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PubMed2026

Dietary soybean or seaweed (Kappaphycus sp.) modulates taste-related gene (tas1r1 and tas1r2.2) expression in Nile tilapia (Oreochromis niloticus).

Taste perception plays a central role in fish feeding behaviour by influencing feed recognition, intake, and nutrient sensing. As aquaculture increasingly adopts plant-based ingredients to replace fishmeal, understanding how these diets affect gustatory mechanisms is critical. This study evaluated TAS-family taste receptor genes in Nile tilapia (Oreochromis niloticus) fed nutritionally formulated diets containing fishmeal (TFM), soybean meal (TSB), red seaweed (Kappaphycus sp., TSW), alongside a natural meal (TNM) reference. Fish were reared for 62 days under controlled conditions, after which growth performance was evaluated, and tongue transcriptomes were analysed using RNA sequencing to identify diet-associated gene expression changes. Candidate TAS1R and TAS2R receptors were identified through conserved domain screening and phylogenetic validation, and differential expression analysis was performed using DESeq2. Growth performance did not differ significantly among diets, although the soybean group showed the highest weight gain. Under the conditions of this study, most taste-related genes remained transcriptionally stable across formulated diets, indicating limited responsiveness of the gustatory system to ingredient substitution. Transcriptional differences were mainly observed in comparisons involving the TNM (TSB vs TNM and TSW vs TNM), where tas1r1 was upregulated, suggesting altered amino acid sensing relative to the non-formulated diet. Among formulated diets, tas1r2.2 was upregulated in the TSW vs TFM comparison, indicating potential modulation of carbohydrate-related taste pathways associated with seaweed inclusion. No reliable TAS2R transcripts were detected, likely due to low expression or tissue-specific distribution. Overall, taste receptor expression in Nile tilapia appears resilient to dietary variation, with selective modulation of TAS1R genes providing molecular insight into chemosensory adaptation to sustainable feed ingredients.

Animals↗

PubMed2026

Mapping convergent regulators of melanoma drug resistance by PerturbFate.

High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.

Humans↗

PubMed2026

Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers.

UNLABELLED: Rapid-acting antidepressants like ketamine and serotonergic psychedelics show promise for treatment-resistant depression (TRD), but the molecular mechanisms that contribute to their therapeutic effects remain unclear. Induced pluripotent stem cells (iPSCs) offer a platform to model human cortical neurons and investigate drug effects in a human-relevant system. Here, iPSCs from individuals with TRD and healthy volunteers (HVs) were differentiated into mature cortical-like neurons and treated for six and 24 hours with agents being investigated as rapid-acting antidepressants, including (2R,6R)-hydroxynorketamine (HNK), psilocybin, lysergic acid diethylamide (LSD), and 2,5-Dimethoxy-4-iodoamphetamine (DOI). Bulk and single-cell RNA sequencing assessed global and cell-type-specific transcriptomic responses. Synaptic proteins were evaluated via Western blotting and immunocytochemistry. To validate translational relevance, transcriptomic results were compared to CSF proteomics from ketamine-treated HVs. Despite differing initial pharmacological targets, overall gene expression across all compounds was highly correlated at matched timepoints compared to vehicle control, suggesting shared downstream effects. Both glutamatergic and serotonergic drugs converged on pathways involving inflammation, mTORC1 signaling, and cellular growth. At the single-cell level, HNK showed distinct cell-type specific alterations: upregulation in excitatory neurons and concomitant downregulation of inhibitory neuron populations. Differentially expressed genes from HNK-treated neurons also overlapped with CSF proteomic signatures from ketamine-treated individuals, supporting the model's translational relevance. This study is the first to assess multiple putative rapid-acting antidepressants in parallel using an iPSC-derived neuron model. Both convergent and drug-specific changes in gene expression and pathway enrichment were observed across diverse compounds, supporting the use of human iPSC-derived neurons in antidepressant drug discovery. CLINICAL TRIAL REGISTRY: www.clinicaltrials.gov, NCT02484456.

Journal Article↗

PubMed2026

Transcriptomic and RNAi analyses reveal chloride channel 3-associated osmoregulation in Litopenaeus vannamei under low-salinity stress.

