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Results for “Functional enrichment analysis”

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PubMed2026

DNA methylome responses to biotic and abiotic stress in Arabidopsis thaliana: A multi-study analysis.

RATIONALE: Plants experience diverse biotic and abiotic stresses that can induce changes in DNA methylation. However, comparisons among existing studies are complicated by differences in analytical methods and experimental designs. We aimed to identify shared and stress-specific DNA methylation responses across studies. METHODS: We reanalysed 16 whole-genome bisulphite sequencing datasets from 13 Arabidopsis thaliana studies using a unified bioinformatics pipeline. Differentially methylated regions (DMRs) were assessed in the CG, CHG and CHH contexts and examined in relation to genes, transposable elements (TEs), Gene Ontology terms, gene-proximal TE superfamilies and epimutation-prone loci. RESULTS: Global methylation levels were generally stable, whereas the number and genomic distribution of DMRs varied according to stress type and methylation context. CG-DMRs occurred primarily in gene bodies, while CHG- and CHH-DMRs were enriched in TEs. Functional analysis identified shared stress-related processes across conditions. Gene-proximal LINE/L1, RathE1_cons and DNA/HAT elements were enriched for stress-responsive methylation changes. A subset of stress-associated CG-DMRs overlapped loci known to accumulate stable epimutations over generations. CONCLUSIONS: Standardized cross-study analysis revealed both shared and stress-specific methylation patterns. The association of stress-responsive DMRs with gene-proximal TEs and epimutation-prone loci suggests potential links among environmental responses, genome regulation and long-term epigenetic variation.

Arabidopsis thaliana↗

PubMed2026

Genetic and clinical insights into the coexistence of multiple myeloma and diffuse large B cell lymphoma from a case report and systematic review with bioinformatics analysis.

BACKGROUND: Multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) are B-cell malignancies that rarely coexist in a single patient, presenting significant diagnostic and therapeutic challenges. While MM primarily involves clonal plasma cells, DLBCL is an aggressive lymphoid neoplasm. Investigating shared genetic mutations and understanding their clinical relevance in both cancers could provide novel insights into their pathogenesis and underlying molecular mechanisms, thereby informing future translational research. MATERIALS AND METHODS: A case report was conducted on a 52-year-old male who presented with abdominal pain and anemia. Imaging revealed lymphadenopathy, and biopsy confirmed high-grade DLBCL with concurrent bone marrow involvement suggestive of MM. Laboratory tests identified monoclonal IgM gammopathy, and the patient was treated with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) chemotherapy for DLBCL followed by autologous stem cell transplantation (ASCT) for MM relapse. A systematic review of the literature was performed using PubMed, Scopus, and Web of Science databases to identify cases of patients diagnosed with both MM and DLBCL. Data on patient demographics, clinical features, treatment regimens, and outcomes were extracted. Additionally, bioinformatics analysis was conducted using publicly available genomic data from cBioPortal and IntOGen to identify driver gene mutations in MM and DLBCL. Functional and pathway enrichment analysis was performed with KEGG and Gene Ontology (GO) databases. RESULTS: The case report highlighted a complex clinical course where the patient initially responded well to R-CHOP chemotherapy for DLBCL, achieving remission, but later relapsed with MM, treated with ASCT and lenalidomide. The systematic review revealed 14 eligible studies in which MM and DLBCL often occur in older patients, either simultaneously or sequentially, with variable treatment responses, including complete remission, partial remission, or relapse. The bioinformatics analysis identified several shared function and cancer-related pathways between two cancers including interleukin and cytokine-mediated signaling pathways, regulation of cell cycle, neurotrophin signaling pathway, FOXO signaling pathway, Epstein Barr virus infection, and viral carcinogenesis. CONCLUSION: This study provides valuable insights into the dual occurrence of MM and DLBCL, emphasizing the importance of tailored treatment approaches. The driver mutations identified highlight overlapping oncogenic pathways rather than implying a shared clonal origin, and may inform future studies exploring their biological and clinical implications. Further research into these shared molecular mechanisms could lead to more effective treatments for patients with coexisting MM and DLBCL.

