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A Comprehensive Characterization of Monoallelic Expression During Hematopoiesis and Leukemogenesis via Single-Cell RNA-Sequencing.
Single-cell RNA-sequencing (scRNA-seq) is becoming a powerful tool to investigate monoallelic expression (MAE) in various developmental and pathological processes. However, our knowledge of MAE during hematopoiesis and leukemogenesis is limited. In this study, we conducted a systematic interrogation of MAEs in bone marrow mononuclear cells (BMMCs) at single-cell resolution to construct a MAE atlas of BMMCs. We identified 1,020 constitutive MAEs in BMMCs, which included imprinted genes such as MEG8, NAP1L5, and IRAIN. We classified the BMMCs into six cell types and identified 74 cell type specific MAEs including MTSS1, MOB1A, and TCF12. We further identified 114 random MAEs (rMAEs) at single-cell level, with 78.1% single-allele rMAE and 21.9% biallelic mosaic rMAE. Many MAEs identified in BMMCs have not been reported and are potentially hematopoietic specific, supporting MAEs are functional relevance. Comparison of BMMC samples from a leukemia patient with multiple clinical stages showed the fractions of constitutive MAE were correlated with fractions of leukemia cells in BMMCs. Further separation of the BMMCs into leukemia cells and normal cells showed that leukemia cells have much higher constitutive MAE and rMAEs than normal cells. We identified the leukemia cell-specific MAEs and relapsed leukemia cell-specific MAEs, which were enriched in immune-related functions. These results indicate MAE is prevalent and is an important gene regulation mechanism during hematopoiesis and leukemogenesis. As the first systematical interrogation of constitutive MAEs, cell type specific MAEs, and rMAEs during hematopoiesis and leukemogenesis, the study significantly increased our knowledge about the features and functions of MAEs.
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A Single-Cell Transcriptomic Atlas Elucidates a Microglial Gene Signature Linking Ferroptosis to Mitochondrial Dysfunction in Epilepsy.
BACKGROUND: Epilepsy is a chronic neurological disorder caused by abnormal synchronous discharges of neurons, with ferroptosis and mitochondrial dysfunction implicated in its progression. However, a lack of resolution at the level of specific cell types has obscured critical roles and molecular mechanisms within the epileptic microenvironment. METHODS: This study integrated single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq data from epilepsy and control samples. We performed dimensionality reduction and clustering to identify 13 cell subpopulations, and then assessed the expression of ferroptosis-related genes (FRGs) and mitochondrial-related genes (MRGs) within 7 major cell types. Three machine learning algorithms were further applied to identify key genes in microglia. Subsequent analyses included immune infiltration, pathway enrichment, and drug-target interaction. Molecular docking and molecular dynamics simulations were used to evaluate the potential binding affinity of the predicted drug. In vivo validation included histopathology, mitochondrial electron microscopy, JC-1 staining, and immunohistochemistry (IHC). RESULTS: We identified six key genes (ATM, TGFBR1, ZEB1, PARP14, GJA1, and ALOX5), which link ferroptosis and mitochondrial dysfunction with a central role for microglia in epilepsy. These genes were associated with immune infiltration, including increased Th1 cell levels and reduced CD8+ T cell abundance. Enrichment analyses implicated these hub genes in orchestrating key epileptogenic processes, including neuroinflammatory pathways, ferroptosis, and interferon response. PARP14 was upregulated in epileptic rats, and GJA1 exhibited stable binding with bleomycin. Histopathological and mitochondrial assays confirmed the presence of ferroptosis and mitochondrial damage in epilepsy. CONCLUSION: This study highlights the interplay between ferroptosis and mitochondrial dysfunction in epilepsy, identifying six key microglial genes as high-priority candidates for future mechanistic and therapeutic investigation. Notably, PARP14 is implicated in epileptogenesis for the first time. The stable binding between GJA1 and bleomycin offers a novel avenue for epilepsy treatment, warranting further experimental validation.
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Single-Cell RNA Sequencing Reveals Bidirectional Development of Infantile Hemangioma.
