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Results for “Single cell transcriptomics”

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PubMed2005

Proteomic and transcriptomic analyses of macrophages with an increased resistance to oxidized low density lipoprotein (oxLDL)-induced cytotoxicity generated by chronic exposure to oxLDL.

The uptake of oxidized low density lipoprotein (oxLDL) by macrophages leads to foam cell formation and fatty streaks, which represent early sites of potential atheroma development. We developed a cell culture model of chronic oxLDL exposure to determine whether hallmark parameters of oxLDL uptake and cytotoxicity are altered during foam cell formation and to determine changes in protein and mRNA expression that distinguish acute and chronic oxLDL exposure. Although the extent of oxLDL uptake did not change, a resistance to oxLDL-induced cytotoxicity was observed in the chronically exposed cells. Macrophages that have been chronically exposed to oxLDL required a 40% higher concentration of oxLDL to achieve 50% survival in a 48-h treatment relative to macrophages subjected to a single oxLDL exposure. A main feature of the differentially expressed proteome was a series of significantly overexpressed antioxidant and antioxidant-related proteins in the oxLDL-exposed cells. A large proportion of these proteins (45%) was overexpressed in the chronically exposed cells prior to the oxLDL treatment, indicative of the unique phenotype produced by the chronic treatment. Analysis of the transcriptome also revealed a broad increase in the expression of antioxidant and antioxidant-related proteins. In addition, the transcriptome experiments found an increased inflammatory response under conditions of both acute and chronic oxLDL exposure. Overall the combined functional, proteomic, and transcriptomic experiments show that macrophages respond to oxLDL by developing an oxidative stress resistance that increases and stabilizes with chronic exposure. Furthermore this protective response and the increased foam cell survival that it supports amplifies their proatherogenic role by promoting a continued inflammatory state.

Animals↗

PubMed2026

Proteogenomic features define subtypes of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

Humans↗

PubMed2026

POU2F3 expression in lung squamous cell carcinoma: transcriptomic and immunohistochemical profiling with prognosis.

BACKGROUND: Lung squamous cell carcinoma (LUSC) lacks well-defined molecular targets. This study investigated the clinical and biological relevance of POU class 2 homeobox 3 (POU2F3), a tuft cell-associated transcription factor, in LUSC. METHODS: RNA sequencing data of patients with LUSC from The Cancer Genome Atlas (TCGA cohort, n = 190) was analysed and compared to a cohort of surgically resected cases analyzed via immunohistochemistry (IHC cohort, n = 137). Prognostic impact was assessed via survival analyses. Transcriptomic features, pathway enrichment, and immune profiles were evaluated via differentially expressed gene analysis, Gene Set Enrichment Analysis, and CIBERSORTx. RESULTS: High POU2F3 expression independently predicted poor overall survival in the TCGA cohort (HR = 2.06, 95% CI: 1.04-4.08, P = 0.039). In contrast, POU2F3 expression was not prognostic in the IHC cohort (P = 0.995). Morphologically, POU2F3-positive tumours were enriched for non-keratinizing and poorly differentiated subtypes. Transcriptomic analysis showed suppression of proliferation and immune-related pathways (FDR < 0.001), with suggestive enrichment of the TGF-β (FDR = 0.143) and p53 (FDR = 0.229) signaling pathways. On immune deconvolution, POU2F3-high tumours showed a nominal increase in activated dendritic cells, which did not withstand multiple testing correction. POU2F3 protein was detected in 12.4% of tumours and was significantly associated with p53 or RB1 abnormalities (single or double) (P = 0.028). CONCLUSIONS: POU2F3 marks a transcriptionally distinct, early-stage subtype of LUSC with keratinization-related features. Its prognostic relevance appears context-dependent and requires prospective validation in uniformly treated cohorts.

Humans↗

PubMed2026

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

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

Humans↗

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↗

PubMed2025

Hepatocyte dedifferentiation in 2D culture reveals extensive transcriptomic and proteomic rewiring.