Bioinformatics analysis↗

PubMed2026

IL1B-centered immune dysregulation involving IL7R, CCR7, ITGB2 and IRF1 across insomnia and inflammatory bowel disease.

BACKGROUND: Insomnia is a prevalent sleep disorder that strongly affects one's quality of life and physical well-being. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestines, and a majority of IBD patients suffer from comorbid insomnia. However, the shared molecular features linking insomnia and IBD remain poorly characterized. METHODS: Common differentially expressed genes (DEGs) were identified in datasets of insomnia (GSE208668) and IBD (GSE179285) using the Limma package. Functional enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Protein-protein interaction (PPI) network construction and hub gene identification was subsequently performed. Furthermore, we validated the reliability of the hub genes using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). In addition, we constructed a TF-miRNA regulatory network of hub genes and assessed the abundance of immune cell infiltration in insomnia and IBD using CIBERSORT, EPIC, and xCell algorithms. Finally, we utilized the DsigDB to predict potential therapeutic candidates. RESULTS: The analysis revealed 75 upregulated and 32 downregulated common DEGs. Functional enrichment analysis revealed the inflammatory response and immune activation as pivotal drivers underlying the pathogenesis of both insomnia and IBD. Five hub DEGs, namely, IL1B, IL7R, CCR7, ITGB2, and IRF1, were subsequently screened and validated. The TF-miRNA-mRNA regulatory network consisted of 5 TFs, 14 miRNA nodes and 5 core mRNA nodes. Immune cell infiltration analysis revealed several patterns shared between insomnia and IBD. Additionally, 10 potential therapeutic drugs for insomnia and IBD were proposed. CONCLUSION: Integrative coexpression network analysis reveals convergent dysregulation of an IL1B-centered immune module (comprising IL7R, CCR7, ITGB2, and IRF1) across insomnia and IBD, a shared immune disturbance and candidate targets for simultaneous intervention upon further mechanistic validation.

Humans↗

PubMed2026

Genome-wide association study reveals candidate genes associated with body weight and wool traits in Ordos fine-wool sheep.

BACKGROUND: The Ordos fine-wool sheep is a high-quality fine-wool breed in China, renowned for its excellent wool quality, meat production, and adaptability to the arid and semi-arid regions of Inner Mongolia. Body weight and wool traits are important economic characteristics in sheep breeding. This study aimed to identify genetic loci associated with body weight (BW), wool length (WL), and wool fineness (WF) in Ordos fine-wool sheep. METHODS: A genome-wide association study (GWAS) was conducted in 388 Ordos fine-wool sheep genotyped using the GenoBaits® Ovine 40K SNP panel. Single nucleotide polymorphisms (SNPs) associated with BW, WL, and WF were identified, and candidate genes located near the SNPs reaching the suggestive threshold were subjected to functional annotation and enrichment analysis. RESULTS: A total of 22 SNPs were identified as potentially associated with BW, WL, and WF traits, corresponding to 27 annotated genes. Functional annotation highlighted six potential candidate genes, including LAMA2, ARHGAP18, IGFBP2, IGFBP5, CA10, and AXIN1, which may play important roles in regulating body weight and wool growth in sheep. CONCLUSIONS: The identified genes provide valuable candidate loci for BW, WL, and WF traits in Ordos fine-wool sheep. The results of this study provide preliminary references for further exploration of the genetic mechanisms of wool traits in Ordos fine-wool sheep and the development of molecular breeding markers.

GWAS↗

PubMed2003

Construction of a gamete-enriched gene pool and RNAi-mediated functional analysis in Dictyostelium discoideum.

Macrocysts in Dictyostelium discoideum possess prototypic features of sexual reproduction and are useful for understanding the basic mechanisms of the reproductive process. Here, we randomly analyzed 1,071 gamete cDNAs, and then constructed a gamete-specific subtraction library, FC-IC. Nucleotide sequences of all 903 FC-IC clones were determined and clustered into 272 independent genes. Expression analysis based on real-time RT-PCR revealed 67 gamete-enriched genes, among which those involved in 'signal transduction' and 'multicellular organization' are prevalent. One of them, FC-IC0003, appeared also to be mating-type specific, and was named gmsA. RNAi-mediated silencing as well as disruption of gmsA reduced the cellular competency for sexual cell fusion, indicating the involvement of this gene in the sexual development of D. discoideum.

