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PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗

PubMed2026

Type 1 interferon perturbates clonal competition by reshaping human blood development.

Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.

Journal Article↗

PubMed2026

An immune exhaustion signature predicts prognosis and identifies patients with diffuse large B-cell lymphoma (DLBCL) who derive preferential benefit from chimeric antigen receptor (CAR)-T cell therapy.

BACKGROUND: The tumor microenvironment (TME) is a key determinant of prognosis in diffuse large B-cell lymphoma (DLBCL). While T-cell exhaustion is implicated in therapeutic failure, its precise molecular hallmarks and utility for predicting response to modern immunotherapies, such as chimeric antigen receptor (CAR)-T cell therapy, remain unclear. METHODS: We performed an integrative analysis of transcriptomic and clinical data from multiple DLBCL cohorts (The Cancer Genome Atlas [TCGA], GSE181063, GSE10846, GSE248835, GSE182434). We used unsupervised clustering, exploratory analysis of single-cell RNA sequencing data, and the least absolute shrinkage and selection operator for variable selection (LASSO-Cox) regression to characterize the exhausted TME, construct a prognostic model, and evaluate its predictive value for CAR-T cell therapy. The model's dynamic behavior was assessed in a proof-of-concept longitudinal cohort of patients treated with the T-cell-engaging bispecific antibody glofitamab. RESULTS: We identified a "high-exhaustion" subtype associated with significantly poorer overall survival (OS; log-rank P = 0.016). Based on this, we developed a five-gene immune exhaustion-Related Prognostic Score (IERPS) that served as a robust independent predictor of poor OS across multiple cohorts. Critically, in a cohort of 256 relapsed/refractory patients, the IERPS was strongly prognostic for event-free survival (EFS) in the standard-of-care (SOC) arm (HR = 2.02, 95% confidence interval [95% CI]: 1.07-3.81, P = 0.029) but lost prognostic significance in the CAR-T arm (HR = 0.70, 95 % CI: 0.35-1.40, P = 0.314). This significant interaction suggests that CAR-T cell therapy may abrogate the poor prognosis associated with a high IERPS. Biologically, exploratory single-cell analysis (n = 4 samples) defined the high-IERPS state by hallmarks of classical T-cell exhaustion, and a descriptive case study showed the score dynamically tracked clinical response to glofitamab. CONCLUSIONS: A state of active T-cell exhaustion and a suppressive TME drive the adverse immune phenotype in DLBCL. Our IERPS model captures this dysfunctional state, acting as a powerful prognostic tool and, more importantly, as a potential predictive biomarker to identify high-risk patients who appear to overcome their inherently poor prognosis through CAR-T cell therapy.

Biomarkers↗

PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗

PubMed2025

A Multi-omics Exploration Revealing SLIT2 as a Prime Therapeutic Target for Peripheral Facial Paralysis: Integrating Single-Cell Transcriptomics and Plasma Proteome Data.

Peripheral facial paralysis (PFP) is a common neurological disorder characterized by facial-nerve dysfunction. Identifying therapeutic targets and understanding the molecular and cellular mechanisms underlying PFP are crucial for developing effective treatment strategies. This study combined Mendelian randomization (MR) analysis and single-cell RNA sequencing (scRNA-seq) to explore potential therapeutic candidates and their roles in PFP pathophysiology. The MR analysis included 1925 publicly available plasma protein cis-heritability instruments. Instrumental variables were selected for MR analysis to identify plasma proteins associated with PFP, followed by colocalization analysis to evaluate shared genetic variants between the identified proteins and PFP. After the initial identification of plasma proteins associated with Bell's palsy using MR analysis, a rat model of facial-nerve injury was established to further dissect underlying mechanisms at cellular and molecular levels. Using scRNA-seq technology, we delved deeply into cellular Heterogeneity and dynamic changes in gene expression in the facial-nerve nucleus tissues under both injured and control conditions, thereby achieving a systematic study ranging from macroscopic genetic associations to microscopic cellular functions. Finally, expression patterns were preliminarily validated by performing in vitro immunofluorescence analysis on the facial-nerve nucleus samples of SD rats. The MR analysis results identified 30 plasma proteins significantly associated with PFP, with nine target genes showing differential expression in the scRNA-seq data. Colocalization analysis demonstrated that slit guidance Ligand 2 (SLIT2), semaphorin 4D (SEMA4D), EGF containing fibulin extracellular matrix protein 1 (EFEMP1), and sprouty related EVH1 domain containing 2 (SPRED2) shared causal variants with PFP. SLIT2 was highly expressed in the microglia and inhibitory neurons in the experimental group, whereas SEMA4D showed elevated expression across multiple glial cell types in the same group. In contrast, EFEMP1 and SPRED2 showed distinct expression patterns in fibroblasts and oligodendrocytes. The role of SLIT2 has been previously well-documented in many central nervous system diseases. However, for the first time, this study detected SLIT2 alteration after facial-nerve injury. Altered intercellular signaling, particularly enhanced SLIT2-ROBO signaling between neurons and glial cells, was observed in the PFP group. Pseudotime analysis revealed dynamic SLIT2 expression during microglia and inhibitory neuron differentiation, mirroring changes in ROBO1 expression. Immunofluorescence analysis of rat facial-nerve nucleus samples verified that SLIT2 protein levels were significantly increased in the facial-nerve nuclei of injured samples. In conclusion, despite the fact that this study is primarily founded on animal models and despite notable differences existing between animals and humans in terms of the facial motor nucleus, this study successfully identified SLIT2 as potential therapeutic targets for PFP. The SLIT2-ROBO axis stands out as a particularly promising candidate. SLIT2 may play a role in modulating neuroimmune interactions and promoting nerve repair. These findings provide a foundation for future clinical studies and targeted interventions to enhance recovery from PFP. Future research should focus on human sample validation to enhance clinical translation.

Animals↗

PubMed2026

Imaging-Guided Omics Technologies for Resolving Rare Cancer States and Advancing Nanomedicine.

The ability to resolve rare and transient cellular states is critical for understanding metastasis, immune evasion, and therapy resistance in cancer, yet these dynamic processes often escape detection by conventional sequencing and imaging approaches. Recent advances at the interface of nanotechnology, high-resolution live-cell imaging, and single-cell/spatial multiomics methods have enabled functional profiling of cells with unprecedented precision within their native microenvironment. In this Mini-Review, we highlight emerging nanoscale platforms that couple real-time phenotypic imaging with molecular readouts, such as FUNseq and CIN-seq, to directly link functional heterogeneity to transcriptomic, proteomic, and epigenomic information. By integrating nanoscale optical imaging, microengineered perturbation tools, and AI-driven computational analysis, these technologies open up new avenues for dissecting rare metastatic, therapy-resistant, or immune-evasive subpopulations. We further discuss how these next-generation imaging-guided single-cell and spatial omics platforms not only advance fundamental cancer biology but also create opportunities to accelerate the development of nanomedicine applications.

Humans↗

PubMed2026

Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.

A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As glucose utilization declines in patients with AD, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (Aβ) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under Aβ-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of patients with AD. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by Aβ aggregates. Using a 13C stable isotope tracer, we verified cellular lactate uptake and its incorporation into tricarboxylic acid (TCA) cycle in neurons under the neurotoxic condition. 13C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.NEW & NOTEWORTHY This study shows that lactate treatment attenuates Aβ-induced cell death in neuron-like cells and supports mitochondrial carbon metabolism. Glycolytic hypometabolism was observed in human AD brain transcriptome and Aβ-treated neuron-like cells. We confirmed that lactate replenished mitochondrial energetics, making neurons more resilient to neurotoxicity. Using 13C tracing and metabolic flux analysis, we found that lactate-derived carbon was incorporated into the TCA cycle and that lactate treatment was associated with restoration of Aβ-suppressed mitochondrial fluxes.

Humans↗

PubMed2026

Transcriptomic changes in the gut mucosa of fasting northern elephant seal pups reveal immune modulation during early microbiome establishment.

Fasting is an integral component of the life-history of many species. Following abrupt weaning, northern elephant seal pups (Mirounga angustirostris) undergo an extended post-weaning fast of approximately 60 days. During this period, enteric bacterial diversity increases, suggesting that host immune regulation may facilitate the establishment of microbial communities. However, the molecular processes occurring within the intestinal mucosa during this transition remain poorly understood. To investigate these mechanisms, we characterized transcriptional changes in the enteric mucosa of male and female northern elephant seal pups sampled at weaning and after one month of fasting. Total RNA isolated from rectal swabs was sequenced and aligned to the Mirounga angustirostris reference genome. Differential gene expression and gene set enrichment analyses were used to identify genes and pathways associated with fasting and sex-specific responses. Fasting was accompanied primarily by transcriptional downregulation, including genes involved in antimicrobial defense, inflammation, protein turnover, and epithelial remodeling. In contrast, several genes associated with B-cell activity and immune recognition were upregulated. Gene Set Enrichment Analysis revealed coordinated activation of immune-regulatory pathways indicating dynamic modulation of intestinal immunity rather than generalized immune suppression. Pronounced sex-specific differences were also observed. Male pups exhibited transcriptional patterns consistent with enhanced immune tolerance, whereas females showed broader immune-pathway activation, including enrichment of pro-inflammatory and stress-response pathways. Several non-coding RNAs also displayed sex-specific changes in expression. Together, these findings suggest that fasting induces transcriptional remodeling of the gut and may contribute to immune regulation during a critical period of microbiome establishment in northern elephant seal pups.

Animals↗

PubMed2025

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Journal Article↗

PubMed2025

Dual RNA isolation from blood: an optimized protocol for host and bacterial RNA purification for dual RNA-sequencing analysis in whole blood sepsis samples.

Dual RNA-sequencing (dual RNA-seq) holds significant promise for deciphering bacterial virulence mechanisms during systemic infections. However, its application in sepsis research is hindered by technical challenges, including a low bacterial burden in blood and limited sample volumes and RNA yield from vulnerable populations, such as neonates. We developed an optimized protocol [dual RNA isolation from blood (DRIB)] for simultaneous stabilization, isolation and purification of high-quality host leukocyte and bacterial RNA from low-volume whole blood samples (0.5 ml). This protocol is compatible with clinical sample collection workflows and high-throughput RNA sequencing. The feasibility of DRIB for dual RNA-seq was validated using a pilot cohort of clinical adult sepsis samples, enabling the investigation of host-bacterial gene expression during sepsis. The DRIB protocol yielded 2.10-6.91 µg of total RNA per clinical sample in our pilot cohort. Dual-species ribosomal RNA (rRNA) depletion and RNA-seq generated 16.6-24.8 million filtered reads per sample, with 63±7% of reads uniquely mapped to host or bacterial sequences. Host genes accounted for 51-68% (8.4-10.9 million) reads, while 0.5-6.7% (79,496-789,808 reads) mapped to bacterial genomes. Bioinformatic analysis revealed that both shared and individual transcriptional patterns were identified in host and bacterial responses, including pathways related to immune metabolism and metal-ion binding. Our optimized DRIB protocol and RNA-seq pipeline effectively captured both host and bacterial RNA transcription in clinical sepsis samples. Expanding this approach to larger cohorts and varying disease timepoints will provide crucial new insights into host-bacterial gene co-expression dynamics in sepsis progression and outcomes.

Humans↗

PubMed2025

Subgenomic divergence and functional innovation following whole-genome duplication in Maleae species of Rosaceae.