BACKGROUND: Primary hepatocytes are commonly used in vitro to model liver metabolism, but prolonged culturing results in dedifferentiation and potentially limits the applicability of this model. METHODS: We characterized the transcriptome and proteome of full liver and primary hepatocytes as either freshly isolated cells or after 24 hours of 2D-culturing. RESULTS: We found that 2D-culturing for 24 hours changes more than 10,000 genes and 3000 proteins compared with freshly isolated cells, accompanied by a decrease in transcriptional heterogeneity and a loss of zonal markers. Moreover, there were changes in proteins associated with the extracellular matrix, in mitochondrial and ribosomal protein abundances, as well as an increase in the abundance of acute-phase response proteins. CONCLUSION: Collectively, primary mouse hepatocytes in culture rewire the transcriptome and proteome, which may affect the utility of this model to study physiological and molecular mechanisms related to the liver. We developed the Shiny app "Hepamorphosis" (https://cbmr.ku.dk/research/resources/shiny-apps/), which allows users to explore RNA/protein correlations, zonation profiles, and cell-type-specific transcription in full liver and cultured hepatocytes.

Hepatocytes↗

PubMed2026

Construction and validation of a β-hydroxybutyrylation-related molecular model for predicting prognosis of papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) usually has a favorable prognosis, yet a subset of patients develops persistent, recurrent, or biologically aggressive disease. The clinical relevance of lysine β-hydroxybutyrylation (Kbhb)-related transcriptional programs in PTC remains unclear. Accordingly, this study aimed to characterize Kbhb-related molecular heterogeneity in PTC, construct a prognostic signature, and explore its association with the tumor microenvironment (TME). METHODS: Transcriptomic and clinical data from PTC samples within The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) cohort were analyzed to identify Kbhb-related differentially expressed genes (DEGs), define molecular subtypes, construct a prognostic signature, and characterize tumor microenvironmental features. Single-cell RNA-sequencing data from PTC were further used to explore the cellular distribution of representative genes. RESULTS: We identified 51 Kbhb-related DEGs in PTC and defined two Kbhb molecular subtypes. The Kbhb_C2 subtype showed shorter progression-free interval (PFI) and a more immune- and stroma-enriched microenvironment. A six-gene prognostic signature comprising TARID, CDSN, PIMREG, KLRC1, SYT13, and NPR3 was then established. High-risk patients had significantly worse PFI in the full, training, and testing cohorts, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.715, 0.793, and 0.771, respectively, in the full cohort. High-risk tumors also exhibited higher stromal, immune, and ESTIMATE scores, altered immune infiltration, and increased expression of multiple immune checkpoint molecules. Single-cell analysis confirmed distinct cell-type-specific expression patterns of representative genes. CONCLUSIONS: Kbhb-related transcriptional programs define clinically relevant molecular heterogeneity in PTC and are closely associated with prognosis and TME remodeling. The identified six-gene signature provides a biologically interpretable framework for risk stratification in PTC.

Papillary thyroid carcinoma (PTC)↗

PubMed2026

Identifying JAK2 and ANXA5 as Key Genes Linking Obstructive Sleep Apnea and Oxidative Stress via Machine Learning and Multilayer Transcriptomic Integration With Functional Validation.

