Single cell RNA-seq and ATAC-seq of human fetal forebrain tissue DAC
Ontology highlight
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PROVIDER: EGAC00001002599 | EGA |
REPOSITORIES: EGA
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Project description:Prioritizing disease-critical cell types by integrating genome-wide association studies (GWAS) with functional data is a fundamental goal. Single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) have characterized cell types at high resolution, and studies integrating GWAS with scRNA-seq have shown promise, but studies integrating GWAS with scATAC-seq have been limited. Here, we identify disease-critical fetal and adult brain cell types by integrating GWAS summary statistics from 28 brain-related diseases/traits (average N = 298 K) with 3.2 million scATAC-seq and scRNA-seq profiles from 83 cell types. We identified disease-critical fetal (respectively adult) brain cell types for 22 (respectively 23) of 28 traits using scATAC-seq, and for 8 (respectively 17) of 28 traits using scRNA-seq. Significant scATAC-seq enrichments included fetal photoreceptor cells for major depressive disorder, fetal ganglion cells for BMI, fetal astrocytes for ADHD, and adult VGLUT2 excitatory neurons for schizophrenia. Our findings improve our understanding of brain-related diseases/traits and inform future analyses.
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Project description:Single cell RNA sequencing of human thymic cells is dependent on isolation of highly pure and viable cell populations. This protocol describes the isolation of CD34+ progenitor and more differentiated CD34- fractions from post-natal thymic tissue to study thymopoiesis. CD34+ cells represent <1% of thymic cells, so this protocol uses magnetic- followed by fluorescence-activated cell separation to isolate highly enriched CD34+ cells. For complete details on the use and execution of this protocol, please refer to Le et al. (2020).
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Project description:PurposeCorneal epithelial homeostasis is maintained by coordinated gene expression across distinct cell populations, but the gene regulatory programs underlying this cellular diversity remain to be characterized. Here we applied single-cell multi-omics analysis to delineate the gene regulatory profile of mouse corneal epithelial cells under normal homeostasis.MethodsSingle cells isolated from the cornea epithelium (with marginal conjunctiva) of adult mice were subjected to scRNA-seq and scATAC-seq using the 10×Genomics platform. Cell types were clustered by the graph-based visualization method uniform manifold approximation and projection and unbiased computational informatics analysis. The scRNA-seq and scATAC-seq datasets were integrated following the integration pipeline described in ArchR and Seurat.ResultsWe characterized diverse corneal epithelial cell types based on gene expression signatures and chromatin accessibility. We found that cell type-specific accessibility regions were mainly located at distal regions, suggesting essential roles of distal regulatory elements in determining corneal epithelial cell diversity. Trajectory analyses revealed a continuum of cell state transition and higher coordination between transcription factor (TF) motif accessibility and gene expression during corneal epithelial cell differentiation. By integrating transcriptomic and chromatin accessibility analysis, we identified cell type-specific and shared gene regulation programs. We also uncovered critical TFs driving corneal epithelial cell differentiation, such as nuclear factor I (NFI) family members, Rarg, Elf3. We found that nuclear factor-κB (NF-κB) family members were positive TFs in limbal cells and some superficial cells, but they were involved in regulating distinct biological processes.ConclusionsOur study presents a comprehensive gene regulatory landscape of mouse cornea epithelial cells, and provides valuable foundations for future investigation of corneal epithelial homeostasis in the context of cornea pathologies and regenerative medicine.
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Project description:BackgroundSkeletal muscle development is a multistep process whose understanding is central in a broad range of fields and applications, from the potential medical value to human society, to its economic value associated with improvement of agricultural animals. Skeletal muscle initiates in the somites, with muscle precursor cells generated in the dermomyotome and dermomyotome-derived myotome before muscle differentiation ensues, a developmentally regulated process that is well characterized in model organisms. However, the regulation of skeletal muscle ontogeny during embryonic development remains poorly defined in farm animals, for instance in pig. Here, we profiled gene expression and chromatin accessibility in developing pig somites and myotomes at single-cell resolution.ResultsWe identified myogenic cells and other cell types and constructed a differentiation trajectory of pig skeletal muscle ontogeny. Along this trajectory, the dynamic changes in gene expression and chromatin accessibility coincided with the activities of distinct cell type-specific transcription factors. Some novel genes upregulated along the differentiation trajectory showed higher expression levels in muscular dystrophy mice than that in healthy mice, suggesting their involvement in myogenesis. Integrative analysis of chromatin accessibility, gene expression data, and in vitro experiments identified EGR1 and RHOB as critical regulators of pig embryonic myogenesis.ConclusionsCollectively, our results enhance our understanding of the molecular and cellular dynamics in pig embryonic myogenesis and offer a high-quality resource for the further study of pig skeletal muscle development and human muscle disease.
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Project description:Oligodendrogenesis in the human central nervous system has been mainly observed at the second trimester of gestation, a much later developmental stage compared to mouse. Here we characterize the transcriptomic neural diversity in the human forebrain at post conceptual weeks (PCW) 8 to 10, using single-cell RNA-Seq. We find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level with single-cell ATAC-Seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of fifty key genes using In Situ Sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mouse and human and describe regulatory mechanisms involved in human OPC specification.
| EGAS00001006136 | EGA
Project description: Not available
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Project description:Single-cell multiomics data continues to grow at an unprecedented pace. Although several methods have demonstrated promising results in integrating several data modalities from the same tissue, the complexity and scale of data compositions present in cell atlases still pose a challenge. Here, we present scJoint, a transfer learning method to integrate atlas-scale, heterogeneous collections of scRNA-seq and scATAC-seq data. scJoint leverages information from annotated scRNA-seq data in a semisupervised framework and uses a neural network to simultaneously train labeled and unlabeled data, allowing label transfer and joint visualization in an integrative framework. Using atlas data as well as multimodal datasets generated with ASAP-seq and CITE-seq, we demonstrate that scJoint is computationally efficient and consistently achieves substantially higher cell-type label accuracy than existing methods while providing meaningful joint visualizations. Thus, scJoint overcomes the heterogeneity of different data modalities to enable a more comprehensive understanding of cellular phenotypes.
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Project description:Formation and segregation of cell lineages forming the heart have been studied extensively but the underlying gene regulatory networks and epigenetic changes driving cell fate transitions during early cardiogenesis are still only partially understood. Here, we comprehensively characterize mouse cardiac progenitor cells (CPCs) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing and transposase-accessible chromatin profiling (ATAC-seq). By leveraging on cell-to-cell transcriptome and chromatin accessibility heterogeneity, we identify different previously unknown cardiac subpopulations. Reconstruction of developmental trajectories reveal that multipotent Isl1+ CPC pass through an attractor state before separating into different developmental branches, whereas extended expression of Nkx2-5 commits CPC to an unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states critically depending on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution.
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Project description:Single-cell ATAC-seq detects open chromatin in individual cells. Currently data are sparse, but combining information from many single cells can identify determinants of cell-to-cell chromatin variation.
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Project description:ObjectiveAlthough glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity.MethodsWe sorted human α- and β-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions.ResultsWe identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to α-cells, while CHODL (chondrolectin) immunoreactivity was only present in β-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes.ConclusionsWe have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.
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