNAs) produced from double-stranded RNA in aging has not been fully addressed. The networks of genes regulated by siRNAs and their partner Argonaute proteins are best understood in C. elegans, a pioneering model of aging and small RNA studies. Here, we describe synergistic lifespan extension of insulin/IGF-1 signaling (IIS) mutant age-1(hx546) by rde-4 or alg-3; alg-4 deficiencies. By analyzing gene expression and siRNA populations in these IIS and RNAi mutants, we show here that redundant spermatogenesis-specific Argonautes ALG-3 and ALG-4 are capable of regulating IIS, potentially through direct control of the Major Sperm Protein (MSP) genes in the germline. MSPs and MSP domains of some mammalian proteins are secreted and directly inhibit the Eph receptor (EphR). In turn, EphR interacts with and destabilizes PTEN, a major negative regulator of IIS. We show that enhanced MSP expression correlates with EphR mislocalization and elevated PTEN levels in oocytes of alg-3/4(-) worms. At the same time, ALG-3/4 expression is regulated by IIS. Thus, we propose mutual regulation of IIS and ALG-3/4 through secreted ligands.

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.

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.

Even before the advent of multicellular life, unicellular creatures would communicate with their neighbours to coordinate their behaviours. Multicellular organisms have the particular challenge of orchestrating the differentiation of stem and progenitor cells to generate and maintain coherent functional tissues. However, stem and progenitor cells face a problem: their differentiation response can be buffeted by oscillations or stochastic fluctuations in intrinsic regulators. This generates cell-to-cell variability, which can be further compounded when extrinsic cues don't provide clear unambiguous instructions. So, left to their own devices, cells may differentiate at different rates or different directions even in response to the same cues. Fortunately, cells in multicellular organisms are not left to their own devices: they continually sense and respond to the behaviours of their neighbours. Here I discuss when, where, and how stem and progenitor cells communicate to synchronise their response to differentiation cues. I highlight technical challenges in identifying such synchronisation mechanisms, and survey emerging technologies that may help overcome these challenges.

Overcoming lysogenization defect (OLD) proteins are diverse ATPase-nucleases functioning in antiphage defense in bacteria. However, the role of these proteins in archaea is currently unknown. We describe a new class of archaeal OLD family ATPases and show that they are apparently not involved in antiviral defense but play an essential role in cell cycle progression. The gene for an OLD family enzyme in Saccharolobus islandicus REY15A, named here Cran1 (Cell cycle-related ATPase and nickase 1), cannot be deleted and exhibits cyclic expression patterns at transcriptional and translational levels, with peak expression during the transition from M-G1 to S phase. Cran1 overexpression causes significant growth retardation, cell size enlargement, and increased cellular DNA content. Cran1 displays potent nickase and ATPase activities in vitro, with the nickase activity dependent on the presence of the ATPase domain. Notably, Cran1 copurifies with chromatin-associated proteins, such as Cren7 and a histone deacetylase homolog, suggesting its involvement in chromatin-related activities. Collectively, our results suggest that Cran1 plays an important role in cell cycle progression, revealing a novel function of OLD family proteins.

Adipocytes play essential roles in lipid metabolism and energy homeostasis, with regional differences affecting their functions and disease susceptibility. However, the mechanisms underlying this regional heterogeneity remain unclear. Here we demonstrate that the Bithorax Complex (BX-C) genes, specifically abdominal A (abd-A) and Abdominal B (Abd-B), define regional differences in Drosophila larval adipocytes. Abdominal adipocytes, expressing abd-A and Abd-B exhibit unique characteristics compared to thoracic adipocytes, with active Wnt/Wingless signaling further amplifying these regional differences. Depleting abd-A and Abd-B in adipocytes delays larval-pupal transition, causes pupal lethality, and attenuates the expression of Wnt/Wg target genes, thereby dampening Wnt signaling-induced lipid mobilization. Additionally, Wnt signaling enhances the transcription of abd-A and Abd-B, establishing a feedforward loop that reinforces the interplay between Wnt signaling and BX-C genes. These findings reveal how the cell-autonomous expression of BX-C genes defines adipocyte heterogeneity, a process further modulated by Wnt signaling in Drosophila larvae.

The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.

The choice between somatic and germline fates is essential for species survival. This choice occurs in embryonic epiblast cells, as these cells are competent for both somatic and germline differentiation. The transcription factor OTX2 regulates this process, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. Yet, how OTX2 achieves this function is not fully characterised. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to enable somatic differentiation. CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs identifies regions where OTX2 binds and opens chromatin. Enforced OTX2 expression maintains accessibility at these regions and also induces opening of ~4000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional regions no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline.