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PubMed2026

Comprehensive characterization of the genes in AP2/ERF family and their involvement in salt-alkali stress response during Nelumbo nucifera seed germination.

Nelumbo nucifera Gaertn. is an economically and ecologically important aquatic plant, but its growth and productivity are severely constrained by soil salinization and alkalization. AP2/ERF transcription factors are key regulators of plant abiotic stress responses; however, their roles in salt-alkali tolerance in N. nucifera remain largely unclear. In this study, we performed a genome-wide identification and characterization of the AP2/ERF gene family in N. nucifera, followed by phylogenetic, structural, and physicochemical analyses. A total of 101 AP2/ERF genes were identified and classified into five subfamilies, showing both evolutionary conservation and species-specific divergence compared with Arabidopsis thaliana. Physiological analyses during seed germination under salt-alkali stress revealed significant changes in malondialdehyde content, proline accumulation, and antioxidant enzyme activities, suggesting activation of oxidative stress defense and osmotic adjustment mechanisms. Transcriptome profiling of seedlings treated with 150 mM salt-alkali solution for 5 and 10 days identified 7,350 differentially expressed genes, including 29 AP2/ERF members responsive to stress. Among them, 13 genes, including AP2-9, ERF23, ERF15, ERF31, ERF34, and DREB21, were consistently upregulated under both treatments, indicating their potential roles in stress adaptation. qRT-PCR validation further confirmed the sustained upregulation of key genes AP2-9, ERF23, ERF34, and DREB21, consistent with transcriptome data. Overall, this study provides the first comprehensive overview of the AP2/ERF gene family in N. nucifera and identifies candidate regulators involved in salt-alkali stress responses, offering valuable insights into the molecular mechanisms of stress adaptation and potential genetic resources for breeding salt-alkali tolerant aquatic plants.

AP2/ERF transcription factors↗

PubMed2026

Fasting-refeeding regimes induce compensatory growth and muscle transcriptomic remodeling in juvenile Qihe gibel carp (Carassius gibelio var. Qihe).

Compensatory growth, an important adaptive response in fish, holds considerable potential for improving feeding efficiency in aquaculture. To identify an optimal fasting-refeeding strategy for juvenile Qihe gibel carp (Carassius gibelio var. Qihe) and to clarify the mechanisms underlying the compensatory growth, we divided two-month-old fish into four groups, namely S0 group (continuous feeding for 28 days), S2 group (4 cycles of 2-day fasting followed by 5-day refeeding), S4 group (fasting for 4 days followed by refeeding for 24 days), and S8 group (fasting for 8 days followed by refeeding for 20 days), then growth performance, muscle tissue morphology, biochemical responses, and muscle transcriptomic profiles under different feeding regimes were investigated. After a 28-day aquaculture experiment, fish in the S4 group exhibited significantly greater body length and weight than those in the S0, S2, and S8 groups, indicating over-compensatory growth. Histological analysis further showed that muscle growth in the S4 group was mainly associated with myofiber hyperplasia. Different feeding regimes also induced distinct changes in hepatic antioxidant and metabolic enzyme activities, as well as intestinal digestive enzyme activities. Transcriptome analysis revealed that the forkhead box O (FoxO) signaling pathway was significantly enriched during compensatory growth. Key genes, including serum/glucocorticoid regulated kinase 1 (sgk1) and insulin receptor substrate 1 (irs1), were predicted to play important roles in this process. Overall, these results indicate that fasting for 4 days followed by refeeding for 24 days (the S4 regime) is the optimal strategy for inducing compensatory growth in juvenile Qihe gibel carp. This study provides new insights into the morphological, physiological, and molecular basis of compensatory growth and offers a scientific foundation for developing efficient and sustainable feeding strategies for this species.

Animals↗

PubMed2026

A murine model of sepsis induces age- and sex-specific chromatin remodeling in myeloid-derived suppressor cells.

INTRODUCTION: Sepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation. METHODS: Here, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis and daily chronic stress using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model, including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing. RESULTS: Unsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression. CONCLUSIONS: These findings define promoter-level epigenetic classes across a targeted locus panel in splenic CD11b+Gr1+ cells within this murine sepsis model and generate mechanistic hypotheses regarding age- and sex-associated chromatin states.