Amino Acid Sequence↗

PubMed2026

Transcriptome Analysis, Machine Learning, and Experimental Identification of CDK7 Affecting the Progression of Pregnancy-induced Hypertension by Influencing Macrophage Polarization.

INTRODUCTION: Pregnancy-induced hypertension (PIH) is a severe pregnancy complication characterized by placental insufficiency, abnormal vascular remodeling, and immune dysregulation, but personalized therapeutic markers remain unclear. This study aimed to identify key genes and explore immune mechanisms in PIH using transcriptome analysis, machine learning, and experimental validation. METHODS: We analyzed the GSE204835 transcriptomic dataset to screen differentially expressed genes (DEGs) and performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Set Enrichment Analysis (GSEA) for functional annotation. Immune infiltration analysis was also performed to examine the immune landscape in PIH. Least Absolute Shrinkage and Selection Operator (LASSO) regression identified key genes, which were validated in a PIH cell model. Flow cytometry and immunofluorescence assays assessed the effect of CDK7 knockdown on macrophage polarization. RESULTS: A total of 1,598 DEGs (1,123 upregulated, 475 downregulated) were identified. Enrichment analyses highlighted associations with embryonic organ development, oxidative phosphorylation, angiogenesis, and oxidative stress. Immune infiltration analysis revealed altered eosinophil and macrophage polarization in PIH. LASSO regression selected 12 key genes, with CDK7 showing the most significant upregulation in the PIH model. CDK7 knockdown promoted macrophage polarization toward the anti-inflammatory M2 phenotype. DISCUSSION: These findings link CDK7 to immune dysregulation in PIH by modulating macrophage polarization, expanding our understanding of PIH's molecular mechanisms. The study's limitations include reliance on public datasets and in vitro models, warranting in vivo validation. CONCLUSION: CDK7 emerges as a potential therapeutic target for PIH, offering new insights into immunoregulatory interventions for this complication.

Female↗

PubMed2004

Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data.

BACKGROUND: Functional genomics studies are yielding information about regulatory processes in the cell at an unprecedented scale. In the yeast S. cerevisiae, DNA microarrays have not only been used to measure the mRNA abundance for all genes under a variety of conditions but also to determine the occupancy of all promoter regions by a large number of transcription factors. The challenge is to extract useful information about the global regulatory network from these data. RESULTS: We present MA-Networker, an algorithm that combines microarray data for mRNA expression and transcription factor occupancy to define the regulatory network of the cell. Multivariate regression analysis is used to infer the activity of each transcription factor, and the correlation across different conditions between this activity and the mRNA expression of a gene is interpreted as regulatory coupling strength. Applying our method to S. cerevisiae, we find that, on average, 58% of the genes whose promoter region is bound by a transcription factor are true regulatory targets. These results are validated by an analysis of enrichment for functional annotation, response for transcription factor deletion, and over-representation of cis-regulatory motifs. We are able to assign directionality to transcription factors that control divergently transcribed genes sharing the same promoter region. Finally, we identify an intrinsic limitation of transcription factor deletion experiments related to the combinatorial nature of transcriptional control, to which our approach provides an alternative. CONCLUSION: Our reliable classification of ChIP positives into functional and non-functional TF targets based on their expression pattern across a wide range of conditions provides a starting point for identifying the unknown sequence features in non-coding DNA that directly or indirectly determine the context dependence of transcription factor action. Complete analysis results are available for browsing or download at http://bussemaker.bio.columbia.edu/papers/MA-Networker/.

Algorithms↗

PubMed2026

Sodium Overload-Related Molecular Subtypes and a Four-Gene Prognostic Signature Predict Survival, Immune Landscape, and Therapeutic Response in Acute Myeloid Leukemia.