Whole-genome duplication (WGD) drives plant evolution by inducing karyotype rearrangements and gene loss through subgenome fractionation. In this study, we investigate post-WGD evolutionary dynamics in Rosaceae, focusing on Maleae species, which uniquely experienced an additional WGD. Using phylogenetic and synteny analyses, we reveal that chromosomal breakpoints act as hotspots for localized fractionation, contributing to blurred homoeologous origins and influencing gene retention patterns. Here, we reconstruct karyotype evolution across Rosaceae subfamilies, highlighting chromosome reductions and lineage-specific rearrangements in Dryadoideae, Rosoideae, and Amygdaloideae. We also identify a bias for retaining transcription factors and hormone-related genes from older WGDs in subsequent polyploidy events. Transcriptome analysis classifies WGD-derived genes in Maleae species, such as apple and loquat, into three expression groups, with hormone-enriched genes playing roles in lignification and fruit-related innovations. These findings demonstrate the interplay between chromosomal breakpoints, biased retention, and functional divergence, revealing their contributions to genomic and phenotypic evolution in Maleae and their adaptive success within Rosaceae.

Genome, Plant↗

PubMed2026

Probiotic Lacticaseibacillus casei 2S-1 Attenuates Escherichia coli-Induced Enteritis via Gut Microbiota Modulation and Host Gene Regulation.

Maintaining gut microbial homeostasis is crucial for host health, whereas infection with Escherichia coli (E. coli) is a major contributor to intestinal inflammation and microbial dysbiosis. Recent research has focused on probiotic strategies for managing enteric inflammatory disorders. Previous studies have shown that beneficial microorganisms show protection through modulating host immune responses, enhancing intestinal epithelial barrier integrity, and inhibiting pathogenic bacteria. To evaluate the prophylactic effectiveness of a recently isolated strain, Lacticaseibacillus casei 2S-1, in a murine model of E. coli-induced enteritis, this study focuses on interactions within the microbiota-intestinal-immune axis, together with host transcriptional responses and pathway enrichment associated with oxidative stress and mitochondrial function. In vitro analysis of probiotic features, including growth dynamics, acidogenic capacity, and tolerance to acidic and bile salt environments, as well as genetic safety profiling, followed the methodical isolation and taxonomic identification of L. casei 2S-1. A preventive intervention protocol was established, and a murine model of enteritis was induced by exposure to E. coli. Histopathological analyses were performed to observe in vivo safety and protective efficacy. Changes in gut microbial structure were characterized by 16S rRNA gene sequencing, while host responses were identified by intestinal immunohistochemistry and transcriptome profiling. L. casei 2S-1 showed probiotic properties. In vitro analyses showed that the strain exhibited tolerance to acidic and bile salt conditions, and its untreated culture supernatant showed antimicrobial activity against pathogenic bacteria. Its safety profile was supported by genomic analysis, which verified the lack of virulence-associated genes and antibiotic resistance factors. In vivo, L. casei 2S-1 pretreatment reduced mortality and intestinal inflammation, modulated gut microbial composition, and preserved intestinal barrier-associated protein expression in infected mice. This study provides experimental evidence supporting the prophylactic effects of L. casei 2S-1 and its associations with gut microbiota modulation and host transcriptional responses, providing a foundation for further investigation of probiotic-based preventive strategies against intestinal infections.

Animals↗

PubMed2026

A network of steroid receptor transcription factors regulates ovarian chromatin remodeling in the transition to ovulation.