Animals↗

PubMed2006

FixJ: a major regulator of the oxygen limitation response and late symbiotic functions of Sinorhizobium meliloti.

Sinorhizobium meliloti exists either in a free-living state in the soil or in symbiosis within legume nodules, where the bacteria differentiate into nitrogen-fixing bacteroids. Expression of genes involved in nitrogen fixation and associated respiration is governed by two intermediate regulators, NifA and FixK, respectively, which are controlled by a two-component regulatory system FixLJ in response to low-oxygen conditions. In order to identify the FixLJ regulon, gene expression profiles were determined in microaerobic free-living cells as well as during the symbiotic life of the bacterium for the wild type and a fixJ null-mutant strain. We identified 122 genes activated by FixJ in either state, including 87 novel targets. FixJ controls 74% of the genes induced in microaerobiosis (2% oxygen) and the majority of genes expressed in mature bacteroids. Ninety-seven percent of FixJ-activated genes are located on the symbiotic plasmid pSymA. Transcriptome profiles of a nifA and a fixK mutant showed that NifA activates a limited number of genes, all specific to the symbiotic state, whereas FixK controls more than 90 genes, involved in free-living and/or symbiotic life. This study also revealed that FixJ has no other direct targets besides those already known. FixJ is involved in the regulation of functions such as denitrification or amino acid/polyamine metabolism and transport. Mutations in selected novel FixJ targets did not affect the ability of the bacteria to form nitrogen-fixing nodules on Medicago sativa roots. From these results, we propose an updated model of the FixJ regulon.

Amino Acids↗

PubMed2026

Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia.

To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.

Aged↗

PubMed2006

Robust analysis of 5'-transcript ends (5'-RATE): a novel technique for transcriptome analysis and genome annotation.

Complicated cloning procedures and the high cost of sequencing have inhibited the wide application of serial analysis of gene expression and massively parallel signature sequencing for genome-wide transcriptome profiling of complex genomes. Here we describe a new method called robust analysis of 5'-transcript ends (5'-RATE) for rapid and cost-effective isolation of long 5' transcript ends (approximately 80 bp). It consists of three major steps including 5'-oligocapping of mRNA, NlaIII tag and ditag generation, and pyrosequencing of NlaIII tags. Complicated steps, such as purification and cloning of concatemers, colony picking and plasmid DNA purification, are eliminated and the conventional Sanger sequencing method is replaced with the newly developed pyrosequencing method. Sequence analysis of a maize 5'-RATE library revealed complex alternative transcription start sites and a 5' poly(A) tail in maize transcripts. Our results demonstrate that 5'-RATE is a simple, fast and cost-effective method for transcriptome analysis and genome annotation of complex genomes.

5' Untranslated Regions↗

PubMed2026

Deciphering differential mRNA and lncRNA expression profiles in response to PEG simulated drought stress in cucumber (Cucumis sativus L.).

Cucumber (Cucumis sativus L.), a vital fruit vegetable of the Cucurbitaceae family, originated in India ∼ 3000 years ago. It is widely used in the culinary, therapeutic, and cosmetic sectors. Cucumber cultivation is significantly impacted by drought stress, especially in arid and semi-arid regions. This study investigates the molecular response to drought using two contrasting cucumber lines: WBC-23-2 (drought-tolerant) and DGPC-59 (drought-sensitive). Drought was simulated using polyethylene glycol (PEG), and effects on physiological and biochemical traits were evaluated. The tolerant line exhibited reduced leaf wilting and higher relative water content (RWC). Based on these physiological markers, transcriptomic profiling was employed to identify the underlying regulatory networks. Analysis identified 4,736 DEGs, suggesting that the tolerant line's superior resilience is driven by preferential activation of genes involved in photosynthesis and glutathione metabolism. Conversely, the sensitive genotype showed enrichment in organonitrogen compound catabolism and water deprivation response. This divergence is further reflected in the regulation of 155 transcription factors (TFs) across various families, indicating distinct regulatory architectures between the two lines. Additionally, 774 drought-responsive long non-coding RNAs (lncRNAs) were identified, acting via cis, trans, and competing endogenous RNA (ceRNA) mechanisms to modulate gene expression. Key candidate genes associated with drought tolerance included WAT1-related protein At5g64700, thaumatin-like protein, berberine bridge enzyme-like 18, probable WRKY transcription factor, and pathogenesis-related protein 1. This study reveals a complex regulatory network of mRNAs, lncRNAs, and TFs underlying drought response and provides a valuable foundation for breeding drought-resilient cucumber cultivars. A web-based genomic resource, CsDTDb, has been developed and made publicly available to facilitate future functional genomics studies related to drought tolerance in cucumber.

DEGs↗

PubMed2026

Low-Grade Myofibroblastic Sarcoma Represents an Epigenetically Distinct Myofibroblastic Tumor With USP6 Upregulation and Stable Genome.

Low-grade myofibroblastic sarcoma (LGMS) is a rare, indolent mesenchymal neoplasm exhibiting myofibroblastic differentiation, with a propensity for local recurrence. The molecular basis of LGMS and its precise relationship with other histological mimics have remained largely undefined. To address this gap, we conducted the first comprehensive multiomics analysis of 6 LGMS cases, integrating whole-exome sequencing, RNA sequencing, and Illumina Methylation EPICv2 array profiling with comparative analysis against public sarcoma methylation cohorts and related fibroblastic tumors. Clinically, patients (median age 35.5 years) presented with small tumors (median size 1.45 cm), predominantly located in the head and neck, displaying classic histological features of diffusely infiltrative spindle cell fascicles with patchy mononuclear inflammation. Two of the 5 patients with follow-up developed local recurrence, and none metastasized (median follow-up duration 92.5 months). Genomically, all LGMS exhibited a low tumor mutational burden (median 2.31 mut/Mb) and a minimal fraction of genome altered, with TP53 and TSC2 deletions and NTRK1 and ERBB3 amplifications found in a subset of cases. No pathogenic fusions were detected. Transcriptomic profiling revealed a distinct signature featuring prominent USP6 overexpression and upregulation of inflammatory and immune-related genes, including CD274 (PD-L1), and enrichment of inflammatory and interferon-gamma response signatures. Epigenetically, LGMS formed a unique methylation cluster closest to inflammatory myofibroblastic tumor, with numerous differentially methylated regions and higher immune infiltration, particularly monocytes, compared with other fibroblastic tumors. These findings establish LGMS as a genomically stable, epigenetically distinct myofibroblastic sarcoma driven by USP6 overexpression and an inflammation-enriched transcriptome. They support its recognition as a standalone entity, facilitate integration into methylation-based sarcoma classifiers for improved diagnostic precision, and nominate USP6-associated pathways and immune checkpoint blockade as promising therapeutic strategies for recurrent or unresectable disease.

Humans↗

PubMed2026

EprX associates with concurrent shifts in antimicrobial resistance and virulence in clinical bloodstream E. coli: a putative adaptive node for bacterial fitness.

Bloodstream infections (BSIs) caused by E. coli represent a growing global threat, driven by escalating antimicrobial resistance (AMR) and sustained virulence. However, the regulatory mechanisms linking these two phenotypes remain poorly understood. Here, we identify EprX, a previously uncharacterized YjbI-type pentapeptide repeat protein (PRP), a locus that our data suggest may influence metabolic and transcriptional profiles in clinical BSI E. coli isolates. Genomic screening of 85 clinical BSI strains reveals that eprX is present in 21.2% of isolates, often within distinct genomic contexts suggestive of mobile acquisition. Using λ-Red recombineering, we constructed eprX knockout mutants. Loss of eprX is associated with altered antimicrobial resistance profiles, increasing susceptibility to gentamicin, ciprofloxacin, and levofloxacin. This phenotype is consistent with upregulation of outer membrane porin genes (ompC, ompF) and downregulation of multidrug efflux pump genes (macB, mdtC, emrB) and two-component regulatory system genes. eprX deficiency also appears to correlate with attenuated virulence in our assays, as evidenced by improved survival of Galleria mellonella larvae (65-95% at 72 h post-infection vs. 40-60% for wild-type strains) and reduced adhesion to and invasion of human HeLa cells. Transcriptomic profiling reveals that eprX carriage is associated with broad, coordinated shifts in the expression of genes involved in LPS transport (lptG/lptF), type ;II secretion system components (gspD/gspE/gspF), autotransporter adhesins (ag43), and flagellar assembly, suggesting potential disruptions in outer-membrane integrity, biofilm formation, and virulence programs. Our data suggests that eprX is a genetic locus whose presence correlates with concurrent shifts in resistance maintenance and virulence traits, representing a putative adaptive node within the E. coli fitness landscape.