Sodium overload has recently emerged as a critical metabolic stressor involved in cancer progression; however, its molecular characteristics and clinical relevance in acute myeloid leukemia (AML) remain unexplored. RNA-seq data sets, clinical annotations, and mutational profiles of AML patients were annotations from The Cancer Genome Atlas and integrated with Genotype-Tissue Expression normal samples. Sodium overload-related genes (SORGs) were obtained from GeneCards. Differentially expressed SORGs (DESORGs) screened by applying the limma statistical model, followed by univariate Cox proportional hazards regression, consensus clustering, functional enrichment, immune infiltration analysis, and pathway evaluation. A prognostic signature was developed through least absolute shrinkage and selection operator regression followed by multivariate Cox modeling. The model's performance was further verified in two external GEO data sets (GSE71014 and GSE37642). Nomogram construction, subgroup analysis, tumor mutational burden (TMB) assessment, drug sensitivity prediction, transcription factor (TF) analysis, and competing endogenous RNA (ceRNA) network analyses were also performed. A total of 57 DESORGs were identified, and 2 sodium overload-related molecular subtypes exhibited distinct survival, immune infiltration, and inflammatory pathway activation. A robust four-gene signature (DOCK1, GABRE, HTR7, ACSM1) stratified patients into high- and low-risk categories with significantly different survival across training and validation cohorts. High-risk patients displayed increased immune infiltration, higher TMB, reduced sensitivity to multiple chemotherapeutic drugs, and inferior predicted response to PD-L1 blockade. TF and ceRNA networks revealed multilayered transcriptional and post-transcriptional regulation of the signature genes. This study identifies sodium overload-related molecular heterogeneity in AML and establishes a validated four-gene prognostic signature that integrates genomic, immunologic, and therapeutic features, offering potential utility for personalized risk assessment and treatment optimization.

Humans↗

PubMed2024

Prenatal cannabis exposure is associated with alterations in offspring DNA methylation at genes involved in neurodevelopment, across the life course.

Prenatal cannabis exposure (PCE) is of increasing concern globally, due to the potential impact on offspring neurodevelopment, and its association with childhood and adolescent brain development and cognitive function. However, there is currently a lack of research addressing the molecular impact of PCE, that may help to clarify the association between PCE and neurodevelopment. To address this knowledge gap, here we present epigenome-wide association study data across multiple time points, examining the effect of PCE and co-exposure with tobacco using two longitudinal studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Christchurch Health and Development Study (CHDS) at birth (0 y), 7 y and 15-17 y (ALSPAC), and ~27 y (CHDS). Our findings reveal genome-wide significant DNA methylation differences in offspring at 0 y, 7 y, 15-17 y, and 27 y associated with PCE alone, and co-exposure with tobacco. Importantly, we identified significantly differentially methylated CpG sites within the genes LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, and LRP5 that are shared between different time points throughout development in offspring. Notably, functional pathway analysis showed enrichment for differential DNA methylation in neurodevelopment, neurotransmission, and neuronal structure pathways, and this was consistent across all timepoints in both cohorts. Given the increasing volume of epidemiological evidence that suggests a link between PCE and adverse neurodevelopmental outcomes in exposed offspring, this work highlights the need for further investigation into PCE, particularly in larger cohorts.

DNA Methylation↗

PubMed2026

Host life-history strategy is a critical determinant of virulent phage infection propensity.

Bacteriophages shape microbial communities through two major lifestyles: virulent (obligately lytic) and temperate (capable of lysogeny). Prevailing phage ecology frameworks focus on how environmental conditions, host density, and physiological state modulate infection modality. This perspective overlooks how host traits exert selective pressure on the distribution of virulent and temperate lifestyles across bacterial species, which limits understanding of phage ecology. To address this critical knowledge gap, we adopt a host-centric, trait-based perspective and use 5821 complete bacterial genomes to build a host life-history space predominantly defined by genome size, metabolic capacity, and growth rate potential. After mapping phage lifestyle association signals, prophage burden formed a continuous gradient across this space. Also, virulent phage association was positively correlated with prophage burden, revealing a nested structure of lifestyle signals. Functional trait analysis identified enrichment of resource-acquisition modules underlying both temperate and virulent associations. Overall, these findings indicate that phage lifestyle is significantly influenced by host life-history strategies, highlighting fast-growing, metabolically versatile hosts as favorable targets for virulent phage isolation and biocontrol applications.