Chloride channels and transporters are important for cellular volume regulation and salinity adaptation in euryhaline crustaceans, yet the intestinal transcriptional relationship between plasma-membrane and intracellular chloride pathways remains unclear in Litopenaeus vannamei. In this study, RNA interference of anoctamin 1 (ANO1) was combined with intestinal transcriptome sequencing under the production-relevant low-salinity condition of salinity 3. ANO1 silencing produced a focused transcriptional response, with 16 differentially expressed genes (DEGs) identified (11 upregulated and 5 downregulated). Functional enrichment indicated that these genes were associated with transporter activity, cytoskeletal organization, extracellular matrix-receptor interaction, membrane lipid metabolism, and vesicular processes. Notably, a transcript encoding chloride channel protein 3 (CLC-3) was significantly upregulated following ANO1 knockdown, suggesting a potential transcriptional relationship between ANO1 and CLC-3 in chloride homeostasis. Based on this finding, CLC-3 was selected for full-length cDNA cloning, sequence characterization, salinity-gradient expression analysis, and RNAi-based functional assessment. The cloned CLC-3 cDNA was 2883 bp in length and encoded an 850 amino acid protein containing a conserved voltage-gated chloride channel (Voltage-CLC) domain and two cystathionine β-synthase domains. Phylogenetic analysis placed LvCLC-3 within the intracellular CLC-c clade, and tissue distribution analysis showed the highest CLC-3 expression in the intestine. Intestinal CLC-3 expression responded nonlinearly to salinity variation, peaking at salinity 20. Under salinity 3, CLC-3 knockdown reduced ANO1, Na+/K+-ATPase alpha subunit, and Na+-K+-2Cl- cotransporter transcript levels, whereas glutamate-gated chloride channel expression increased. Mild hepatopancreatic structural alterations were also observed after CLC-3 knockdown. These findings suggest that CLC-3 is a salinity-responsive intracellular chloride-transporter candidate associated with intestinal ion-transport-related transcriptional responses after ANO1 suppression in L. vannamei, although the underlying physiological mechanism requires further validation.

Animals↗

PubMed2024

Omics studies in Behçet's disease.

PURPOSE OF REVIEW: In this review, we aimed to highlight recent findings from "-omics" studies in Behçet's disease. RECENT FINDINGS: Recent genomic studies in Behçet's disease identified possible risk loci associated with Behçet's disease related uveitis, neurologic involvement and gastrointestinal involvement. Additionally, sex-specific genetic effects were determined in Behçet's disease. Transcriptomic analyses of immune cells in Behçet's disease revealed that key inflammatory pathways such as NF-κB and MAPK have roles in Behçet's disease pathogenesis. Proteomic studies have highlighted the role of immune cell derived extracellular vesicles and identified potential biomarkers for vascular involvement and examined HLA I-bound immunopeptidomes. Metabolomics studies are still limited, but recent research has pointed to alterations in fatty acid metabolism and lipid profiles in Behçet's disease patient. SUMMARY: Omics studies have gained importance in the field of Behçet's disease through the generation of large data sets and efforts to extend their application are intensifying. These studies can provide opportunities for understanding Behçet's disease pathogenesis when they lead to testable hypotheses. Current challenges include the choice of appropriately homogeneous patient and control groups, effective data management and sharing, high cost and a rapidly increasing gap between the wealth of observational data generated and the relative paucity of controlled experimental efforts that could lead to mechanistic understanding.

Behcet Syndrome↗

PubMed2025

Integrative Genomic, Transcriptomic and Epigenomic Analysis Reveals cis-regulatory Contributions to High-altitude Adaptation in Tibetan Pigs.