Obstructive sleep apnea (OSA) is a common and severe sleep disorder closely associated with oxidative stress (OS). This study aims to identify and validate potential OS-related genes associated with OSA through bioinformatics methods. We successfully identified OS-related differentially expressed genes (OS-DEGs) by combining the limma test, weighted correlation network analysis (WGCNA), and OS-related genes from the GeneCards database. Key genes and potential biological roles were further identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), enrichment analysis, protein-protein interaction (PPI) network analysis, Lasso regression analysis, random forest algorithm, and support vector machine recursive feature elimination (SVM-RFE) method. Evaluate and validate the accuracy of key genes through receiver operating characteristic (ROC) curve analysis. The human single-cell RNA sequencing (scRNA-seq) dataset is used for cell classification annotation, analysis of key gene single-cell expression profiles, and virtual gene knockout experiments based on the scTenifoldKnk algorithm. Integrating scRNA-seq sequencing, pseudotime trajectory inference, cell-cell communication analysis, and bulk immune infiltration deconvolution reveals monocyte subtype remodeling in OSA. Finally, the expression levels of key genes in clinical samples were validated using real-time quantitative PCR (RT-qPCR) and Western blotting. A total of 57 common DEGs, indicating significant enrichment in OS, inflammation, and tumor pathways, particularly prominent in the immunometabolism pathway. By integrating DEGs, WGCNA, PPI results, and machine learning methods, key genes Janus kinase 2 (JAK2) and ANXA5 were screened out. JAK2 was significantly upregulated under disease conditions, while ANXA5 was significantly downregulated. ROC curve exhibited high accuracy (area under the curve [AUC] > 0.85). Human scRNA-seq analysis revealed that key genes were predominantly highly expressed in monocytes. Virtual knockout experiments demonstrated that these key genes play a crucial role in regulating immune responses and inflammatory reactions. PPI networks and enrichment analysis verified that downstream genes S100P, ALOX5AP, PROK2, and PADI4 may collaboratively participate in immune response and inflammation regulation. Finally, clinical sample experiment further validated the results of bioinformatics analysis. This study provides new research insights for the diagnosis, mechanism research, and treatment development of OSA in the future by integrating multilayer transcriptomic and machine learning techniques.

Humans↗

PubMed2026

Single-cell RNA sequencing reveals disease associated changes in brain endothelial cells in the 5XFAD mouse.

Vascular dysfunction is a key contributor to Alzheimer’s disease (AD) pathology, where changes to the endothelium and its crucial role in maintaining blood-brain barrier (BBB) integrity have been of particular emphasis. The transgenic 5XFAD (5X Familial Alzheimer’s Disease) mouse model, which exhibits AD-related amyloidosis through FAD associated mutations in amyloid precursor protein (APP) and presenilin-1 (PS1), has become a widely adopted preclinical model in AD-related research studies. The need for cross-study standardization, accessibility, and data reproducibility has led to the widespread implementation of the C57BL/6J genetic background for maintaining this model. However, its reliability for studying vascular dysfunction and BBB alterations has been questioned due to conflicting reports in the literature. This variation is often attributed to the previously documented protective nature of the C57BL/6J background and loss of genetic background diversity. Since prior studies have mostly relied on imaging or functional assays, we herein utilized single-cell RNA sequencing (scRNAseq) to investigate AD-related molecular changes to endothelial cell populations in the 5XFAD mouse model. To initially build this resource, we focused on 12-month-old male mice, which revealed differentially expressed genes between 5XFAD and wildtype animals that mapped to signaling pathways involved in DNA damage, immune reactivity, and inflammation, among others. Many of these transcriptomic changes were zonated along the arteriovenous axis and occurred in AD genome-wide association study (GWAS) risk-associated genes. Overall, we anticipate this resource will help clarify the use of the 5XFAD model for studying AD-associated vascular changes and provide the foundation for expanded molecular profiling of brain endothelial cells under AD-associated conditions.