Animals↗

PubMed2025

Efficacy of Repeated Administration of Cultured Human CD34+ Cells Against Streptozotocin-Induced Diabetic Nephropathy in Rats.

To date, no clinical trial has investigated the potential of CD34+ cells to treat diabetic nephropathy. This study examined the efficacy of human CD34+ cells against diabetic nephropathy in rats. Rats were administered streptozotocin (STZ) intraperitoneally and divided into three groups: normal control, STZ control, and STZ plus cell therapy. The STZ-plus-cell-therapy group was administered human umbilical cord blood-derived CD34+ cells weekly for three weeks. At eight weeks, the rats' renal function, pathology, and transcriptome profiles were assessed. Although blood glucose levels did not differ between the STZ-administered groups, urinary albumin excretion was significantly lower at 6 weeks in the STZ-plus-cell-therapy group than in the STZ control group (p < 0.001). Serum creatinine levels tended to be higher in the STZ control group and lower in the STZ-plus-cell-therapy group. Cell therapy significantly improved mesangial expansion, interstitial fibrosis, peritubular capillary rarefaction, and glomerular macrophage infiltration compared with the STZ control (p < 0.0001). Kidney transcriptomics revealed significant upregulation of genes related to M2 macrophage markers, cell homing, and angiogenesis in the STZ-plus-cell-therapy group. In rats with STZ-induced diabetic nephropathy, human CD34+ cells ameliorated renal injury through their anti-inflammatory and pro-angiogenic effects.

Animals↗

PubMed2006

Genome-wide analysis of spatial and temporal gene expression in rice panicle development.

The basic structure of a rice inflorescence (the panicle) is determined by the pattern of branch formation, which is established at the early stages of panicle development. In this study we conducted global transcriptome profiling of the early stages of rice panicle development from phase transition to floral organ differentiation. To generate a meristem-specific gene-expression profile, shoot apical meristems (SAMs) and subsequently formed, very young panicles were collected manually and used for cDNA microarray analysis. We identified 357 out of 22,000 genes that are expressed differentially in the early stages of panicle development, and the 357 genes were classified into seven groups based on their temporal expression patterns. The most noticeable feature is that a fairly small number of genes, which are extensively enriched in transcription factors, are upregulated in the SAM immediately after phase transition. In situ hybridization analysis showed that each gene analysed exhibits a unique and interesting localization of mRNA. Remarkably, one of the transcription factors was proven to be a close downstream component of the pathway in which LAX, a major regulator of panicle branching, acts. These results suggest that our strategy--careful collection of meristems, global transcriptome analysis and subsequent in situ hybridization analysis--is useful not only to obtain a genome-wide view of gene expression, but also to reveal genetic networks controlling rice panicle development.

Gene Expression Profiling↗

PubMed2004

A Genome-wide view of the Escherichia coli BasS-BasR two-component system implicated in iron-responses.