Bacteriophages↗

PubMed2026

Admission whole-blood transcriptomic characterization of a neutrophil-predominant systemic immune response in patients with acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury (TBI) is accompanied by systemic immune responses, but their whole-blood transcriptomic features at hospital arrival remain incompletely characterized. We aimed to characterize these features in patients with acute TBI compared with healthy controls. METHODS: In this single-center prospective observational study, we performed whole-blood RNA sequencing on hospital-arrival samples from 42 patients with acute TBI and 21 healthy controls. Analyses included differential expression (limma-voom; FDR < 0.05, |log2FC| > 0.7), functional enrichment, Ingenuity Pathway Analysis, CIBERSORTx LM22 deconvolution, and per-sample neutrophil degranulation signature scoring. RESULTS: Differential expression analysis identified 996 upregulated and 863 downregulated genes, with marked upregulation of inflammation-, innate immunity-, and neutrophil-related genes including DUSP1, HMGB2, MMP9, and S100A8. Canonical pathways with positive IPA z-scores included Neutrophil degranulation, Neutrophil Extracellular Trap Signaling Pathway, and Toll-like Receptor Signaling; upstream regulators included TNF, IL1B, IFNG, and STAT3. Deconvolution identified 7 of 22 differing subsets (q < 0.05), with relatively higher myeloid and lower lymphoid fractions in TBI. The Neutrophil degranulation signature score correlated with Injury Severity Score within TBI (Spearman ρ = +0.55; q < 0.001). CONCLUSIONS: Admission whole-blood transcriptomics characterized a neutrophil-predominant systemic transcriptional response in patients with acute TBI. This response was also evident among patients without major extracranial injury and was associated with total ISS. However, because the study lacked an appropriately matched non-TBI trauma comparator, the findings should be interpreted as a descriptive characterization of a systemic injury response accompanying TBI and do not establish a TBI-specific molecular signature or mechanism.

gene expression↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed2024

Analysis of different expression RNA binding protein genes in mouse microglia cell from the brains of mice 72 h after subarachnoid hemorrhage or sham operation.

BACKGROUND: The prognosis of brain injury caused by subarachnoid hemorrhage (SAH) is poor. Previous studies showed that abnormal function of RBPs might be involved in brain injury, neuroinflammation and further affect microglia homeostasis. However, no studies have systematically analyzed the genome-wide abnormal expression of RBPs genes in microglia during SAH. METHODS: RNA-seq data of microglia from the SAH mouse group (SAH) and control sham-operated mouse group (sham) were downloaded from the GEO database in GSE167957, including four samples from the sham group and four samples from the SAH group for subsequent analysis.Utilizing GO and KEGG functional enrichment analyses, we conducted a comprehensive study of differentially expressed genes (DEGs), alternative splicing patterns, and co-expression networks to gain deeper insights into the differential expression of RNA-binding proteins (RBPs) and differential alternative splicing events (ASEs) between the SAH (subarachnoid hemorrhage) and sham groups. This analysis aimed to elucidate the potential mechanisms underlying the aberrant expression of RBPs in microglia during brain injury caused by SAH. RESULTS: ASEs and co-expression analyses of differentially expressed RBPs and differential ASEs were carried out in microglia in terms of gene expression. GO and KEGG functional enrichment analysis showed that aberrantly expressed RBPs such as Mcm7, Mtdh, SRSF3, and Hnrnpa2b1 may affect and regulate downstream Csnk1d, Uckl1 and other protein phosphorylation-related genes by alterative splicing. CONCLUSION: RBPs were aberrantly expressed in microglia during the development of brain injury secondary to SAH, regulating alterative splicing of downstream genes and influencing the progression of SAH brain injury in this study. This implies that RBPs are important for the identification of new therapeutic targets for brain injury after SAH.

