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Human body single-cell atlas of three-dimensional genome organization and DNA methylation.
Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multiomic profiling of three-dimensional (3D) genome structure and DNA methylation for 86,689 single nuclei across 16 tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, which indicates that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers a reference for exploring gene regulation in human health and disease.
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IPGCA: A Comprehensive Single Cell Atlas of 1 074 127 Porcine Intestinal Cells Revealing Cellular Dynamics, Genetic Regulation, and Cross-Species Conservation.
The porcine intestinal tract is vital for nutrient absorption, immune regulation, and various physiological processes. However, a comprehensive understanding of its cellular composition and gene regulatory landscape remains limited. Here, the Integrated Pig Gut Cell Atlas (IPGCA) is presented, a comprehensive single cell resource comprising 1 074 127 cells spanning five intestinal segments, six developmental stages, and nine breeds. IPGCA enables the discovery of previously overlooked cell types (e.g., Paneth cells) and reveals dynamic B cell remodeling during weaning. Combining with genome-wide association studies (GWAS), complex traits are linked to potential causal cell types. Furthermore, the utility of IPGCA as a reference for the deconvolution of bulk RNA-seq data is demonstrated, enabling the identification of cell type interaction expression quantitative trait loci (ieQTLs) and deconvolutional eQTLs (decon-eQTL). Co-localization analyses implicate enterocyte BNC2 functions in loin muscle area trait and endothelial cell BAG3 in backfat thickness. Strikingly, comparative analysis with human intestinal atlases reveals a high degree of conservation, reinforcing the pig's value as a model for human gut biology. To empower the community, scGutDB (http://alphaindex.zju.edu.cn/scgut) is developed, an interactive platform for data exploration. IPGCA provides a foundational resource for agricultural genomics, precision breeding, and translational studies of intestinal physiology and diseases.
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Single-cell Stereo-seq reveals regulatory mechanisms driving regeneration of injured proximal tubules during AKI.
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function. Proximal tubule (PT) cells play a central role in AKI. However, the specific populations and states of PT that facilitate repair remain poorly understood. Here, we combine spatial enhanced resolution omics sequencing with single-nucleus RNA sequencing to profile kidney transcriptomes during AKI. We identify an ischemia-reperfusion injury-induced PT subtype, termed proliferative PT, that likely initiates renal regeneration and exhibits a gene expression enriched in mitosis and metabolic processes. Acsm2 is expressed in proliferative PT and is associated with cell cycle progression. Functional studies reveal the protective role of Acsm2 via deficiency and overexpressing mice. Finally, we identify a subcluster of Fibroblast (FIB_C2) that participates in PT repair through cell-cell communication with proliferative PT. Our study provides an integrated high-resolution spatiotemporal atlas of AKI and reveals the important role of Acsm2 in kidney regeneration.
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Comprehensive scRNA-seq analysis to identify new markers of M2 macrophages for predicting the prognosis of prostate cancer.
BACKGROUND: Prostate cancer (PCa) has become the highest incidence of malignant tumor among men in the world. Tumor microenvironment (TME) is necessary for tumor growth. M2 macrophages play an important role in many solid tumors. This research aimed at the role of M2 macrophages' prognosis value in PCa. METHODS: Single-cell RNA-seq (scRNA-seq) data and mRNA expression data were obtained from the Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA). Quality control, normalization, reduction, clustering, and cell annotation of scRNA-seq data were preformed using the Seruat package. The sub-populations of the tumor-associated macrophages (TAMs) were analysis and the marker genes of M2 macrophage were selected. Differentially expressed genes (DEGs) in PCa were identified using limma and the immune infiltration was detected using CIBERSORTx. Then, a weighted correlation network analysis (WGCNA) was constructed to identify the M2 macrophage-related modules and genes. Integration of the marker genes of M2 macrophage from scRNA-seq data analysis and hub genes from WGCNA to select the prognostic gene signature based on Univariate and LASSO regression analysis. The risk score was calculated, and the DEGs, biological function, immune characteristics related to risk score were explored. And a predictive nomogram was constructed. CCK8, Transwell, and wound healing were used to verify cell phenotype changes after co-cultured. RESULTS: A total of 2431 marker genes of M2 macrophage and 650 hub M2 macrophage-related genes were selected based on scRNA-seq data and WGCNA. Then, 113 M2 macrophage-related genes were obtained by overlapping the scRNA-seq data and WGCNA results. Nine M2 macrophage-related genes (SMOC2, PLPP1, HES1, STMN1, GPR160, ABCG1, MAZ, MYC, and EPCAM) were screened as prognostic gene signatures. M2 risk score was calculated, the DEGs, Immune score, stromal score, ESTIMATE score, tumor purity, and immune cell infiltration, immune checkpoint expression, and responses of immunotherapy and chemotherapy were identified. And a predictive nomogram was constructed. CCK8, Transwell invasion, and wound healing further verified that M2 macrophages promoted the proliferation, invasion, and migration of PCa (p < 0.05). CONCLUSIONS: We uncovered that M2 macrophages and relevant genes played key roles in promoting the occurrence, development, and metastases of PCa and played as convincing predictors in PCa.
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Mapping cell type-resolved transcriptomic profiles to patient survival in pancreatic cancer.