Histidine-to-aspartate (His-->Asp) phosphorelay (or two-component) systems are very common signal transduction mechanisms that are implicated in a wide variety of cellular responses to environmental stimuli in both prokaryotes and eukaryotes. Determination of the entire genomic sequence of Escherichia coli revealed that this gram-negative bacterium has 29 His-kinases and 32 response regulators. Of the 29 His-kinases, 23 have already been experimentally characterized at least to some extent in terms of their physiological functions. No physiological stimulus has yet been identified for each of the remaining 6 His-kinases (BasS, CreC, RstB, YfhK, YehU, and YpdA). Here we characterized the BasS-BasR two-component system with reference to its physiological function, taking genetic approaches together with genome-wide transcriptome profiling. First we showed that the hypothetical yfbE operon that appears to be implicated in the modification of lipopolysaccharides is regulated at the level of transcription in response to external iron, and then we showed that the BasS-BasR system is essential for this iron-dependent induction of yfbE. Another PhoQ-PhoP two-component system was also implicated in the full induction of yfbE in response to iron, but it was not essential. To gain more insight into the BasS-BasR system, we conducted genome-wide transcriptome analysis by microarray, finding that many of the uncovered putative iron-induced and BasS-BasR-dependent genes are somehow associated with acidic and/or anaerobic growth conditions. In this respect, it was found that mutant cells defective in the BasS-BasR system were sensitive to mild-acid growth conditions in the presence of a relatively high concentration of iron. These results are discussed with regard to a comprehensive picture of the His-->Asp phosphorelay signaling network in E. coli.

Aspartic Acid↗

PubMed2026

Integrative analysis of transcriptome and chromatin accessibility reveals promoter-proximal regulation and identifies candidate ABC transporters associated with cold stress responses in maize.

BACKGROUND: Low-temperature stress is a formidable environmental constraint that severely limits the growth and productivity of maize (Zea mays L.), particularly during the highly vulnerable early seedling stage. While cold tolerance is a critical agronomic objective, the integrated transcriptional and epigenetic regulatory mechanisms that govern this trait remain largely elusive. Characterizing these coordinated molecular networks is fundamental to the genetic enhancement of cold resilience in maize. METHODS: Using two maize inbred lines contrasting in chilling response (ZHB12 tolerant, B73 sensitive), we performed integrative time‑course RNA‑seq and ATAC‑seq to thoroughly and systematically characterize the precise dynamic interplay between gene expression and chromatin accessibility under cold stress conditions at the seedling stage. RESULTS: Physiological assessments confirmed that ZHB12 possesses superior cold tolerance, manifested by significantly attenuated electrolyte leakage and reduced foliar damage compared to B73. Transcriptomic profiling revealed a massive, time-dependent divergence in gene expression between the two genotypes, with a major regulatory transition identified at 24 h of cold exposure. Functional enrichment analysis demonstrated that ZHB12 preferentially activates a robust defense repertoire, including Photosystem II electron transport, diterpenoid biosynthesis, and ATP biosynthetic pathways. Notably, multiple ATP-binding cassette (ABC) transporter genes were coordinately upregulated under chilling, suggesting their potential involvement in cellular homeostasis. ATAC-seq analysis indicated that cold stress is associated with chromatin remodeling in ZHB12, with increased accessibility observed in proximal promoter regions. Integrative analysis identified a core set of dual-responsive genes, in which increased promoter accessibility coincided with transcriptional upregulation. These genes were predominantly enriched in transporter activity and transcriptional regulation, suggesting potential epigenetic link to the superior stress response of ZHB12. CONCLUSION: Our findings reveal extensive transcriptional and chromatin accessibility changes in ZHB12 under cold stress. The observed associations between promoter accessibility and gene activation, particularly in genes involved in transport processes, highlight candidate regulators potentially contributing to cold tolerance. This study provides a molecular framework and identifies high-value candidate genes that may inform future efforts in breeding cold-tolerant maize, pending functional validation.

Zea mays↗

PubMed2025

Radiogenomic MRI biomarkers for noninvasive prediction of GPC3 expression and tumor microenvironment in hepatocellular carcinoma.