Animals↗

PubMed2026

DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults.

Despite the substantial variability in physical function among older adults, the molecular mechanisms remain poorly characterized, particularly within skeletal muscle. This study aimed to determine the patterns of DNA methylation in skeletal muscle associated with physical function in healthy older adults. We analyzed DNA methylation (EPIC v2 array; 875,554 CpG sites) in skeletal muscle from 92 healthy older adults (median age 74; 62% female). Associations were examined across five phenotypes: Short Physical Performance Battery (SPPB), 6-min walk test (6MWT), handgrip strength, perceived disability (PAT-D), and lifestyle health (modified Life's Essential 8). Linear regression models adjusted for age, sex, race, BMI, and muscle fiber composition. Genomic inflation corrected via the BACON method (FDR < 0.05). Gene set enrichment analysis was performed on suggestive hits (FDR < 0.1). We identified significant differentially methylated probes (DMPs) and regions (DMRs) across all phenotypes: SPPB (70 DMPs, 22 DMRs), 6MWT (16 DMPs, 566 DMRs), handgrip strength (2 DMRs), PAT-D (19 DMPs, 1 DMR), and lifestyle health (2 DMPs). DMRs largely overlapped promoters. Identified genes overlapped known musculoskeletal and neurological GWAS hits, including RUNX2 and FOXL1 (bone mineral density), IGFBP3 (muscle mass), and NEK1 and SHANK1 (neurological function). Enrichment analysis revealed that 6MWT-associated genes relate to nervous and skeletal system development, while handgrip-associated genes involve cytoskeletal dynamics and protein assembly. Epigenetic variation in aging skeletal muscle is associated with physical function. The enrichment of pathways related to nervous and musculoskeletal development suggests specific epigenetic mechanisms underlying functional decline, offering potential targets for intervention in older adults.

DNA methylation↗

PubMed2025

Gene and pathway analysis of genome-wide genetic associations of bladder cancer.

BACKGROUND: Although genetic variants associated with bladder cancer (BCa) risk have been identified through hypothesis-driven and genome-wide association studies, a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved. MATERIALS AND METHODS: In this 2-stage functional genomics study, we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics, followed by a meta-analysis of gene-level significance p values, to obtain a consensus gene ranking in terms of association with BCa. Subsequently, we performed preranked gene-set enrichment analysis to identify the functional pathways involved in BCa genetic susceptibility. Joint analysis with gene-set enrichment analysis, based on somatic alteration frequency, was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa. RESULTS: Other than the well-known BCa genes (such as FGFR3, MYC, TERT, CCNE1, and TP63), we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development, including SETD2, a possible tumor suppressor gene involved in chromatin remodeling. We further demonstrated convergence between genetic associations and somatic alterations at both the gene (eg, FGFR3 and TERT) and pathway levels (eg, cell cycle and chromatin modification), as well as functional ontologies specifically implicated in germline predisposition to BCa (eg, CD8/TCR signaling, immune checkpoints, and cytokine signaling). CONCLUSIONS: We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the development of BCa by affecting antitumor immunity, response to toxic exposure, and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.

Bladder cancer↗

PubMed2025

Anoikis classification of lung squamous cell carcinoma reveals correlation with clinical prognosis and immune characteristics.