Animals↗

PubMed2026

FANCI promotes esophageal squamous cell carcinoma progression and cell cycle regulation and interacts with FANCD2.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor clinical outcomes, and reliable molecular biomarkers and therapeutic targets remain limited. Fanconi anemia group I protein (FANCI) is a core component of the Fanconi anemia (FA) pathway, but its expression pattern, clinical significance, and functional role in ESCC have not been comprehensively defined. This study aimed to investigate FANCI expression and prognostic value in ESCC, assess its effects on malignant cellular phenotypes and tumor growth, and explore its potential mechanistic relationship with Fanconi anemia group D2 protein (FANCD2) and cell-cycle regulation. METHODS: Multi-cohort analyses were performed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, together with ESCC single-cell RNA sequencing (RNA-seq) data. FANCI functions were assessed by bidirectional gain- and loss-of-function experiments in vitro (proliferation, colony formation, migration, invasion, apoptosis, and cell-cycle assays) and by xenograft models in vivo. Mechanistic studies included protein-protein interaction (PPI) analyses, co-immunoprecipitation (Co-IP), and immunofluorescence (IF) colocalization. RESULTS: FANCI was consistently upregulated in ESCC across bulk transcriptomic datasets and was further supported by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC). FANCI discriminated ESCC from normal tissues in TCGA-ESCC and was independently validated in GSE53624 [area under the curve (AUC) =0.940 and 0.975, respectively]. FANCI was associated with poorer overall survival (OS) and shorter disease-free interval (DFI), and these findings were validated in an independent GEO cohort. Functionally, FANCI promoted ESCC cell proliferation, migration, and invasion, while inhibiting apoptosis; FANCI knockdown suppressed tumor growth in vivo and induced G2/M cell-cycle arrest. Mechanistically, FANCI physically interacted with FANCD2, colocalized with FANCD2 in the nucleus, and was associated with altered FANCD2 protein abundance, consistent with cell-cycle and DNA repair-related programs. Single-cell analysis indicated that FANCI was enriched in epithelial cells and associated with higher activity of malignant functional programs. In TCGA-ESCC, FANCI-high tumors showed distinct mutation profiles, a trend toward increased tumor mutation burden (TMB), and altered immune-associated signatures. CONCLUSIONS: FANCI is upregulated in ESCC and is associated with diagnostic and prognostic value. It promotes malignant phenotypes and tumor growth, potentially through a FANCI-FANCD2-linked cell-cycle/DNA repair program, supporting FANCI as a candidate biomarker and therapeutic target in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed2026

A pro-inflammatory metastasis-associated macrophage subset induces tumor-promoting mesothelial cell conversion in ovarian cancer via IL-1α secretion.

Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment, yet the functional specialization of TAM subsets in metastatic progression remains incompletely defined. Here, we characterized distinct TAM populations contributing to tumor-promoting mesothelial cell conversion in high-grade ovarian carcinoma using single-cell RNA sequencing of patient-derived macrophages from ascites (ascTAMs) and omental metastases (omTAMs). TAMs from these anatomical sites were clearly distinguishable by polarization states, with omTAMs exhibiting a mixed M1⁺/M2⁺ phenotype, in contrast to the M1low/M2⁺ profile observed in ascTAMs. Transcriptomic analysis further revealed functional divergence of these subsets. Notably, omTAMs displayed gene signatures associated with mesothelial-to-mesenchymal transition (MMT), a critical process enabling tumor invasion across the peritoneal lining. Functionally, conditioned media from omTAMs, similar to that from classically activated M1 macrophages, induced MMT in primary mesothelial cells via TGFβ and ERK/p38 MAPK signaling pathways. This phenotypic transition enhanced transmesothelial tumor cell invasion. Proteomic analysis identified IL-1α as a key MMT-inducing factor secreted by pro-inflammatory macrophages. Mechanistically, IL-1α cooperates with TGFβ by activating an autocrine TGFβ/TGFBR1 feedback loop in mesothelial cells, thereby amplifying MMT. Consistent with these findings, IL1A expression was enriched in omTAM clusters across independent patient samples and was confirmed by immunohistochemical analysis of clinical samples. From a therapeutic perspective, our study identifies new avenues to counteract the mesothelial reprogramming driven by IL-1α⁺ TAMs, potentially impeding metastatic progression. Created in BioRender. Heidemann, S. (2026) https://BioRender.com/aeu6yd0 .

Female↗

PubMed2025

Molecular differences between young and mature stria vascularis from organotypic explants and transcriptomics.

The stria vascularis (SV) is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and mature mice to create a platform for advancing SV research. We validated our model by demonstrating that the proliferative behavior of the SV in vitro mimics SV in vivo. We also provided evidence for pharmacological experimentation by investigating the role of Wnt/β-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing from in vivo neonatal and mature mouse SV and surrounding tissue and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss.

Biochemistry↗

PubMed2026

Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.

With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein-disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.

Journal Article↗

PubMed2026

BCL11B enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL.