BACKGROUND: Glypican-3 (GPC3) is frequently overexpressed in hepatocellular carcinoma (HCC) and plays a key role in immune and metabolic remodeling of the tumor microenvironment. Reliable noninvasive biomarkers for predicting GPC3 status could improve patient stratification and support precision immunotherapy. METHODS: This multicenter retrospective study included 274 patients with pathologically confirmed hepatocellular carcinoma from three institutions, 34 external cases with MRI from The Cancer Imaging Archive, and 363 transcriptomic profiles from The Cancer Genome Atlas. Contrast-enhanced T1-weighted imaging and diffusion-weighted imaging were analyzed. Tumor and peritumoral regions were segmented manually and radiomic features extracted using PyRadiomics. Feature selection was performed with correlation filtering and least absolute shrinkage and selection operator regression. Machine learning classifiers including logistic regression, random forest, support vector machine, k-nearest neighbor, and decision tree were trained with 10-fold cross-validation and tested on independent external cohorts. A radiomics score was calculated for each patient. Radiogenomic analysis correlated radiomics scores with transcriptomic data using weighted gene co-expression network analysis. Hub genes and enriched pathways were identified, and immune infiltration and predicted immunotherapy response were assessed using computational methods. RESULTS: The random forest model using contrast-enhanced T1-weighted imaging achieved an area under the curve of 0.966 in training and 0.935 in internal validation. The integrated contrast-enhanced T1-weighted imaging plus diffusion-weighted imaging model reached an internal validation area under the curve of 0.979. In external testing, the best performance was obtained with a support vector machine model (area under the curve 0.756). Radiomics scores were significantly correlated with GPC3 expression (R = 0.78, p < 0.05). Transcriptomic analysis identified a 10-gene signature enriched in hypoxia and lipid metabolism pathways that stratified patients into prognostic subgroups (concordance index 0.720, hazard ratio 4.07, p < 0.0001). High-risk patients had greater immune infiltration and a lower predicted immune evasion score, suggesting a potential benefit from immunotherapy. CONCLUSIONS: MRI-based radiomics models can noninvasively predict GPC3 expression in hepatocellular carcinoma. Radiomics scores reflect underlying hypoxia and lipid metabolism pathways and stratify patients by prognosis and predicted immunotherapy response. These findings support radiogenomics as a translational approach to imaging-guided precision treatment in hepatocellular carcinoma.

Humans↗

PubMed2026

Overexpression of TCF7L2 promotes the viability and migration of MHCC-97H human hepatocellular carcinoma cells by upregulating MT-ND4L.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with high metabolic adaptability. TCF7L2, a transcription factor implicated in type 2 diabetes and cancer, is overexpressed in HCC. However, its specific role in HCC metabolic reprogramming is not well defined. We aimed to elucidate the previously unrecognized molecular mechanisms through which TCF7L2 impacts HCC progression. METHODS: To investigate the function of TCF7L2, a stable MHCC-97H cell line with TCF7L2 overexpression was established via lentiviral transduction. Cell viability and migration were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays. Transcriptomic profiling [RNA sequencing (RNA-seq)] was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis [Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA)] and bioinformatics promoter analysis (the JASPAR CORE database) were conducted. Clinical correlations, survival analysis, and tumor microenvironment (TME) interrogation were performed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and single-cell datasets [Human Protein Atlas (HPA), CellChat]. Drug sensitivity was predicted via the Genomics of Drug Sensitivity in Cancer (GDSC) database. RESULTS: TCF7L2 overexpression significantly promoted HCC cell proliferation and migration. Transcriptomic analysis revealed that TCF7L2 drives a profound metabolic shift, with key enrichments in lipid homeostasis, fatty acid β-oxidation, and the PI3K/Akt pathway. Mechanistically, TCF7L2 directly binds to the promoter of CPT1A, the rate-limiting enzyme of fatty acid oxidation, and indirectly upregulates the mitochondrial gene MT-ND4Lvia a strong positive correlation with the mitochondrial transcription factor TFAM. In clinical cohorts, TCF7L2 was overexpressed in HCC and its expression correlated positively with MT-ND4L, MKI67, and SNAI1, and served as a predictor of poor overall survival (OS). Furthermore, TCF7L2-high tumors were enriched in hepatic progenitor cell (HPC)-like niches, mediated by enhanced ANGPTL4 signaling. High TCF7L2 expression predicted increased sensitivity to PI3K/mTOR pathway inhibitors. CONCLUSIONS: TCF7L2 acts as a master metabolic regulator in HCC, coordinating lipid catabolism and mitochondrial biogenesis to drive aggressive tumor behavior. It further remodels the TME towards an HPC-like state and predicts sensitivity to metabolic-targeted therapies. These findings identify TCF7L2 as a key prognostic biomarker and a promising therapeutic target.

