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Watt, Dauber, Szkop and colleagues find that H3K4me3 remodels 5′UTR selection in hypoxia and that this process is independent of HIF-1 transcriptional mechanisms.

The authors identify a chemical cocktail to generate totipotent-like cells, which they then use to build an embryo model. This model captures a developmental spectrum from early embryogenesis to post-implantation events.

Khawaja et al. show sex-specific differences in neuronal-activity regulation by chaperone-mediated autophagy and that loss of chaperone-mediated autophagy leads to defective neuronal physiology and increased seizure susceptibility, linking chaperone-mediated autophagy to neuronal excitability.

Nguyen, Collier et al. find a mitochondria–lysosome inflammatory pathway regulated by the SUMO E3 ligase MAPL, which promotes vesicular mtDNA transport to lysosomes and subsequent gasdermin-dependent lysosomal permeabilization to activate pyroptosis.

Wu, Zhang and colleagues introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive learning-based method for spatial transcriptomics analysis that detects low-variance structures.

The authors show that the endoplasmic reticulum-phagy receptor FAM134B interacts with SCAP to regulate cholesterol biosynthesis, sequestering SCAP when endoplasmic reticulum cholesterol is high but dissociating upon low cholesterol levels, allowing SCAP to activate cholesterol synthesis.

We present CellNavi, a deep learning framework that predicts driver genes that orchestrate cellular transitions by modelling cell states on a biologically meaningful manifold. We demonstrated how CellNavi predictions of driver genes have potential applications in advancing cell therapy, uncovering key factors that drive cellular diseases, and identifying crucial genes involved in drug responses.

Ageing and cancer are often seen as divergent tissue fates. In our study, we identify a protective programme, called senescence-coupled differentiation (or seno-differentiation), that eliminates cancer-prone stem cells by pushing them to differentiate. Whether melanocyte stem cells follow this path or bypass it under carcinogenic stress determines tissue outcomes: hair greying or melanoma development.

This Review discusses the effects of three age-associated stressors—loss of proteostasis, oxidative damage and dysregulated nutrient sensing—on global protein synthesis and highlights how altered translation is used by the cell as a stress sensor.

Mohri et al. show that, in response to genotoxic stress, melanocyte stem cells undergo senescence-associated differentiation, causing their depletion and protecting them against melanomagenesis. This process is suppressed by carcinogens.

The regulatory mechanisms that drive oncogene expression in gliomas remain poorly understood. A study now identifies a role for widespread rearrangements of the enhancer connectome. Such rearrangements are linked to known genetic risk variants, revealing how genetic predisposition contributes to malignancy.

The authors integrate single-cell transcriptomic data with prior gene graphs to produce a biologically meaningful cell state manifold that can predict driver genes for genetic perturbations and differentiation events across diverse cell types.

Vanni et al. show a role for microtubules in YAP/TAZ mechanosignalling. Mechanoresponsive microtubule reorganization into centrosomal arrays allows for AMOT delivery to pericentrosomal proteasomes and degradation, leading to YAP/TAZ activation.

Li, He, Liu and colleagues characterize the dynamic bivalent chromatin landscape during mouse peri-implantation development. They find that factor ZBTB17 works with KDM6A/B to resolve transiently maintained bivalent domains and prime gene activation.

During wound healing, epithelial gaps trigger curvature-dependent ER remodelling. Tubules form at convex cell edges and promote lamellipodial crawling, whereas ER sheets at concave edges support purse-string contractions. Cytoskeletal forces drive this reorganization and position the ER as a key mechanotransducer in tissue repair.

Glioblastoma (GBM) heterogeneity might arise because of the activation of various gene core regulatory circuitries (CRCs). A new study highlights the central role of HOXB3 in GBM CRCs and how peptide-mediated perturbation of HOXB3-related CRCs in GBM holds potential as treatment for a subset of patients.

Zhang et al. delineate the heterogeneity of core regulatory circuitry in glioblastoma and identify HOXB3 condensation as a vulnerability that may be targeted with a therapeutic peptide in mouse models.