Infantile hemangioma (IH) affects 5-10% of all infants and up to 30% of premature newborns. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of IH in humans. In this study, we performed single-cell RNA sequencing on hemangioma samples from 3 infants diagnosed with IH. A total of 36,237 high-quality cells were clustered into 10 major cell types, including endothelial cells and hemangioma mural cells. Endothelial cells in IH exhibit strong proliferative capacity and heterogeneity. Furthermore, cell-cell communication analysis and immunofluorescence colocalization revealed that hemangioma mural cells, which constitute >50% of IH, can release ligands such as VEGFA and PGF and act on endothelial cells, thus promoting endothelial cell proliferation and angiogenesis. We also found that the expression levels of VEGFA and Ki-67 are significantly higher in IH than in normal infant skin tissue. Finally, we also found that adrenaline receptor beta 1 is specifically expressed in EC1 and EC2, adrenaline receptor beta 2 is specifically expressed in EC3, and adrenoceptor alpha is specifically expressed in hemangioma mural cells. In summary, our study provides a cellular atlas of proliferative-phase IH and reveals the important roles of endothelial cells and hemangioma mural cells in the development of IH.
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Single-Nucleus Transcriptomics Uncovers Xaf1-Driven PANoptosis as a Therapeutic Target in Aminoglycoside-Induced Hearing Loss.
Aminoglycoside antibiotics are essential in managing many life-threatening diseases. However, their derivatives, such as neomycin, are associated with severe side effects such as persistent sensorineural hearing loss. Therefore, it is essential to elucidate the molecular and biochemical mechanisms of aminoglycoside-induced ototoxicity and identify targets for alleviating ototoxic injury. Here, we provide a detailed cochlear cell atlas of neomycin-induced acute and chronic ototoxicity-related changes through single-nucleus RNA sequencing profiling. Utilising this cochlear cell atlas, we used the Augur and scDist algorithms to evaluate cell-type-specific susceptibility to neomycin injury. We observed aberrant expression of X-linked inhibitor of apoptosis (Xiap)-associated factor 1 (Xaf1) in neomycin-exposed cochleae using the cochlear cell atlas, and we identified a novel role for Xaf1 in facilitating PANoptosis through overexpression and knockdown assays in vitro. Finally, we assessed the protective role of Xaf1 against neomycin-induced ototoxicity by Xaf1 knockdown in cochlear hair cells using adeno-associated virus-based gene delivery. Mechanistically, Xaf1 orchestrates PANoptosis activation through direct interaction with and transcriptional regulation of ZBP1, establishing its hierarchical position upstream in the signalling cascade. This study presents detailed cochlear cellular maps of neomycin-induced ototoxicity and serves as a valuable resource for identifying transcriptome-wide disease-driving perturbations at the single-cell level. More importantly, we identified Xaf1 as a critical target for modulating the PANoptosis pathway, offering a promising treatment strategy for aminoglycoside-induced ototoxicity.
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Single-cell transcriptome atlas and genome-wide Mendelian randomization reveal chemokine involvement in diverse immune cells in type 2 diabetes.
BACKGROUND: Chemokine-driven immune dysregulation is increasingly recognized as a hallmark of T2D pathogenesis(T2D), where insulin resistance and metabolic stressors drive chronic inflammation. While chemokine cascades are hypothesized to mediate diabetic immunopathology, causal mediators remain undefined. METHODS: We employed Mendelian Randomization (MR) of genome-wide association studies to identify causal inflammatory mediators, serological validation in streptozotocin-induced murine T2D models, and single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMC) to map immune cell heterogeneity and intercellular communication networks. RESULTS: MR prioritized IFN-γ, CCL7, MIF, and CXCL9 as genetically supported T2D effectors. Murine validation confirmed CCL7 and MIF as robust circulating mediators. scRNA-seq revealed compartment-specific chemokine receptor dynamics (CCR4/5/6, CXCR3/4/5, CX3CR1), dominated by enhanced CCL5-CCR5 and CCL6-CCR2 crosstalk. CONCLUSION: This work establishes a systems-level framework for chemokine signaling in T2D immunopathogenesis, identifying nodal regulators of immune crosstalk as potential therapeutic vulnerabilities.
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Multiset multicover methods for discriminative marker selection.
