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Page 349 of 494-
Multiomics and deep learning dissect regulatory syntax in human development.
Transcription factors establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility and regulating gene expression1. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs or single modalities2. Here we present the Human Development Multiomic Atlas, a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and more than 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs that influence accessibility, including composite motifs exhibiting distinct syntactic constraints that are predicted to mediate transcription factor cooperativity. We identify 'hard' syntactic rules requiring precise motif spacing and orientation, 'soft' rules allowing flexible motif arrangements, and ubiquitous motifs inhibiting accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell-type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.
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Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.
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Single-nucleus profiling of the left ventricle of the mouse heart after chronic stress.
It is widely accepted that stress and cardiac disease are related, but the exact mechanism is still up for debate. Although stress has been scientifically confirmed as a causative factor, there is still a lack of qualitative and quantitative indicator systems for stress-induced cardiac injury. The forensic evidence frequently indicates that cases of sudden cardiac death are often preceded by prolonged exposure to chronic stress factors. However, the cellular responses and mechanisms that trigger and regulate these activities in the pathological and physiological processes of chronic stress are still poorly understood. The left ventricle (LV), as a critical target organ in cardiovascular diseases, still has unclear cellular heterogeneity under chronic stress. Using single-nucleus RNA sequencing (snRNA-seq), we established a cellular atlas of 99,154 LV cells (42,491 stress and 56,663 control), comprehensively profiling all major cardiac cell types. The resulting dataset not only provides a foundation for deciphering the molecular mechanisms underlying chronic stress in cardiovascular dysfunction but also enables the identification of potential biomarkers for future diagnostic and therapeutic strategies.
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Comprehensive analysis of the potential cuproptosis-related biomarker LIAS that regulates prognosis and immunotherapy of pan-cancers.
Lipoic acid synthetase (LIAS) has been demonstrated to play a crucial role in the progression of cancer. Exploring the underlying mechanisms and biological functions of LIAS could have potential therapeutic guidance for cancer treatment. Our study has explored the expression levels and prognostic values of LIAS in pan-cancer through several bioinformatics platforms, including TIMER2.0, Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2.0), and Human Protein Atlas (HPA). We found that a high LIAS expression was related to the good prognosis in patients with kidney renal clear cell carcinoma (KIRC), rectum adenocarcinoma (READ), breast cancer, and ovarian cancer. Inversely, a high LIAS expression showed unfavorable prognosis in lung cancer patients. In addition, the genetic alteration, methylation levels, and immune analysis of LIAS in pan-cancer have been evaluated. To elucidate the underlying molecular mechanism of LIAS, we conduct the single-cell sequencing to implicate that LIAS expression was related to hypoxia, angiogenesis, and DNA repair. Thus, these comprehensive pan-cancer analyses have conveyed that LIAS could be potentially significant in the progression of various cancers. Moreover, the LIAS expression could predict the efficacy of immunotherapy in cancer patients.
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Systematic CRISPRi perturbation of 1,408 autism risk genes maps multilevel transcriptional convergence in human cortical neurons.
Genetic heterogeneity in autism spectrum disorder (ASD) complicates the identification of shared molecular pathways amenable to therapeutic intervention. Here, we perform a CRISPRi Perturb-seq screen targeting 1,408 ASD risk genes in human embryonic stem cell-derived immature cortical neurons and profile the resulting transcriptomic effects by single-cell RNA sequencing. We identify 215 ASD risk genes whose repression induces significant global transcriptomic dysregulation. Leveraging this functional atlas, we characterize candidate genes based on transcriptional similarity to established ASD hub genes. We identify gene programs recurrently dysregulated across perturbations, anchored by processes governing microtubule dynamics, neuron differentiation, cell migration, and transmembrane transport. We further identify CHAMP1 as a previously unrecognized regulator of Wnt signaling and define specific ASD risk genes that modulate the rate of cortical neuron differentiation. Analysis of differentially expressed genes reveals both convergent and perturbation-specific downstream transcriptional responses. Together, these findings provide a multilevel map of transcriptomic convergence in ASD and establish a framework for identifying both pathway-level and genotype-specific therapeutic strategies.
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Integrative bulk and single-cell transcriptomic analysis identifies a migrasome-associated lncRNA signature predictive of prognosis and immune landscape in clear cell renal cell carcinoma.
INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is characterized by high recurrence and metastasis rates, leading to poor prognosis. Migrasomes, a class of organelles mediating intercellular communication, and long noncoding RNAs (lncRNAs) both play critical roles in tumor progression; however, the prognostic significance of migrasome-associated lncRNAs in ccRCC remains unclear. METHODS: Migrasome-associated lncRNAs were identified using The Cancer Genome Atlas (TCGA) dataset, and a prognostic risk signature was constructed. The associations between the model and overall survival (OS), functional enrichment, tumor mutation burden (TMB), tumor microenvironment (TME) characteristics, immune evasion, and drug sensitivity were evaluated. Single-cell transcriptomic analysis was performed to determine cell type-specific expression patterns and intercellular communication networks. Functional roles of key lncRNAs were validated in vitro using qRT-PCR, CCK-8 proliferation assays, wound-healing assays, Transwell assays, colony formation assays, immunofluorescence, and Western blotting. RESULTS: The risk signature stratified patients into high- and low-risk groups with significantly different survival outcomes. High-risk patients exhibited elevated TMB and enhanced immune evasion potential. Drug sensitivity analysis revealed distinct therapeutic response profiles between the groups. Single-cell transcriptomic analysis uncovered pronounced cellular heterogeneity and TME characteristics associated with the prognostic signature. High-risk cells were predominantly enriched within tumor epithelial clusters and displayed distinct intercellular communication patterns. Knockdown of FOXD2-AS1 markedly suppressed tumor cell proliferation and migration and reduced the expression of migrasome marker proteins. DISCUSSION: This study presents a novel migrasome-associated lncRNA risk signature with significant prognostic and therapeutic implications for ccRCC. The signature captures distinct immune, genomic, and pharmacologic features, and its core lncRNAs may promote tumor progression through migrasome-mediated signaling pathways, warranting further mechanistic investigation.
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Single-cell deconstruction of medulloblastoma microenvironment elucidates subtype-specific immune architectures and prognostic molecular signatures.
Medulloblastoma (MB), the most common malignant pediatric brain tumor, exhibits molecular heterogeneity classified into WNT, SHH, GP3, and GP4 subtypes, each with distinct prognoses and therapeutic vulnerabilities. Despite advances in multimodal therapies, treatment-related morbidity and incomplete understanding of tumor microenvironment (TME) heterogeneity impede precision medicine. Through integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic profiles from 38 MB specimens, we systematically mapped subtype-specific TME features. WNT MB demonstrated sparse immune infiltration but enriched supportive stromal cells (pericytes, astrocytes/oligodendrocytes) and elevated angiogenesis, correlating with superior prognosis. In contrast, SHH, GP3, and GP4 subtypes exhibited immunosuppressive TMEs dominated by tumor-associated macrophages (TAMs) and T cells. Myeloid subtyping revealed 11 functionally distinct TAM clusters: WNT-enriched microglia-derived M1-polarized subsets with anti-tumor activity, SHH-specific M2-like classical TAMs promoting immune evasion, and GP4-associated ECM-remodeling TAMs driving malignancy. T cell profiling identified CD8+ exhaustion and CD4+ regulatory T cell enrichment in non-WNT subtypes, underpinning immunosuppression. Pseudotime trajectory analysis uncovered myeloid differentiation routes from proliferative TAMs to terminal immunosuppressive subsets, regulated by subtype-specific transcription factors (XBP1, STAT6). CellChat analysis highlighted MIF-CD74 and MDK-LRP1 ligand-receptor pairs as key mediators of tumor-TME crosstalk in non-WNT subtypes. Secretome-receptor clustering stratified MB into three TME-driven subtypes: SHH (matrix remodeling), GP3/GP4 (neuronal differentiation), and WNT (angiogenesis), with tumor cells as primary secretory sources. Prognostic core genes (SHH: EMILIN3, CD163; GP3/GP4: SEMA3A, TULP1) predicted survival outcomes and demonstrated diagnostic specificity. This first comprehensive TME atlas of MB subtypes elucidate mechanisms of immunosuppressive niche formation and provides actionable core targets for precision immunotherapy.
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Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy.
