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PubMed2026

Adaptive genomic evolution and WD40-regulated temporal dynamics of anthocyanins support leaf photoplasticity in Parrotia subaequalis.

BACKGROUND: Parrotia subaequalis, a Tertiary relict endemic to China, plays a significant role in phylogeny and adaptive evolution as a key species in the early differentiation of angiosperms. It has abundant leaf colors and great potential as an ornamental tree. RESULTS: This study assembled the first chromosome-level genome of P. subaequalis (Contig N50 = 2.15 Mb), revealing transposable element proliferation, key paleopolyploid events and dynamic gene family evolution, including the expansion of secondary metabolite transport and synthesis genes (such as WD40, 2OG-FeII_Oxy) and the contraction of gene families related to flower morphogenesis (such as F-box-like, K-box). Through integrative transcriptomics and targeted metabolomics approaches, we further revealed that the color transition of young leaves from red to green was driven by temporal accumulation differences of malvidin-3,5-O-diglucoside, whose biosynthesis is progressively down-regulated during leaf development. WGCNA revealed that a subset of WD40 genes (light-signaling, TTG1/HOS15-like, etc.) coexpresses with anthocyanin biosynthetic genes, like 4CLL9, GT1, in anthocyanin-related modules enriched for auxin signaling and hydrolase activity, suggesting a potential link between WD40 expansion and photoprotective plasticity. Relevant regulatory networks were found to complement the species-specific gene pool related to leaf color regulation. CONCLUSION: This genomic resource of P. subaequalis advanced our understanding of early angiosperm adaptation through neofunctionalized regulatory networks and established a foundation for molecular breeding aimed at enhancing environmental resilience while preserving ornamental traits.

Anthocyanins↗
PubMed2026

Pan-genome characterization of the maize 4CL gene family and its dynamic responses to abiotic stress.

1.Pan-genome analysis across 26 maize inbred lines identified 13 Zm4CL genes (nine core and four near-core) classified into three evolutionary clades.2.Structural variations (SVs) are significantly associated with the expression and altered conserved protein domains of key Zm4CL genes.3.Zm4CL genes exhibit distinct tissue-specific expression patterns and dynamic enzymatic and transcriptional responses to stresses, particularly cold and drought.4-Coumarate:CoA ligase (4CL) is a key enzyme in the phenylpropanoid pathway and plays important roles in plant growth, development, and responses to environmental stresses. However, a comprehensive pan-genome analysis of the 4CL gene family in maize is still lacking. In this study, 13 Zm4CL genes were identified from a maize pan-genome comprising 26 diverse inbred lines, including nine core genes and four near-core genes. Phylogenetic analysis classified these genes into three evolutionary clades, while Ka/Ks analysis indicated that most members have been maintained under purifying selection, although several genes exhibited greater evolutionary divergence and relatively relaxed evolutionary constraints. Structural variation (SV) analysis revealed significant associations between SVs and the expression of Zm4CL2 and Zm4CL3, while sequence comparisons suggested that SVs were also associated with alterations in conserved protein domains in some genotypes. Transcriptome analyses revealed distinct tissue-specific expression patterns and diverse transcriptional responses to abiotic and biotic stresses. Enzyme activity assays showed that cold stress significantly increased 4CL activity at 12 h, whereas heat, salt, and alkali stresses caused an initial decrease followed by recovery, while drought had no significant effect. Time-course RT-qPCR further validated dynamic expression changes of representative Zm4CL genes under cold and drought stresses. Overall, this study provides a comprehensive pan-genome framework for understanding the evolutionary conservation, regulatory diversification, and stress-responsive characteristics of the maize Zm4CL gene family, providing valuable resources for future functional studies and the genetic improvement of stress tolerance in maize.

Zea mays↗
PubMed2026

The genome of Thesium ramosoides (Santalales) reveals evolutionary dynamics associated with parasitism and alpine adaptation.