MHCC-97H hepatocellular carcinoma cells (MHCC-97H ↗

PubMed2026

Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer.

Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.

Humans↗

PubMed2025

IGF1R deficiency mitigates acute lung injury by promoting anti-inflammatory transcriptional profiles.

BACKGROUND: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and COVID-19 are characterized by hyperinflammation, commonly referred to as "cytokine storm". The insulin-like growth factor (IGF) pathway, particularly the type 1 receptor (IGF1R), plays a critical role in lung homeostasis and has been implicated in the pathogenesis of pulmonary inflammatory diseases. In mice, widespread Igf1r deficiency attenuates lung inflammation and alveolar damage in bleomycin (BLM)-induced ALI. METHODS: We analyzed single-cell RNA sequencing datasets from lung tissue of COVID-19 cases and control donors as well as mouse lungs to determine Igf1r and IGF family expression across pulmonary cell types. Furthermore, we conducted bulk RNA sequencing on lungs from Igf1r-deficient mice three days after BLM or saline instillation, followed by differential expression and functional enrichment analyses. Findings were further tested through protein detection, assessment of DNA damage and methylation in lung tissues, and functional assays using Igf1r-deficient primary mouse embryonic fibroblasts (MEFs). RESULTS: IGF1R was broadly expressed across multiple cell types in both human and mouse lungs under normal and pathological conditions. Other IGF family members showed cell-type-specific expression, which was modulated by lung injury. Transcriptomic profiling revealed differentially expressed genes between BLM-challenged and control mouse lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. Igf1r deficiency in BLM-challenged mice reversed a large fraction of the transcriptional changes triggered by BLM, including "cytokine storm"-related gene expression. Functional enrichment analysis additionally revealed significant modulation of pathways related to DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetic regulation. In vitro, Igf1r-deficient MEFs exhibited decreased mitochondrial respiration and glycolysis, protection against BLM-induced nuclear damage and mitochondrial accumulation, and decreased histone H3 acetylation. Moreover, Igf1r-deficient mouse lungs displayed increased global DNA methylation following BLM challenge. CONCLUSIONS: IGF1R is a key modulator of the inflammatory and molecular response to ALI pathogenesis. IGF1R deficiency dampens the "cytokine storm", modifies transcriptional and epigenetic profiles and promotes protective cellular responses. These findings highlight IGF1R signaling as a potential therapeutic target in ARDS and related lung injuries.

Animals↗

PubMed2026

DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.

Recurrent high-grade serous ovarian carcinoma (HGSOC) and endometrial cancer remain major clinical challenges with limited effective treatment options. DExH-box helicase 9 (DHX9), a DNA/RNA helicase essential for genomic stability, has not yet been explored as a therapeutic target in gynecologic cancers. In this study, we show that a selective DHX9 inhibitor (DHX9i) suppresses proliferation in a subset of HGSOC and endometrial cancer cell lines by inducing DNA damage, chromosomal instability, and mitotic failure. This effect was independent of microsatellite instability status and prior resistance to platinum or PARP inhibitors. Genomic analysis indicated that DHX9i resistance was unlikely to be driven by single-gene mutations but was instead associated with copy-number alterations in mitotic spindle and microtubule-regulating genes in both HGSOC and endometrial cancer. Transcriptomic profiling further revealed consistent alterations in microtubule- and spindle-associated pathways in DHX9i-resistant models following DHX9i treatment. Mechanistically, DHX9i induced mitotic defects in DHX9i-sensitive models, whereas resistant lines maintained mitotic integrity. Given the convergence of resistance-associated features on microtubule-related pathways, we combined DHX9i with the microtubule-stabilizing agent paclitaxel to enhance mitotic stress. This combination triggered mitotic disruption and enhanced cytotoxicity in DHX9i-resistant cells. In vivo, the combination led to sustained tumor regression and prolonged survival in both DHX9i-sensitive and DHX9i-resistant models without notable toxicity. Overall, our findings define genomic, transcriptomic, and phenotypic characteristics associated with differential responses to DHX9i and support the clinical evaluation of the DHX9i-paclitaxel combination as a therapeutic strategy in recurrent gynecologic cancers.

Female↗