Markers are increasingly being used for several high-throughput data analysis and experimental design tasks. Examples include the use of markers for assigning cell types in scRNA-seq studies, for deconvolving bulk gene expression data, and for selecting marker proteins in single-cell spatial proteomics studies. Most marker selection methods focus on differential expression (DE) analysis. Although such methods work well for data with a few non-overlapping marker sets, they are not appropriate for large atlas-size datasets where several cell types and tissues are considered. To address this, we define the phenotype cover (PC) problem for marker selection and present algorithms that can improve the discriminative power of marker sets. Analysis of these sets on several marker-selection tasks suggests that these methods can lead to solutions that accurately distinguish different phenotypes in the data.
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Mapping the tumor microenvironment in bladder cancer and exploring the prognostic genes by single-cell RNA sequencing.
Despite substantial advances in the treatment using immune checkpoint inhibitors (ICIs), the clinical expected therapeutic effect on bladder cancer has not been achieved, in which the tumor microenvironment (TME) occupies a notable position. In this research, 10X single-cell RNA-sequencing technology was conducted to analyze seven primary bladder tumor tissues (three non-muscle-invasive bladder cancer (NMIBC) and four muscle-invasive bladder cancer (MIBC)) and seven corresponding normal tissues adjacent to cancer; eight various cell types were identified in the bladder cancer (BC) TME, and a complete TME atlas in bladder cancer was made. Moreover, bladder cancer epithelial cells were further subdivided into 14 subgroups, indicating a high intra-tumoral heterogeneity. Additionally, the differences between NMIBC and MIBC were compared based on differential gene expression heatmap, copy number variation (CNV) distribution heatmap, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network mutual analysis, and the Kaplan-Meier survival prognosis analysis were used to identify six key genes associated with the prognosis of bladder cancer: VEGFA, ANXA1, HSP90B1, PSMA7, PRDX6, and PPP1CB. The dynamic change of the expression distribution of six genes on the pseudo-time axis was further verified by cell pseudo-time analysis.
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A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.
Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snRNA-seq) studies have identified multiple transcriptional states of microglia in human AD brain. However, the characteristics and potential functions of G protein-coupled receptors (GPCRs) across different states remain poorly systematized. This review systematically searched and reviewed snRNA-seq studies based on human brain tissue published between 2020 and 2025. By re-analyzing GPCR expression across these datasets, we focuses on characterizing the differential expression characteristics and potential functions of GPCRs in five key AD-related microglial states: disease-associated microglia, tau-associated microglia, inflammation-associated microglia, proliferation-associated microglia, and interferon-associated microglia. Furthermore, we cross-reference these findings with single-cell sequencing data from human induced pluripotent stem cell (hiPSC)-derived microglia to prioritize a conserved set of GPCRs of high interest. In summary, by integrating transcriptomic evidence from both post-mortem human brain and hiPSC models, this review not only refines the understanding of microglial heterogeneity in AD but also provides a set of candidate GPCR targets for subsequent validation and drug discovery efforts against AD.
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Single-cell analysis of angiotensin-converting enzyme II expression in human kidneys and bladders reveals a potential route of 2019 novel coronavirus infection.
BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.
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The Hippo-Yki pathway governs growth and cell fate in the posterior silk gland of the silkworm.
The posterior silk gland (PSG) of the silkworm (Bombyx mori) is a specialized organ that synthesizes vast quantities of silk fibroin; however, the cell-type-specific mechanisms regulating its development remain largely unclear. Leveraging our previously constructed single-cell atlas, we performed high-dimensional weighted gene coexpression network analysis (hdWGCNA). The analysis revealed a gene module strongly correlated with fibroin-synthesizing cells (FBSs) in the PSG. Pathway analysis revealed significant enrichment of the Hippo signaling pathway within this module, with its downstream transcriptional coactivator, Yorkie (Yki), being identified as a top-ranked hub gene. Strikingly, PSG-specific Yki overexpression or knockdown induced severe developmental defects from early larval stages. Transcriptomic profiling combined with cellular deconvolution demonstrated that Yki is essential for maintaining the transcriptional identity and proportional homeostasis of the FBS population. Our study establishes the Hippo-Yki pathway as a central developmental regulator that coordinates organ growth and FBS fate specification in the silk gland, offering new genetic insights into potential targets for improving silk production.