Plant species adapting to complex environments experience contrasting selection pressures that drive the expansion and contraction of different gene families. However, few studies have investigated simultaneous genomic responses to such diverse selective forces. Here, we generate a high-quality genome assembly for the hemiparasitic plant Thesium ramosoides, the first for the largest genus in the Santalales, and explore the genomic basis underlying the evolution of parasitism and alpine adaptation. Unlike many other parasitic plants, the Thesium genome has not undergone additional rounds of whole-genome duplication, making it particularly tractable for studying gene family evolution. Our analyses reveal substantial loss of photosynthesis-related genes and contraction of biotic defense gene families, likely reflecting adaptation to a hemiparasitic lifestyle and reduced pathogen pressure at high altitudes. The absence of key root hair development genes correlates with the degenerate root hair phenotype observed in this species. Furthermore, hallmarks of high-altitude adaptation include the expansion of gene families involved in responses to hypoxia. Notably, expansion of gene families associated with meristem development is consistent with the presence of below-ground crown buds that enable rapid regeneration after mountain fires. Unexpectedly, we detected tandem duplication and diversification of the strigolactone receptor gene D14, which regulates secondary shoot formation, but not of its ancestral paralog KAI2, which mediates seed germination in response to the smoke-derived compound karrikin. This finding suggests divergent signaling mechanisms underlying fire adaptation across different parasitic plant lineages. By integrating time-series transcriptomic data, we propose a post-fire "defense first, repair later, recovery last" model, in which resources are reallocated from immediate defense to rapid repair and ultimately to long-term recovery, to explain the adaptation of T. ramosoides to fire-prone habitats. Our study provides critical insights into the complex and contrasting genomic dynamics that drive adaptation to multiple co-occurring selection pressures.

Genome, Plant↗
PubMed2026

The extracellular matrix in cancer-associated fibrosis: molecular mechanisms and clinical relevance.

The ECM is a dynamic component of the tumor microenvironment with a critical role in cancer progression, invasion, metastasis, immune exclusion, and response to therapy. Recent advances in proteomic analyses investigating the insoluble ECM fractions (termed "matrisome analysis"), along with single-cell RNA sequencing and spatial transcriptomics, have revealed cancer-specific patterns of ECM remodeling. These studies have identified a panel of recurrently upregulated ECM proteins, including annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C, actively contributing to tumor growth, invasion, angiogenesis, and immune exclusion. The expression of the cancer-associated ECM is largely driven by cancer-associated fibroblasts (CAFs), whose molecular diversity has been dissected through single-cell profiling and consolidated in emerging CAF atlases across cancers. By investigating the matrisome composition and CAF heterogeneity, these studies have unraveled the pivotal role of the stroma in shaping tumor biology. Based on these discoveries, ECM proteins and CAFs are now being explored as biomarkers and therapeutic targets. Future integration of multi-omics datasets with clinical outcomes will help to translate these insights into novel biomarkers for patient stratification and stroma-directed therapeutic interventions.

Humans↗
PubMed2026

Integrated single-cell transcriptomics, Mendelian randomization, and machine learning identify CEBPZ as an immune-related biomarker in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic, immune-mediated oral mucosal disease with complex pathophysiology and potential for malignant transformation. Understanding its molecular basis is critical for the development of precise diagnostic and therapeutic strategies. OBJECTIVES: We aimed to identify key immune-related biomarkers and characterize cellular dynamics in OLP, with a particular focus on the role of CEBPZ in disease pathogenesis. MATERIAL AND METHODS: We analyzed single-cell RNA sequencing (scRNA-seq) data from OLP lamina propria samples (GSE211630) to identify disease-specific T-cell subpopulations using high-dimensional weighted gene co-expression network analysis (hdWGCNA) for oxidative stress-related gene modules.-data-based Mendelian randomization (SMR) integrated FinnGen genome-wide association study (GWAS; 342,499 Europeans) data with Genotype-Tissue Expression (GTEx) expression quantitative trait loci (eQTL) data to identify causal genes. Machine learning (ML) models (least absolute shrinkage and selection operator (LASSO) and convolutional neural network (CNN)) were developed using bulk RNA-seq datasets (GSE52130 and GSE38616) for diagnostic purposes. RESULTS: We identified OLP-specific T-cell populations (clusters 0, 3, 5, 7, 13, and 15) with enhanced migration inhibition factor (MIF) pathway signaling toward B cells and monocytes. Two oxidative stress-associated modules contained hub genes, including CEBPZ. Summary-data-based Mendelian randomization analysis identified 231 OLP-associated genes, with CEBPZ uniquely intersecting LASSO-selected markers (odds ratio (OR) = 1.057, 95% confidence interval (95% CI) = 1.013-1.102, p = 0.010). Machine learning models achieved area under the curve (AUC) values ranging from 0.653 to 0.745, with the CNN model reaching a validation accuracy of 0.735. CEBPZ showed elevated expression in OLP T cells and correlated with enhanced MIF-(CD74+CXCR4) signaling. CONCLUSIONS: This integrative approach identifies CEBPZ as a pivotal biomarker linking genetic susceptibility, oxidative stress, and immune dysregulation in OLP. Our diagnostic models offer promising tools for OLP management.