The Qinghai-Tibet Plateau, characterized by its extreme environmental conditions, presents significant challenges to life, making it an ideal region for studying adaptation and evolution. Tibetan pigs, known for their high genetic diversity and exceptional adaptability to high altitudes, serve as excellent models for investigating high-altitude adaptation. While previous studies have extensively identified genetic determinants associated with high-altitude adaptation, the molecular mechanisms, particularly cis-regulatory patterns, remain poorly understood. Here, we conducted a selective sweep analysis using 484 genomes from Chinese and Western pig breeds across various altitudes, revealing 38.56 Mb of genomic regions under selection in Tibetan pigs. Enrichment analysis identified the lung as the primary functional tissue involved in high-altitude adaptation, supported by tissue-specific transcriptional and regulatory patterns observed between Tibetan and Meishan pigs (low altitude). By integrating genomic, RNA-seq, ATAC-seq, and H3K27ac HiChIP data, we constructed comprehensive enhancer-promoter regulatory maps of candidate genes and pinpointed promising genetic determinants associated with high-altitude adaptation, including SNPs in EPAS1, KLF13, SPRED1, and CFD. These loci were predicted to influence chromatin accessibility and the interactions of regulatory elements, with altered binding strength of relevant transcription factors. Further in vitro experiments confirmed that these loci function as allele-specific enhancers, modulating the expression of target genes. Our findings elucidate the regulatory basis of high-altitude adaptation in Tibetan pigs and provide valuable insights for exploring hypoxia-related diseases in livestock and humans.

Animals↗

PubMed2026

Recurrent reversible mutations at gaf1 driving metastable TORC1 inhibitor resistance in fission yeast.

Metastable phenotypic inheritance is often attributed to epigenetic mechanisms, but reversible genetic alterations can produce similar instability. Here, we investigated the basis of unstable resistance to TORC1 inhibitor (rapamycin plus caffeine) in Schizosaccharomyces pombe. Six independent, metastable resistant mutants were isolated. Genetic mapping positioned the causal lesion to a single Mendelian locus, which sequencing identified as gaf1, encoding a GATA transcription factor and a key negative regulator of growth downstream of TORC1. In each mutant, distinct loss-of-function mutations (insertions, deletions, or point mutations) were found in gaf1 in the resistant state, and these mutations precisely reverted to the wild-type sequence upon loss of resistance. Restoring the wild-type gaf1 allele abolished resistance, indicating that reversible genetic disruption of gaf1 is both necessary and sufficient for the metastable phenotype. Furthermore, strong resistance in several strains from a genome-wide deletion library was due to secondary, inactivating mutations in gaf1, underscoring its role as a recurrent adaptive target under rapamycin plus caffeine treatment. Mechanistically, gaf1 inactivation established a distinct basal transcriptome and pronounced derepression of translation and metabolic programs upon drug treatment. While rapamycin plus caffeine triggered extensive chromatin remodeling and H3K9 methylation contributed partially to resistance, these epigenetic changes were most consistent with a downstream modifying layer. Our study shows that metastable drug resistance in fission yeast is predominantly associated with recurrent, reversible genetic inactivation of the central transcriptional regulator gaf1, demonstrating how rapidly reversible genetic switches can drive adaptive evolution.IMPORTANCEDistinguishing between genetic and epigenetic inheritance is fundamental to understanding how cells adapt to environmental stress. In the fission yeast Schizosaccharomyces pombe, rapid and reversible drug resistance is often assumed to be driven by epigenetic switches that change gene activity without altering DNA. However, our study reveals that this instability can be caused by physical mutations in a single gene, gaf1, which acts as a genetic toggle. These mutations appear under drug pressure and precisely revert to the original sequence when the drug is removed. We also demonstrate that these spontaneous mutations can contaminate standard laboratory yeast collections, leading to potential misinterpretation of experimental data. These findings broaden our understanding of unstable inheritance and show that DNA sequences can be far more dynamic than previously recognized during rapid evolution and the development of drug resistance.

TORC1 signaling↗

PubMed2026

Epigallocatechin gallate is associated with PDGFRB downregulation and altered PI3K-AKT signaling in gastric cancer.