Steroid receptors are transcription factors activated by progesterone, androgen, and glucocorticoid that bind the same canonical DNA sequence to modulate genome function in response to steroid hormones. However, the mechanisms defining unique physiological roles of these conserved receptors within the same tissue context, including the ovary, remain elusive. Here, we describe the dynamic association between each steroid receptor cistrome in the mouse ovary responding to the hormonal switch from follicle development to ovulation and generate chromatin conformation maps to define steroid receptor roles in promoter-enhancer interactions and gene transcription. Ovulatory hormones trigger progesterone receptor (PGR) and glucocorticoid receptor (NR3C1 [also known as GR]) binding to novel chromatin sites, promoting transcriptional activation of genes that are required for ovulation, whereas AR-chromatin interactions and androgen receptor (AR)-associated genes are repressed. Integration of genomic and transcriptomic data illustrates two parallel modes of PGR-mediated gene activation. Unique cooperation between PGR and GR enables their recruitment to previously inaccessible promoters, increasing histone acetylation, chromatin accessibility, and transcription activation, with PGR being the indispensable component of this transcriptional complex. Alternatively, PGR tethered to enhancers interacting with preaccessible, AR/GR-bound promoters induces gene activation. Our findings illustrate the multifaceted steroid receptor interactions that translate progressive change in steroid environments to collectively reprogram granulosa cell genome function to switch from follicle development to ovulation.

Journal Article↗

PubMed2026

OsDUF3615 regulates grain size and quality traits by modulating cell proliferation and starch metabolism in rice.

Domains of Unknown Function (DUFs) are widely distributed across diverse genomes and are increasingly recognized as important regulators of plant growth, development, and stress responses. DUF3615 is a highly conserved plant-specific protein motif; however, its biological function remains largely unknown. Previously, the gene OsGAPC3, a key regulator of grain quality, was isolated and functionally characterized in rice. Transcriptome analysis during the dissection of the OsGAPC3-mediated regulatory pathway revealed that OsDUF3615 is significantly upregulated in Osgapc3 mutants, suggesting its potential involvement in rice development and grain traits. In this study, we show that OsDUF3615 is constitutively expressed in rice and encodes a nucleus-localized protein. Functional analysis demonstrated that overexpression of OsDUF3615 significantly promotes cell proliferation and expansion in the lemma along the grain width axis, leading to increased grain width and thousand-grain weight. Moreover, OsDUF3615 modulates grain filling dynamics and alters the accumulation of major storage compounds, including starch and free fatty acids, thereby affecting both nutritional composition and eating quality traits, such as taste value. Collectively, our findings identify OsDUF3615 as a key regulator of rice grain development and quality formation, providing valuable genetic resources for the molecular breeding of high-quality rice varieties.

OsDUF3615↗

PubMed2026

From immature to mature epithelium: unveiling structural dynamics and transcriptional programs in rainbow trout intestinal barrier.

The intestinal epithelium is crucial for nutrient absorption, immune defense, and barrier function in farmed fish. However, the molecular mechanisms underlying its development and maturation in salmonids remain poorly characterized, hindering our ability to address pervasive gut health challenges in aquaculture. In this study, we use the RTgutGC cell line to implement an epithelial maturation model with the aim of characterizing the global transcriptional program in rainbow trout (Oncorhynchus mykiss). We evaluated in vitro culture conditions to generate a polarized epithelial barrier with high transepithelial electrical resistance (TEER = 75.8 Ω × cm2), low permeability (6.2 × 10-6 cm/s), and well-defined apical specializations, including microvilli-like structures and clusters of these structures (brush border). Comparative transcriptomic profiling between immature (7 days post-seeding, dps) and mature (28 dps) epithelia revealed 3,817 differentially expressed genes (DEGs). Functional enrichment analysis showed that maturation was characterized by the downregulation of proliferative and ribosomal pathways and the concerted upregulation of processes critical for barrier function, including transmembrane transport, proteolysis, cell adhesion, extracellular matrix organization, and tight junction assembly. We identified a core set of 60 genes indicators of epithelial maturation, encompassing solute transporters (slc26a6, slc43a2), tight junction proteins (tjp1, cldn1, cldn3, cldn5, cldn18, among others), and structural components essential for microvilli formation and polarization (cdhr5b, pard6a). By integrating ultrastructural, functional, and transcriptomic data, this study established a framework for future mechanistic investigations into gut development and maturation in vitro. This set of mature epithelium indicators has diverse applications, such as the design of nutritional and pharmacological interventions to improve gut health and resilience in farmed fish.