CEBPZ↗
PubMed2026

Multi-omics analysis to uncover constitutive priming and dynamic metabolic reprogramming conferring white rust resistance in Brassica juncea.

White rust, caused by Albugo candida, is one of the most devastating diseases of Indian mustard (Brassica juncea), causing yield losses of up to 90%. Durable resistance sources within cultivated Brassica germplasm remain limited. In this study, near-isogenic lines (NILs) of B. juncea cv. Varuna harbouring resistance from an East European source (Donskaja-IV, possessing a single CC-NB-LRR protein-coding R gene) was used to investigate the molecular basis of resistance through integrated transcriptomic and metabolomic analyses at 48 and 96 hours post-inoculation (hpi). Transcriptomic profiling revealed that the resistant Varuna_WRR line exhibited significantly higher unique transcript expression (18.76%) compared to the susceptible parent (8.41%) during the progression of infection. Principal component analysis showed clear separation between genotypes based on infection status, time, and genetic background. In the resistant line, upregulated genes were enriched in ethylene-activated signaling, protein phosphorylation, endoplasmic reticulum stress response, pectin biosynthesis, and hypersensitive response at 48 hpi, shifting toward programmed cell death, protein ubiquitination, abscisic acid metabolism, and starch biosynthesis at 96 hpi. Conversely, the susceptible line displayed broad downregulation of primary metabolic processes, indicating metabolic exhaustion. Metabolomic analysis demonstrated that the resistant genotype accumulated higher levels of defense-related amino acids (proline, glutamine, glutamic acid, serine, threonine, glycine), carbohydrates, organic acids, and polyamines, supporting enhanced nitrogen assimilation, energy reserves, membrane stability, and signaling. Together, these findings indicate that constitutive priming and dynamic activation of defense signaling, protein turnover, and osmoprotectant accumulation underpin the enhanced resistance in Varuna_WRR against Albugo candida. This integrated multi-omics approach provides valuable insights for breeding durable white rust resistance in Brassica juncea.

Brassica juncea↗
PubMed2025

Comparative transcriptomics uncovers poplar and fungal genetic determinants of ectomycorrhizal compatibility.

Ectomycorrhizal symbiosis supports tree growth and is crucial for nutrient cycling and temperate and boreal ecosystems functioning. The establishment of functional ectomycorrhiza (ECM) first requires the association of compatible partners. However, host and fungal genetic determinants governing mycorrhizal compatibility are unknown. To identify such factors in poplar and its fungal associates, we mined existing and de novo tree and fungal transcriptional datasets. We identified co-expressed genes enabling ECM symbiosis at early and mature stages of the interaction. These sets of genes can be divided into general fungal-sensing and ECM-specific components. We highlight the importance of fungal modulation of plant JA-related defenses and the regulation of secretory pathways for ECM compatibility, including upregulation of key fungal small secreted proteins, the downregulation of plant secreted peroxidases, and the downregulation of plant cell wall remodeling proteins concomitantly with the upregulation of fungal glycosyl hydrolases acting on pectin. Not only gene regulation, but also its temporal scale and dynamics seem to play a crucial role for mycorrhizal compatibility. The expression profile of the host Common Symbiosis Pathway and nutrient transporters was also studied, revealing constitutive levels of expression and moderate upregulation in compatible ECM interactions. Overall, these results underscore the importance of novel biological functions during the establishment of ECM symbiosis, help us gain insights into the molecular events determining mycorrhiza compatibility, and serve as a data-rich transcriptomic resource to open new research questions in the field.