BACKGROUND: Imipridone ONC201 is the first FDA-approved therapy for H3K27-altered diffuse midline glioma; however, clinical responses remain limited. Defining tumor-intrinsic determinants and microenvironmental, extrinsic factors that shape sensitivity or resistance to imipridones will identify actionable therapeutic opportunities and inform improved clinical strategies. METHODS: To identify mechanisms of imipridone resistance, we obtained postmortem brain tissue from DMG patients who had received imipridones and/or standard care. Single-nucleus RNA and open-chromatin sequencing were performed on N = 22 cases. Immunofluorescence-based myeloid phenotyping was performed on N = 46 cases. Mitochondrial copy-number analysis was performed on N = 19 cases. Validation of imipridone sensitivity, its effect on mitochondrial density, and its synergy with inhibition of mitochondrial biogenesis were assessed in DMG primary cells. RESULTS: We established a single-cell RNA/open-chromatin atlas from postmortem DMG cases and found imipridone treatment resulting in regressed mesenchymal transition, reduced myeloid-derived suppressive cells, and reversed aberrant H3K27-altered enhancer activity. Resistant tumors showed increased mitochondrial density, turnover, and membrane potential. Mitochondrial biogenesis and PPARGC1A emerged as resistance biomarkers and actionable targets. CONCLUSIONS: These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.
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CYB561 a potential prognostic biomarker for liver hepatocellular carcinoma.
Liver hepatocellular carcinoma (LIHC) is a malignancy characterized by a high rate of recurrence, metastasis, and poor prognosis. Cytochrome b561 (CYB561) has been previously reported to be associated with tumor progression, but it has not been revealed in LIHC. The aim of this study was to investigate the prognostic value and potential function of CYB561 in LICH. The expression level, clinical correlation, prognosis, and biological function of CYB561 in LIHC were analyzed using The Cancer Genome Atlas（TCGA), Gene Expression Omnibus (GEO), TIMER2, Kaplan-Meier Plotter, and GEPIA2 databases. The expression of CYB561 in LIHC tissue samples was analyzed by immunohistochemical staining. The effect of CYB561 on the proliferation and migration of LIHC cells was investigated by using CYB561 knockdown in vitro. GSE149614 dataset was used to analyze the expression distribution of CYB561 in LIHC on a single-cell dimension. This study showed that CYB561 mRNA and protein were highly expressed in LIHC. High expression of CYB561 suggests poor prognosis in LICH patients and is an independent risk factor for LIHC. Wound-healing experiment, transwell experiment, and clonal formation experiment confirmed that CYB561 knockdown could inhibit the proliferation and migration of LIHC cells. Functional enrichment analysis showed that CYB561 was related to biological processes such as cell adhesion and immune response. KEGG enrichment analysis showed that CYB561 interacts with tumor-related signaling pathways. Single-cell analysis showed that CYB561 was mainly expressed in hepatocytes. Cells with high CYB561 expression had a higher degree of malignancy. Our study found that abnormal expression of CYB561 in LIHC suggested poor prognosis of LIHC and was related to tumor migration and proliferation. CYB561 is a potential prognostic predictor or therapeutic biomarker.
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CXCL13 as a Prognostic Biomarker and Immune Microenvironment-Associated Gene in Endometrial Carcinoma: A Multi-Omics Investigation.
Immune remodeling within the tumor microenvironment (TME) influences the progression and clinical outcome of uterine corpus endometrial carcinoma (UCEC), but the contribution of chemokine-related regulatory genes remains incompletely characterized. This study aimed to evaluate the prognostic relevance of CXCL13 and its association with immune microenvironmental features in UCEC using publicly available transcriptomic and single-cell datasets. RNA-sequencing profiles and clinical annotations from 589 UCEC cases in The Cancer Genome Atlas (TCGA) were analyzed to assess TME composition using ESTIMATE (Estimation of Stromal and Immune cells in MAlignant Tumours using Expression data) and CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts), followed by survival analysis, differential gene expression analysis, protein-protein interaction network construction, Cox regression, and gene set enrichment analysis. A public single-cell RNA-sequencing dataset from the Gene Expression Omnibus (GEO; GSE173682) was further used to infer the cellular sources of CXCL13. Elevated CXCL13 expression was associated with favorable overall survival and enrichment of immune-activation pathways. CIBERSORT-based analysis indicated that high CXCL13 expression correlated with increased estimated fractions of CD8+ T cells and plasma cells, together with transcriptional features related to tertiary lymphoid structure-associated immune activation, whereas several immunosuppressive cell populations showed lower estimated abundance. Single-cell analysis suggested that CXCL13 was mainly expressed by follicular helper T cells and exhausted CD8+ T cells. These findings indicate that CXCL13 may serve as a prognostic biomarker associated with an immune-active TME in UCEC. Further histological, spatial, and functional validation is warranted to confirm its mechanistic role and translational potential.