BACKGROUND: Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide. Epigallocatechin gallate (EGCG), a natural polyphenol derived from green tea, exhibits anticancer properties; however, its molecular targets and regulatory mechanisms in GC are not fully elucidated. This study aimed to identify candidate EGCG-associated genes in GC and generate a hypothesis for future mechanistic investigation. METHODS: Differentially expressed genes (DEGs) in GC were identified and intersected with EGCG-associated targets retrieved from The Cancer Genome Atlas (TCGA) and GeneCards public databases. Least absolute shrinkage and selection operator (LASSO) regression and Cox proportional hazards analyses were performed to screen prognostically relevant genes. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curves. Functional enrichment analysis was conducted to explore biological significance. Public single-cell RNA sequencing datasets were analyzed to determine the cellular localization of platelet-derived growth factor receptor beta (PDGFRB), while DepMap transcriptomic data were used to assess its expression across GC cell lines. In vitro assays, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell migration, and Western blotting, were performed to evaluate the biological effects of EGCG on GC-associated signaling pathways. RESULTS: Thirty-eight EGCG-associated DEGs were identified. Enrichment analysis revealed these genes were involved in cancer-associated pathways. LASSO-Cox modelling identified four candidate genes. Among them, PDGFRB was selected for further investigation based on its prognostic relevance and favorable diagnostic performance. PDGFRB expression was significantly higher in the TCGA genomically stable (GS) subtype than in the other molecular subtypes and was predominantly localized to cancer-associated fibroblasts (CAFs) and pericytes in single-cell RNA sequencing analysis. DepMap data demonstrated heterogeneous PDGFRB expression across GC cell lines. In vitro experiments showed that EGCG inhibited proliferation, migration, and invasion, reduced PDGFRB protein expression, and was associated with apoptosis-related protein changes and altered PI3K-AKT signaling. CONCLUSIONS: Our findings suggest that EGCG treatment was associated with reduced PDGFRB expression and altered PI3K-AKT signaling in GC cells. These findings identify PDGFRB as a candidate EGCG-associated gene and provide a hypothesis for future mechanistic investigation.

Gastric cancer (GC)↗

PubMed2026

Trimethylamine-producing microbe Bacillus megaterium KCTC 3007 promotes antitumor immunity in endometrial cancer via type I interferon response pathways.

BACKGROUND: Endometrial cancer (ECa) is one of the most common gynecologic malignancies, with limited therapeutic responses in metastatic or recurrent cases. The bacterial microbiota has emerged as a key modulator of carcinogenesis and antitumor immunity. However, the role of endometrial microbiota in ECa pathogenesis and prognosis remains poorly understood. METHODS: We performed comprehensive multi-omics analysis integrating metatranscriptomics, transcriptomics, and targeted metabolomics from 60 ECa and 18 benign patients. RNA sequencing enabled simultaneous profiling of active tissue-resident microbiota and host gene expression. Serum metabolomics was conducted on all patients. Identified microbial-metabolite associations were validated through in vitro co-culture experiments using peripheral blood mononuclear cells (PBMCs), cancer cell lines, RNA sequencing, and live cell imaging. RESULTS: ECa patients exhibited significantly altered microbial diversity and composition compared to benign controls. Through integrated multi-omics analysis, we identified Bacillus megaterium (BM) KCTC 3007 as a beneficial microbe associated with prolonged recurrence-free survival. In an exploratory analysis of ECa subtypes, Cupriavidus taiwanensis and Marinomonas primoryensis showed potential links to poor prognosis, although these observations warrant caution due to the limited size of certain subgroups. Tissue BM abundance positively correlated with serum trimethylamine N-oxide (TMAO) levels, particularly in postmenopausal women. In vitro experiments demonstrated that BM KCTC 3007 enhanced antitumor immunity by promoting interleukin and type I interferon expression, expanding CD8 + T cell populations, and increasing immune cell-tumor cell interactions. RNA sequencing revealed activation of interferon alpha response and immune cell proliferation pathways, with IFNAR1 identified as a key upstream regulator. TMAO treatment recapitulated these immune-activating effects, enhancing CD8 + T cell responses and preferentially inducing pyroptotic cancer cell death. CONCLUSIONS: We provide the first evidence that tissue-resident BM KCTC 3007 promotes antitumor immunity in ECa through TMAO production and subsequent type I interferon-mediated immune activation. This integrated multi-omics approach establishes a complete microbe-metabolite-host mechanistic pathway and highlights the therapeutic potential of TMAO-producing probiotic strains for ECa treatment. Video Abstract.

