Reviews & Analysis

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.

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.

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.

The transition of a pluripotent stem cell into a differentiated lineage is one of the most complex yet precisely orchestrated events in developmental biology. A study now reveals that mechanical and osmotic forces, long considered background players in guiding this transition, are essential regulators of chromatin accessibility and cell fate decisions.

ATM inhibitors (ATMi) cause cell death by enabling CtIP to induce excessive DNA resection. A study now shows that ERCC6L2 regulates resection by forming condensates with CtIP to prevent its degradation. Loss of ERCC6L2 decreases sensitivity to ATMi, which suggests that ERCC6L2 deficiency can be a biomarker for ATMi resistance.

The AMP-dependent protein kinase AMPK is thought to be activated only when cellular energy levels are low. However, a study now finds that intracellular AMP is generated from extracellular adenosine in an intricate growth signalling cascade, explaining how AMPK can be regulated by extracellular cues.

In this Review, Lusk et al. discuss emerging insights into nuclear pore complex variability with regard to composition and dilation state, and propose nuclear mechanics as a key determinant of driving such plasticity and any associated diseases.

A study now indicates that CD160⁺CD8⁺ T cells in patients with colorectal cancer modulate anti-tumour immune responses and may influence disease progression. Their combination with immune checkpoint blockade therapy has emerged as a promising strategy to enhance therapeutic efficacy and patient outcomes in colorectal cancer.

During development as cells exit a pluripotent state, chromatin looping interactions are strengthened, but the mechanism for this is unknown. A study now shows that CTCF–RBP interactions increase upon differentiation of embryonic stem cells to neural stem cells, and that the non-coding RNA Pantr1 collaborates with CTCF and RBPs to contract the genome.

Gene fusions are potent drivers of cancer, and nuclear condensates are known to have a role in transcription. By creating synthetic fusion oncogenes, we show that nuclear condensate formation might be a general feature of fusion oncoprotein-directed transcription, including in brain tumour development.

In this Review, Andersson et al. discuss emerging insights into ageing of the haematopoietic system and its role in driving organismal ageing, in particular inflammageing and immunosenescence, as well as in rejuvenation of the immune system.

How multiple chaperones are organized to co-ordinate their activities has been unclear. We observed that the chaperone PDIA6 forms phase-separated condensates in the endoplasmic reticulum to which several additional chaperones are recruited. These multi-chaperone condensates constitute a dedicated endoplasmic reticulum sub-compartment that facilitates protein biogenesis and prevents protein misfolding and aggregation.

To better understand trophoblast development, scientists have long sought stem cells that model the trophectoderm at the early blastocyst stage. Gao, Li et al. now derive trophectoderm stem cells from morula-stage embryos, representing an earlier pre-implantation stage than previously reported trophoblast stem cells.

Dietary nutrients are key regulators of antitumour immune responses. Our study reveals that galactose, a sugar commonly found in the diet, reprograms hepatocytes to prevent T cell exhaustion and enhance antitumour immune responses. This effect is mediated by increased production of IGFBP1, suggesting that galactose may offer a novel dietary approach to support cancer immunotherapy.

Whether the telomerase protein TERT has moonlighting functions by acting catalytically in telomere elongation and non-catalytically in extratelomeric functions has long been debated. A study now demonstrates that TERT can regulate physiological levels of inflammatory signals independently of its catalytic functions.

During early brain development, proper cell fate acquisition requires time-sensitive control of gene expression. New work shows that AIRIM variants disrupt cell fate by altering ribosome abundance and the translation of specific mRNAs. The findings pinpoint regulated ribogenesis as a key factor in early human brain development.

This Review discusses transcription-coupled DNA repair in response to the stalling of RNA polymerase II on different types of DNA lesions and highlights the molecular details for the different steps in the process that have recently emerged.