The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cisregulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed-phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2 and activating epithelial-mesenchymal transition transcription signatures. Immunophenotypic and single-cell RNA sequencing analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34+ cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15% to 4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults. Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

Humans↗

PubMed2006

Probing the transcriptome of neuronal cell types.

Distinct neuronal cell types acquire and maintain their identity by expressing different genes. Recently it has become feasible to measure this cell type specific expression by isolating and amplifying mRNA from small populations of fluorescently labeled neurons and probing this mRNA with microarrays. Prior to this, most neuronal gene expression studies used tissue homogenates or randomly selected single cells and were, therefore, not well suited to studying transcriptional differences between cell types. Microarray studies of purified cell types have enabled investigators to identify the transcriptional signatures of, for example, subtypes of pyramidal neurons and interneurons in the neocortex, modulatory dopaminergic and serotonergic neurons, and the striatal neurons that form the so-called 'direct' and 'indirect' pathways through the basal ganglia. These studies are opening up new approaches to understanding brain circuitry, plasticity and pathology and are refining the concept of the neuronal cell type.

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↗

PubMed2026

Lactylation-related immune-metabolic dysregulation defines prognostic and therapeutic stratification in lung adenocarcinoma.

BACKGROUND: Lactylation links lactate metabolism with inflammatory signaling and immune regulation in tumors. However, its cellular distribution and translational value in lung adenocarcinoma (LUAD) remain unclear. METHODS: Single-cell RNA-sequencing datasets GSE189357 and GSE171145 were integrated to characterize lactylation-related activity, intercellular communication, and malignant epithelial cell states in LUAD. Single-cell-derived lactylation-related differentially expressed genes were mapped to TCGA-LUAD and multiple GEO cohorts. Univariate Cox regression and machine learning algorithms were used to construct a lactylation-related prognostic signature (LRPS). The associations of LRPS with prognosis, immunotherapy response, drug sensitivity, genomic alterations, immune infiltration, and inflammation- and metabolism-related pathways were evaluated. KRT7 was further validated using virtual knockout analysis, spatial transcriptomics, and in vitro and in vivo experiments. RESULTS: lactylation-related transcriptional activity showed heterogeneous distribution across LUAD cell populations and was associated with altered cell-cell communication. In malignant epithelial cells, LRTS-high and LRTS-low states exhibited distinct metabolic, inflammatory, and tumor-related pathway activities. LRPS showed stable prognostic performance in TCGA-LUAD and multiple GEO cohorts and remained an independent prognostic factor. Low LRPS was associated with greater potential benefit from immunotherapy, whereas different LRPS groups displayed distinct drug sensitivity, genomic alteration, and immune microenvironment patterns. KRT7 was highly expressed in LUAD and associated with poor prognosis. KRT7 knockdown suppressed LUAD cell proliferation, migration, invasion, colony formation, and tumor growth in vivo. CONCLUSIONS: This study identifies lactylation-related immune-metabolic dysregulation as a clinically relevant feature of LUAD and develops a single-cell-guided LRPS for prognosis and therapeutic stratification. KRT7 emerged as an LRPS-related functional candidate with experimentally supported roles in malignant LUAD phenotypes.

Immunotherapy↗

PubMed2003

Molecular markers to identify patients at risk for recurrence after primary treatment for prostate cancer.

Accurate prognostication is a prerequisite for accurate therapeutics and management of prostate cancer because indolent tumors may require no intervention, whereas aggressive tumors lead to patient mortality. There is a critical need to define these subgroups of patients with prostate cancer differing in clinical outcome. Prognostic nomograms based on clinical data provide useful predictions of clinical states and outcomes, but they need further refinements to improve accuracy and universality. Genomic and proteomic analyses have provided many novel markers that may help define prognostic parameters based on the underlying biology of prostate cancer progression at the molecular level. These molecular markers are likely to augment traditional prognostic modalities by providing a set of molecularly defined and quantifiable variables. Encompassing the genome, transcriptome, and proteome of prostate cancer will likely provide "molecular signatures" that will bridge prognostication, prediction, and treatment in a single continuum.

Adenocarcinoma↗