Female↗

PubMed2002

[Transcriptomes for serial analysis of gene expression].

The availability of the sequences for whole genomes is changing our understanding of cell biology. Functional genomics refers to the comprehensive analysis, at the protein level (proteome) and at the mRNA level (transcriptome) of all events associated with the expression of whole sets of genes. New methods have been developed for transcriptome analysis. Serial Analysis of Gene Expression (SAGE) is based on the massive sequential analysis of short cDNA sequence tags. Each tag is derived from a defined position within a transcript. Its size (14 bp) is sufficient to identify the corresponding gene and the number of times each tag is observed provides an accurate measurement of its expression level. Since tag populations can be widely amplified without altering their relative proportions, SAGE may be performed with minute amounts of biological extract. Dealing with the mass of data generated by SAGE necessitates computer analysis. A software is required to automatically detect and count tags from sequence files. Criterias allowing to assess the quality of experimental data can be included at this stage. To identify the corresponding genes, a database is created registering all virtual tags susceptible to be observed, based on the present status of the genome knowledge. By using currently available database functions, it is easy to match experimental and virtual tags, thus generating a new database registering identified tags, together with their expression levels. As an open system, SAGE is able to reveal new, yet unknown, transcripts. Their identification will become increasingly easier with the progress of genome annotation. However, their direct characterization can be attempted, since tag information may be sufficient to design primers allowing to extend unknown sequences. A major advantage of SAGE is that, by measuring expression levels without reference to an arbitrary standard, data are definitively acquired and cumulative. All publicly available data can thus be stored in a unique database, facilitating whole-genome analysis of differential expression between cell types, normal and diseased samples, or samples with and without drug treatment. SAGE data are readily amenable to statistical comparisons, allowing to determine the level of confidence of the observed variations. A major limitation of SAGE is that, because each analysis is obligatory performed on the whole set of expressed genes, it can hardly be performed on multiple samples, for example in kinetics studies or to compare the effects of large numbers of drugs. To overcome this limitation, high-throughput detection of a subset of mRNAs is more rapidly performed by parallel hybridization of mRNAs on arrays of nucleic acids immobilized on solid supports. From this point of view, a SAGE platform is a powerful instrument for selecting the most informative subset of genes, assembling them to design microarrays dedicated to a specific problem and calibrating measurement by comparison with a standard cell model for which SAGE data are available. This approach is an attractive alternative to strategies based exclusively on pangenomic arrays. A very large amount of SAGE data are already available and the problem is now to extract their biological meaning. Knowledge on metabolic pathways is already organized so that its successful integration in a SAGE platform can be undertaken. For other cell components and pathways, the problem lies on the lack of controlled vocabulary to describe gene activities, starting form a clear definition of the concept of biological function itself. Progress in gene and cell ontology is expected to facilitate computer-based extraction of biological knowledge from existing and forthcoming SAGE data.

Animals↗

PubMed2025

Multi-Omics Analysis of Experimentally Evolved Candida auris Isolates Reveals Modulation of Sterols, Sphingolipids, and Oxidative Stress in Acquired Amphotericin B Resistance.

Clinical isolates of Candida auris show a high prevalence of resistance to Amphotericin B (AmB)-an uncommon trait in most Candida species. Alterations in ergosterol biosynthesis can contribute to acquired AmB resistance in C. auris laboratory strains but are rarely seen in clinical isolates. In this study, we experimentally evolved two drug-susceptible Clade II isolates of C. auris to develop AmB resistance. The evolved strains displayed a four to eight fold increase in MIC50 compared to the parental cells. We analyzed changes in their karyotype, genome, lipidome, and transcriptome associated with this acquired resistance. In one lineage, AOX2 was upregulated, and its deletion reversed the AmB resistance phenotype. The aox2Δ mutant also failed to evolve AmB resistance under experimental conditions. In the same lineage, restoring the UPC2 S332R and RTG3 S101T mutations to the wild-type allele restored AmB susceptibility. In another lineage, the ergosterol and sphingolipid pathways were observed to play a critical role, and upregulation of the ERG genes elevated the total sterol content, while significant downregulation of HSX11 (glucosylceramide synthase) resulted in lower levels of glucosylceramides. To our knowledge, this study is the first to show that AmB resistance in C. auris can be acquired through mechanisms both dependent on or independent of sterol content modulation, highlighting Aox2 and Upc2 as key regulators of amphotericin resistance.