Traditional bulk-level transcriptomic sequencing cannot link cell type-specific gene expression to patient survival. In this study, we integrate single-nucleus RNA-seq and longitudinal data from 152 patients with pancreatic ductal adenocarcinoma (PDAC), profiling 1.2 million cells to construct a prognostic map connecting cell type-resolved gene expression with overall survival. Using a single-cell-resolved spatial transcriptomic platform, we further analyze 3.1 million cells and correlate their spatial distribution with therapeutic response. To empower the translational research community, we develop ctPANDA, an interactive platform offering cell-type-level prognostic insights. This atlas identifies PLOD2 as a promising target, with elevated expression predicting poorer outcomes across eight cell types. We have developed a proof-of-concept compound that can effectively degrade PLOD2 and inhibit PDAC progression in vivo. Collectively, this study advances the prognostic analysis from bulk-level to cell-type resolution, establishing a framework linking gene expression to clinical outcomes and providing actionable insights for target discovery and precision oncology.
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Single-cell spatial transcriptomics reveals tumor microenvironment heterogeneity in primary and lymph node-metastatic small cell lung cancer.
Lymph node metastasis (LNM) is a critical prognostic and therapeutic determinant in small cell lung cancer (SCLC), yet its spatial cellular ecosystem remains poorly understood. Here, we perform single-cell spatial transcriptomics using the CosMx Spatial Molecular Imager on 105 primary and metastatic lymph node specimens from 75 SCLC patients, generating a comprehensive atlas of over 600,000 cells. We identify three LNM-enriched malignant subclusters with distinct metabolic and angiogenic programs that spatially correlate with immune exclusion features. Spatial analysis reveals vascular-immune crosstalk, wherein endothelial cells orchestrate immune activation through avoidance of malignant cells while forming functional perivascular niches with cytotoxic T cells during LNM. Cellular neighborhood analysis delineates distinct multicellular niches and identifies a pan-immune hotspot (PIHs-1) whose abundance is an independent predictor of survival. This study provides a high-resolution spatial map of the SCLC tumor microenvironment during LNM and establishes spatially defined architectures as both mechanistic insights and translatable biomarkers.
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Protoplast Isolation for Plant Single-Cell RNA-seq.
The growth and development of plants depends on diversified gene expression in different cell types. Compared to traditional bulk RNA sequencing, droplet-based single-cell RNA sequencing (scRNA-seq) allows for transcriptome profiling of individual cells within heterogeneous tissues. scRNA-seq provides a high-resolution atlas of cellular characterization and vastly improves our understandings of the interactions between individual cells and the microenvironment. However, the difficulty in protoplast isolation has limited the application of single-cell sequencing technology in plant research. Here we describe a high-efficiency protoplast isolation protocol for scRNA-seq.
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Single-cell atlas of the developing Down syndrome brain cortex.
Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic cause of intellectual disability, yet the mechanisms disrupting fetal brain development remain unclear. We performed single-cell transcriptomic and chromatin accessibility profiling of approximately 250,000 cells from 15 DS and 15 control human fetal cortices (10-20 weeks postconception). Our analysis revealed a subtype-specific reduction in RORB- and FOXP1-expressing excitatory neurons and widespread disruption of neurodevelopmental transcriptional programs. Chromosome 21 transcription factors BACH1, PKNOX1 and GABPA emerged as dosage-sensitive hubs regulating genes linked to intellectual disability. Antisense oligonucleotide-mediated normalization of these transcription factors in human neural progenitors in vitro partially rescued target gene expression. Benchmarking a humanized in vivo model captured additional molecular and cellular signatures of DS, complementing the in vitro model. Together, we present a resource defining the gene-regulatory landscape underlying cortical development in DS and highlight molecular pathways for further investigation.
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Spatially resolved single-cell atlas reveals the macroevolutionary trajectory of animal hearts.
Animal hearts display diverse anatomical structures during adaptive evolution. Here, we present a multiomics atlas of adult hearts from 27 species across chordates, arthropods, and mollusks. Joint analysis indicates that Bilateria hearts share a core gene repertoire, taking a stepwise "add-on" approach as a universal evolutionary strategy. The "proto-heart" is populated by key cell types, including cardiomyocytes, fibroblasts, endothelial cells, and neural cells, which maintained core signatures while evolving with shifts in living environments and corresponding adaptations in the cardiovascular system. Additionally, we reveal an evolutionarily conserved cardiomyocyte state dynamic potentially linked to cardiac development and stress responses. Finally, we identify a common molecular program underpinning chamber evolution from a ventricular foundation. This work establishes a resource for understanding the intrinsic mechanisms of heart evolution.
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Single-cell multiomic atlas of healthy pediatric bone marrow reveals age-dependent differences in lineage differentiation driven by stromal signaling.
Childhood is a critical period for hematopoietic development and susceptibility to hematologic disease. Here we generated a multimodal single-cell atlas of healthy human bone marrow, capturing mRNA and surface protein expression in 90,710 cells, including over 20,000 hematopoietic stem and progenitor cells (HSPC) and mesenchymal stromal cells (MSC) from nine donors ranging from infancy to young adulthood (2-32 years). Young pediatric (YP) bone marrow (<10 years) was compositionally and molecularly distinct from adolescent and young adult (AYA) bone marrow (≥13 years), with hematopoietic output shifting from B cell dominance in YP bone marrow to myeloid and T cell bias in AYA bone marrow. Spatial transcriptomics of six bone marrow biopsies (0-23 years) confirmed these age-dependent changes. Two lymphoid progenitor (LyP) subsets regulated this lineage shift: CD127+ LyP cells with B cell-biased output were enriched before age 10, whereas CD127- LyP cells with combined lymphoid and myeloid features predominated thereafter. Stromal signaling showed corresponding age-dependent changes, with increased interleukin-7 production by bone marrow MSC in YP compared to AYA, indicating niche-mediated regulation of HSPC lineage potential during ontogeny. This single-cell atlas provides a comprehensive resource for understanding hematopoietic development and early-life origins of hematologic disease.