Mycorrhizae↗
PubMed2026

A chromosome-level genome assembly and developmental transcriptome profiling reveal stage-specific remodeling of the molecular chaperone system in Helicoverpa armigera.

Helicoverpa armigera is one of the most destructive lepidopteran pests worldwide owing to its remarkable polyphagy, long-distance migration, and rapid adaptation to insecticides. Here, we present a chromosome-level genome assembly of H. armigera generated from a field-collected individual in southwestern China, providing a valuable resource for future population genomic and pangenome studies. Developmental transcriptome analyses of first-instar larvae, fifth-instar larvae, and adults identified 6817, 3519, and 5518 differentially expressed genes, respectively, including 797 shared among all developmental transitions. Functional enrichment and co-expression network analyses revealed extensive transcriptional reprogramming, characterized by coordinated regulation of glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation, indicating dynamic metabolic remodeling during development. Genome-wide analysis identified 77 heat shock protein (HSP) genes belonging to six subfamilies. These genes were unevenly distributed across chromosomes, with HSP20 members exhibiting extensive tandem duplication. Expression profiling revealed pronounced stage specificity, suggesting progressive remodeling of molecular chaperone networks during development. Early larvae primarily relied on HSP40/HSP60/HSP70 and HSP10/HSP60 chaperone systems; fifth-instar larvae exhibited HSP20-centered proteostasis; and adults predominantly expressed HSP40 together with multiple HSP70 members, accompanied by enrichment of stress response and metamorphosis-related functions. This study provides new insights into developmental transcriptional regulation, metabolic remodeling, and stage-specific specialization of molecular chaperone networks in H. armigera, establishing a foundation for future studies of stress adaptation, population genomic variation, and developmental mechanisms.

Cotton bollworm↗
PubMed2026

Multiomics analysis reveals that senescent CXCL16+ macrophages promote lung adenocarcinoma progression through TGF-β signalling.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains a leading cause of cancer-related mortality worldwide. Although, immunotherapy has become a cornerstone of first-line treatment, only 20-30% of patients achieve a durable clinical benefit, largely because of the complexity and heterogeneity of the tumour immune microenvironment. Emerging evidence indicates that cellular senescence, particularly within immune cells, contributes to tumour progression by impairing antitumour immunity; however, its mechanistic role in LUAD remains incompletely understood. METHODS: We performed an integrative multiomics analysis incorporating genome-wide association studies (GWASs), bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics to characterize immune heterogeneity in LUAD. Cellular senescence was validated by performing staining for senescence-associated β-galactosidase and the canonical markers p16 and p21. SHAP analysis was applied to evaluate the contribution of CXCL16+ macrophages. Functional roles were assessed using coculture assays, in vitro and in vivo tumour models, orthotopic tumour implantation, and multiplex immunofluorescence staining of clinical specimens. RESULTS: A summary data-based on Mendelian randomization analysis integrating GWAS and TCGA data identified CXCL16 as a senescence-associated gene that is causally linked to the LUAD risk. Single-cell RNA sequencing revealed that CXCL16 is predominantly expressed in macrophages, and the pseudotime analysis together with β-galactosidase staining confirmed its association with macrophage senescence. Spatial transcriptomics and immunofluorescence staining showed the marked enrichment of CXCL16+ macrophages in LUAD tissues. The cell-cell communication analysis further revealed a strong association between the number of CXCL16+ macrophages and the activation of the TGF-β signalling pathway within the tumour microenvironment. Functionally, CXCL16+ macrophages promoted LUAD progression via TGF-β signalling, as validated in vitro and in subcutaneous and orthotopic tumour models. Molecular dynamics simulations additionally suggested that LUAD patients with high levels of CXCL16+ macrophage infiltration may exhibit increased sensitivity to bosutinib. CONCLUSIONS: CXCL16 promotes macrophage senescence, and senescent CXCL16+ macrophages drive LUAD progression through TGF-β signalling. These findings identify CXCL16+ macrophages as a biologically and therapeutically relevant immune cell population, highlighting a potential target for precision intervention in LUAD.