Amphotericin B↗

PubMed2015

Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

INTRODUCTION: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock. METHODS: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients. RESULTS: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states. CONCLUSIONS: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

Adult↗

PubMed2026

Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers.

Rapid-acting antidepressants like ketamine and serotonergic psychedelics show promise for treatment-resistant depression (TRD), but the molecular mechanisms that contribute to their therapeutic effects remain unclear. Induced pluripotent stem cells (iPSCs) offer a platform to model human cortical neurons and investigate drug effects in a human-relevant system. Here, iPSCs from individuals with TRD and healthy volunteers (HVs) were differentiated into mature cortical-like neurons and treated for six and 24 h with agents being investigated as rapid-acting antidepressants, including (2 R,6 R)-hydroxynorketamine (HNK), psilocybin, lysergic acid diethylamide (LSD), and 2,5-Dimethoxy-4-iodoamphetamine (DOI). Bulk and single-cell RNA sequencing assessed global and cell-type-specific transcriptomic responses. Synaptic proteins were evaluated via Western blotting and immunocytochemistry. To validate translational relevance, transcriptomic results were compared to CSF proteomics from ketamine-treated HVs. Despite differing initial pharmacological targets, overall gene expression across all compounds was highly correlated at matched timepoints compared to vehicle control, suggesting shared downstream effects. Both glutamatergic and serotonergic drugs converged on pathways involving inflammation, mTORC1 signaling, and cellular growth. At the single-cell level, (2 R,6 R)-HNK showed distinct cell-type specific alterations: upregulation in excitatory neurons and concomitant downregulation of inhibitory neuron populations. Differentially expressed genes from (2 R,6 R)-HNK-treated neurons also overlapped with CSF proteomic signatures from ketamine-treated individuals, supporting the model's translational relevance. This study is the first to assess multiple putative rapid-acting antidepressants in parallel using an iPSC-derived neuron model. Both convergent and drug-specific changes in gene expression and pathway enrichment were observed across diverse compounds, supporting the use of human iPSC-derived neurons in antidepressant drug discovery. Clinical Trial Registry: www.clinical trials.gov, NCT02484456.

Journal Article↗

PubMed2026

Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.

Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR-dCas9-DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR-dCas9-TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12-18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide 'alpha-beta-methylome' ( https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/ ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.

Humans↗

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↗

PubMed2026

Temporal Transcriptomic Profiling of NMBA-Induced Rat Esophageal Squamous Carcinogenesis Identifies Early Inflammatory Activation and Late NRF2-Associated Oxidative-Stress Remodeling.

Temporal molecular events during early esophageal squamous carcinogenesis remain incompletely defined, in part because human precursor tissues are difficult to obtain sequentially. We used the N-nitrosomethylbenzylamine (NMBA)-induced rat model to characterize stage-associated transcriptional programs during esophageal squamous carcinogenesis. Vehicle-control reference esophageal tissues and NMBA-treated esophageal tissues, collected at weeks 6 and 29, were profiled using Affymetrix Rat Genome 230 2.0 arrays, followed by pathway analysis and qRT-PCR validation of selected genes. Relative to vehicle-control reference tissues, 173 genes were differentially expressed at week 6, whereas 1628 genes were differentially expressed at week 29, indicating marked expansion of transcriptional dysregulation during carcinogenic progression. Sixteen genes were differentially expressed only at week 6, while 157 genes were altered at both time points. Pathway analysis suggested that inflammatory and immunologic processes were prominent during the early response to NMBA exposure, whereas late-stage carcinogenesis was characterized by NRF2-associated oxidative-stress response and dysregulation of multiple glutathione S-transferase family members. A subset of progression-associated genes, including Defb4, Gsta2, Sbsn, Spink5, Plcd4, Hbb, and Hba-a2, showed increasing dysregulation from week 6 to week 29. These findings define temporally distinct molecular programs in NMBA-induced esophageal squamous carcinogenesis and provide a framework for prioritizing candidate pathways and genes relevant to esophageal cancer prevention, early detection, and progression biology.