BACKGROUND: Anoikis is a new mode of cell death that has been shown to correlate significantly with tumors. However, the clinical prognostic significance of anoikis in lung squamous cell carcinoma (LUSC) remains poorly studied. METHODS: The differentially expressed ARGs and candidate genes were selected by the differential analysis to construct a predictive model. Independent prognostic gene was determined by Cox and LASSO analysis and we used the HCC95 and NCI H520 cell line to verify the gene function. We used the data from TCGA, GEO, GeneCards, and Harmonizome databases to analyze the immune microenvironment, functional enrichment, and drug sensitivity analysis. RESULTS: We identified 717 differentially expressed and selected 3 ARGs (FADD, SNAI1, and BAG4) to construct a predictive model. We found that SNAI1 is an independent prognostic gene and confirmed that knocking out the SNAI1 inhibited the HCC95/NCI H520 cell proliferation. We used single-sample gene-set enrichment analysis (ssGSEA) to evaluate the immune infiltration based on the 3 ARG expression levels. We constructed a risk score and provided a visual representation of the prophetic implications of the ARGs-based signature through a nomogram. We found 15 susceptible drugs in the high-risk group and 15 sensitive drugs in the low-risk group by the drug sensitivity analysis. CONCLUSION: We used ARGs to construct a prognosis model for LUSC that can accurately predict the prognosis of LUSC patients. ARGs, especially SNAI1, play an essential role in developing LUSC. These findings could provide individualized treatment plans and new research ideas for LUSC patients.

Humans↗

PubMed2026

Integrative Multi-Omics Analysis of Stem Growth Habit Divergence in Wild Soybean (Glycine soja).

Stem architecture is a major determinant of lodging resistance, biomass accumulation, and harvest efficiency in soybean. However, the molecular features associated with contrasting stem growth habits in wild soybean remain incompletely characterised. Here, we performed an integrated transcriptomic, metabolomic, and epigenomic analysis of stem growth-habit divergence in wild soybean, comparing the wild-type accession ZYD7068 with contrasting vining and erect mutant lines derived from carbon-ion beam mutagenesis. Pairwise transcriptomic comparisons identified between 20 311 and 28 705 differentially expressed genes per contrast, with a core set of 2672 genes consistently altered across the comparisons. Functional enrichment, gene set variation analysis, and gene set enrichment analysis converged on xylem and phloem pattern formation as a prominent molecular pathway associated with growth-habit divergence. Random forest analysis identified BBR-BPC and ARF transcription factor families as major molecular discriminators, while metabolomic profiling revealed distinct metabolic profiles involving amino-acid-derived and lipid-associated metabolites. Whole-genome bisulfite sequencing revealed context-specific DNA methylation differences, including substantial variation in CHG methylation among erect mutant lines. Integrated network and in silico perturbation analyses prioritised four candidate genes associated with vascular development for future functional validation. Together, these results provide a multi-layer molecular resource for investigating stem growth-habit divergence in G. soja and establish testable candidate pathways and genes for subsequent functional studies and soybean improvement.

glycine soja↗

PubMed1991

Functional characterization of tumor-infiltrating lymphocytes, lymph-node lymphocytes and peripheral-blood lymphocytes from patients with breast cancer.

Mononuclear cell infiltration is frequently seen within human solid tumors. Effector cells within the tumor site usually fail to exhibit cytotoxic or natural killer activity when freshly isolated; however, they develop potent and sometimes specific cytotoxicity after expansion in IL2. Thus, local tumor environment may influence lymphocyte function. In our study, we disaggregated human breast-cancer and lymph-node tissue to obtain lymphocyte-enriched cell fractions. Besides phenotypic analysis, functional characterization with regard to proliferation and cytokine production of tumor-infiltrating lymphocytes (TIL), peripheral-blood lymphocytes (PBL) and lymph-node lymphocytes (LNL) was the aim of our study. TIL showed an enrichment of CD8+ cells with a corresponding decrease in CD4+ cells in comparison with PBL and LNL. In response to PHA, TIL showed decreased 3H-thymidine uptake, but TIL were significantly stimulated by rhIL2. TIL produced low levels of IL2, TNF and IFN gamma upon mitogen/phorbol ester stimulation, while PBL produce high levels of TNF and IFN gamma but low levels of IL2. Under the same experimental conditions, LNL produce high levels of TNF and IL2 but low levels of IFN gamma. Mitogen-mediated TNF secretion was increased after addition of autologous tumor cells in TIL and LNL, whereas IFN gamma secretion tended to be suppressed. Our results indicate different patterns of activities of TIL, LNL and PBL from breast-cancer patients.

Breast Neoplasms↗