Animals↗

PubMed2024

Spatiotemporal single-cell roadmap of human skin wound healing.

Wound healing is vital for human health, yet the details of cellular dynamics and coordination in human wound repair remain largely unexplored. To address this, we conducted single-cell multi-omics analyses on human skin wound tissues through inflammation, proliferation, and remodeling phases of wound repair from the same individuals, monitoring the cellular and molecular dynamics of human skin wound healing at an unprecedented spatiotemporal resolution. This singular roadmap reveals the cellular architecture of the wound margin and identifies FOSL1 as a critical driver of re-epithelialization. It shows that pro-inflammatory macrophages and fibroblasts sequentially support keratinocyte migration like a relay race across different healing stages. Comparison with single-cell data from venous and diabetic foot ulcers uncovers a link between failed keratinocyte migration and impaired inflammatory response in chronic wounds. Additionally, comparing human and mouse acute wound transcriptomes underscores the indispensable value of this roadmap in bridging basic research with clinical innovations.

Humans↗

PubMed2025

Multiomic Analyses Reveal the Molecular Mechanisms of Arid Adaptation in a Desert Rodent Species.

Organisms living in desert habitats face multiple simultaneous pressures, such as high temperatures and arid, and the population dynamics and community diversity of small rodents are strongly affected by climate extremes. However, the potential mechanisms by which desert rodents adapt to arid remain largely unexplored. Here, we assembled a 3.18 Gb genome, including 25,812 protein-encoding genes, for Orientallactaga sibirica, which is widely distributed across both arid and semihumid environments in Eurasia. Orientallactaga sibirica has longer ears and hind limbs to enhance heat dissipation, which may be related to the positively selected genes, such as Fgf10, Fgf11, Hoxc4, Hoxd1, and Bmp4. The renal transcriptome revealed increased fat and carbohydrate metabolism for metabolic water production in O. sibirica residing in arid habitats. Pathways such as material metabolism, oxidative stress response, osmoregulation, and water and salt reabsorption were enriched in candidate genes, such as Avp, Ang, and Ace, under positive selection in O. sibirica. Moreover, amino acid replacement was observed in the protein sequences of seven candidate genes, including Aldh7a1, Lnpep, Wnk4, C1qc, and Awat2, and these specific amino acid replacements of genes such as Umod and Scnn1a were related to unique osmoregulation, osmotic protection, and water retention compensation mechanisms. Water deprivation under laboratory conditions induced the upregulation of Umod and Aldh7a1 expression, further supporting the results observed in the wild population. These findings demonstrate that the positively selected genes related to limb development and specific amino acid replacements in the genes Umod and Scnn1a for unique osmoregulation in the renal vascular system may contribute to arid adaptation in the desert rodent species O. sibirica. This study provides novel insights into the adaptive evolution of desert small mammals and can serve as a reference for future research on renal damage-related diseases, such as human kidney stones and salt-sensitive hypertension.

Animals↗

PubMed2025

E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility.

Quiescent cells actively repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce reentry from quiescence, but how it overcomes chromatin-mediated repression remains unclear. Here, we show that inducible E2F1 expression triggers exit from quiescence and progression through the cycle without changes in chromatin accessibility, by harnessing regulatory elements with limited, pre-existing accessibility. Using time-resolved transcriptomics, we demonstrate that E2F1 induces an accelerated transcriptional program compared to serum. Unlike serum, which triggers broad chromatin remodeling, E2F1-induced activation occurs in a context of limited accessibility. ChIP-seq reveals that E2F1 directly binds target sites in quiescent cells to upregulate canonical genes. Biochemical reconstitution shows that E2F1 binds nucleosomes and accesses internal E2F sites within histone-wrapped DNA. These findings suggest that E2F1 can engage nucleosome-associated DNA and initiate transcription without major chromatin reorganization, redefining transcription factor-chromatin dynamics during cell fate transitions and establishing E2F1 as a potent regulator of cell-cycle reentry.

Journal Article↗