Animals↗

PubMed2026

ACE2 and Parkinsonism‑related bone metabolic alterations: signaling pathways and hub gene analysis.

Clinical co-occurrence of Parkinson's disease (PD) and age-related bone loss in elderly patients has garnered increasing attention, yet its molecular mechanisms remain incompletely elucidated. This study used an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in Ace2-/y mice to investigate the regulatory mechanisms of bone-brain axis-related genes and signaling pathways. Behavioral tests assessed motor and non-motor symptoms. Immunohistochemistry, Western blot, and histopathological staining analyzed dopaminergic neuron activity, microglial activation, and bone metabolic abnormalities. GEO dataset transcriptomics and weighted gene co-expression network analysis (WGCNA) identified key hub genes, with receiver operating characteristic (ROC) curves evaluating their diagnostic value in public single-disease transcriptome data. MPTP significantly exacerbated motor dysfunction and depression-like behaviors; Ace2 deletion lowered total Wnt, β-catenin, BMP and IGF-1 protein abundance alongside reduced phosphorylation ratios of their downstream kinases in brain and bone, while upregulating RANKL/RANK/OPG-associated inflammatory mediators, accompanied by elevated total α-synuclein, Casp3 and Bax protein levels. The parallel reduction of these signaling proteins only suggests potential perturbation of related cascades; WGCNA identified 10 hub genes (e.g., DNM1, OCRL, OPA1), whose dysregulation was linked to synaptic dysfunction and inflammation. ROC analysis based on single-disease datasets showed high diagnostic accuracy for PD and `osteoporosis (OP) (AUC: 0.683-0.981), with core genes influencing synaptic, MAPK, Rap1, and Ras pathways. These preclinical findings indicate that Ace2 deficiency is associated with concurrent pathological abnormalities in the brain and transient bone metabolic disturbance under short-term MPTP treatment in growing young male mice; coordinated dysregulation of shared signaling pathways was observed in the two tissues, consistent with a potential bone-brain axis pathological phenotype, though causal bidirectional tissue cross-talk cannot be confirmed in the current experimental design, providing candidate targets that warrant further validation.

Animals↗

PubMed2026

Leveraging the genetics of psychiatric disorders to prioritize potential drug targets and compounds.

Genetics can inform biologically relevant drug development and repurposing, which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the genome-wide association studies of four psychiatric disorders [attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] and genes encoding drug targets. We conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We conducted multiple molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder. We reveal candidate drug targets associated with a single or multiple disorders that implicate glutamate signaling. Drug prioritization indicated genetic support for psychotropic medications, including several top-ranked antipsychotics for schizophrenia. We also observed genetic support for commonly used psychotropics for psychiatric treatment (e.g., clozapine, duloxetine, and lithium). Revealed opportunities for drug repurposing included cholinergic drugs for ADHD, estrogen modulators for depression, and matrix metalloproteinases for ADHD and depression. Our findings indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Our extensive analyses highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders, providing novel opportunities for improving patient outcomes. Depicted is the series of analyses conducted to generate a list of prioritized drug targets and compounds. First pairings of genome-wide association study (GWAS) traits with drugs are generated using enrichment analyses. Next, a series of molecular trait analyses is conducted to generate and rank a list of potential drug targets for each GWAS trait. Finally, enrichment and molecular trait results are combined to generate a ranked list of prioritized drugs for each GWAS trait based on supporting genetic evidence. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, DBP = Diastolic blood pressure, T2D = Type 2 diabetes, RNA = ribonucleic acid, XWAS = both transcriptome and proteome-wide association studies, MR = Mendelian randomization, coloc = colocalization.

Humans↗