Humans↗
PubMed2025

Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.

Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.

Animals↗
PubMed2025

Single-cell-scale spatial transcriptome of the developing and adult mouse ovary.

Mammalian ovary development is essential for female fertility, involving the complex spatial patterning of diverse cell types to establish the finite reserve of ovarian follicles. While single-cell transcriptome analyses have provided important insights into the mechanisms driving specification and developmental trajectories of ovarian cells, they disrupt this crucial spatial context. To overcome this limitation, we used 10X Genomics Visium HD spatial transcriptomics to analyze the developing mouse ovary while maintaining its native cellular architecture. We captured all ovarian cell types at eight key fetal and postnatal timepoints, generating a near single cell resolution library of spatial gene expression across ovarian development. This comprehensive dataset allows analysis of dynamic transcriptional signatures associated with unique spatial patterning throughout development, including the establishment of cortex and medulla and assembly of ovarian follicles in each region. This dataset represents a fundamental resource for the investigation of regulatory mechanisms driving spatial patterning of the ovary and opens new avenues to explore the spatial determinants of female fertility and reproductive longevity.

Journal Article↗
PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗
PubMed2026

Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.

While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.

CRISPR interference screening↗
PubMed2026

Machine learning and multi-omics clustering to map cellular rewiring and immune evasion in ccRCC.

Immune checkpoint blockade (ICB) efficacy in clear cell renal cell carcinoma (ccRCC) is limited by tumor microenvironment (TME) heterogeneity. Because traditional bulk-derived models lack spatial resolution, we developed an integrated framework connecting macroscopic survival risks to microscopic TME structures. We applied ten algorithms to establish multi-omics subtypes and evaluated 101 machine-learning combinations across three independent cohorts to generate a Consensus Machine Learning-driven Signature (CMLS). The signature's spatial and cellular origins were decoded using spatial transcriptomics (ST) and a 140,000-cell scRNA-seq atlas. Expression of key genes was experimentally validated via RT-qPCR in 17 paired ccRCC clinical tissues. We identified two molecular subtypes with distinct clinical and epigenetic profiles. SuperPC optimization yielded a 24-gene CMLS serving as an independent prognostic factor. scRNA-seq and ST deconvolution revealed these signals predominantly originate from cancer-associated fibroblasts (CAFs) and malignant epithelial cells, which collaborate to drive spatial immune exclusion. RT-qPCR confirmed significant overexpression of five core CMLS genes in ccRCC versus adjacent normal tissues. Low CMLS scores correlated with enhanced ICB responsiveness, whereas high-CMLS tumors demonstrated specific vulnerability to dasatinib and dabrafenib. The CMLS translates spatial immune-exclusion dynamics into a quantifiable metric, outperforming tumor mutational burden in predicting ICB benefits, providing a robust tool for patient stratification in ccRCC.

Humans↗
PubMed2026

Tahoe-100M: Mapping drug-induced molecular phenotypes at single-cell resolution.

We present Tahoe-100M, a giga-scale single-cell perturbation atlas comprising 100 million transcriptomes from 50 diverse cancer cell lines treated with 1,100 drug-dose conditions. This parallel profiling of thousands of perturbations at single-cell resolution with minimal batch effects is enabled by the Mosaic platform, which multiplexes genetically distinct cell models into balanced "cell villages." Beyond cataloging transcriptomic shifts, Tahoe-100M systematically quantifies cellular phenotypes, including proliferation, cytotoxicity, lineage-specific vulnerabilities, and cell-cycle changes. It captures population-level transcriptomic heterogeneity, characterizing whether drug responses drive cells toward divergent fates or convergent states. Pathway-based signatures define drug-induced expression programs, classify mechanisms of action, reveal off-target activities, and expose adaptive stress responses associated with resistance. By unifying cellular and molecular readouts, this broadly applicable perturbation atlas advances our ability to model gene regulation, drug response, and network dynamics. Its public release enables the training of AI frameworks to advance predictive models of cell behavior.

Humans↗
PubMed2025

Escape from TGF-β-induced senescence promotes aggressive hallmarks in epithelial hepatocellular carcinoma cells.

Transforming growth factor-β (TGF-β) signaling and cellular senescence are key hallmarks of hepatocellular carcinoma (HCC) pathogenesis. Despite provoking senescence-associated growth arrest in epithelial HCC cells, elevated TGF-β activity paradoxically correlates with increased aggressiveness and poor prognosis in advanced tumors. Whether the transition between these dichotomous functions involves modulation of the senescence phenotype during disease progression remains elusive. Exploiting the epithelial HCC cell line Huh7 as a robust model, we demonstrate that chronic exposure to TGF-β prompts escape from Smad3-mediated senescence, leading to the development of TGF-β resistance. This altered state is characterized by an optimal proliferation rate and the acquisition of molecular and functional traits of less-differentiated mesenchymal cells, coinciding with differential growth capacity in 2D and 3D culture conditions, epithelial-to-mesenchymal transition (EMT), and increased invasiveness in vitro, and metastasis in vivo. Mechanistically, resistant cells exhibit defective activation and nuclear trafficking of Smad molecules, particularly Smad3, as ectopic activation of the TGF-β/Smad3 axis is able to reinstate TGF-β sensitivity. An integrated transcriptomic landscape reveals both shared and distinct gene signatures associated with senescent and TGF-β resistant states. Importantly, genetic ablation and molecular studies identify microtubule affinity regulating kinase 1 (MARK1) and glutamate metabotropic receptor 8 (GRM8) as critical modulators of the resistance phenomenon, potentially by impairing spatiotemporal signaling dynamics of Smad activity. Our findings unveil a novel phenomenon wherein epithelial HCC cells may exploit senescence plasticity as a mechanism to oppose TGF-β anti-tumor responses and progress towards more aggressive HCC phenotypes.

Humans↗
PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗
PubMed2026

A single-nucleus transcriptome atlas of soybean anthers.

Anther development is crucial for plant sexual reproduction. However, a high-resolution, cell-type-specific transcriptomic atlas of this process is lacking for the legume crop soybean (Glycine max). Here, we construct a comprehensive transcriptional atlas of developing soybean anthers using single-nucleus RNA sequencing (snRNA-seq). We identify and characterize nine distinct cell types spanning both somatic and reproductive lineages. Our analysis reveals robust transcriptional continuity across anther developmental stages and dynamic reprogramming during key transitions. Notably, the shift from diploid meiocytes to haploid unicellular microspores is marked by the induction of previously inactive genes, despite an overall reduction in transcript abundance. Subsequently, within bicellular microspores, generative and vegetative cell lineages exhibit sharply divergent transcriptional programs: generative cells specialize in mRNA export and turnover, whereas vegetative cells up-regulate translational machinery. Evolutionary analysis further indicates that generative-cell-specific genes are subject to more relaxed purifying selection compared to those specific to vegetative cells. Functional validation using mutants generated by CRISPR/Cas9-mediated genome editing and EMS mutagenesis reveals the essential roles of OSD1A and PKSA in pollen development and fertility. This high-resolution atlas provides fundamental insights into the transcriptional regulation of soybean anther development and serves as a valuable resource for manipulating male fertility to advance hybrid breeding programs. The data are available at https://databases.genedenovo.com/pollen.

Glycine max↗