Single cell transcriptomic and spatial landscapes of the developing human pancreas
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ABSTRACT:
PROVIDER: PRJNA808751 | ENA |
REPOSITORIES: ENA
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Project description:The progress made in directed differentiation of stem cells has shown that understanding human pancreas development can provide cues for generating unlimited amounts of insulin-producing beta cells for transplantation therapy in diabetes. However, current differentiation protocols have not been successful in reproducibly generating functional human beta cells in vitro, partly due to incomplete understanding of human pancreas development. Here, we present detailed transcriptomic analysis of the various cell types of the developing human pancreas, including their spatial gene patterns. We integrated single cell RNA sequencing with spatial transcriptomics at multiple developmental timepoints and revealed distinct temporal-spatial gene cascades in the developing human pancreas.
2022-12-21 | GSE197317 | GEO
Project description:The progress made in directed differentiation of stem cells has shown that understanding human pancreas development can provide cues for generating unlimited amounts of insulin-producing beta cells for transplantation therapy in diabetes. However, current differentiation protocols have not been successful in reproducibly generating functional human beta cells in vitro, partly due to incomplete understanding of human pancreas development. Here, we present detailed transcriptomic analysis of the various cell types of the developing human pancreas, including their spatial gene patterns. We integrated single cell RNA sequencing with spatial transcriptomics at multiple developmental timepoints and revealed distinct temporal-spatial gene cascades in the developing human pancreas.
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Project description:Single cell transcriptomic and spatial landscapes of the developing human pancreas - spatial transcriptomics
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Project description:Pancreatic and duodenal homeobox 1 (PDX1) is crucial for pancreas organogenesis, yet the dynamic changes in PDX1 binding in human or mouse developing pancreas have not been examined. To address this knowledge gap, we performed PDX1 ChIP-seq and single-cell RNA-seq using fetal human pancreata. We integrated our datasets with published datasets and revealed the dynamics of PDX1 binding and potential cell-lineage-specific PDX1 bound genes in the pancreas from fetal to adult stages. We identified a core set of developmentally conserved PDX1 bound genes that reveal the broad multifaceted role of PDX1 in pancreas development. Despite the well-known, dramatic changes in PDX1 function and expression, we found that PDX1 bound genes are largely conserved from embryonic to adult stages. This points towards a dual role of PDX1 in regulating the expression of its targets at different ages, dependent on other functionally-congruent or directly-interacting partners. We also showed that PDX1 binding is largely conserved in mouse pancreas. Together, our study reveals PDX1 targets in the developing pancreas in vivo and provides an essential resource for future studies on pancreas development.
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Project description:Methylomic trajectories in the developing human pancreas
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Project description:A number of studies have reported cell heterogeneity within the developing mouse pancreas, as well as the transcriptional profiles corresponding to various cell states. The upstream mechanisms that initiate and maintain gene expression programs across cell states, however, remain largely unknown. Here, we applied single-nucleus ATAC-Seq to developing mouse pancreas to generate an atlas of chromatin accessibility, at single-cell resolution. Our goals were first, to generate an atlas of chromatin accessibility of embryonic mouse pancreas, at single-cell resolution, that can serve as a resource for the field. We aimed to provide such a resource not only for epithelial cells within the pancreas, but for non-epithelial (e.g., mesenchymal) as well. Our second goal was to identify gene regulatory networks governing cell fate transitions through integration of single-cell chromatin accessibility and gene expression data.
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Project description:Understanding the spatial distribution of gene expression in the pancreas could provide new insights into its function and islet biology. Visium spatial gene expression is a powerful tool for quantifying gene expression of cells within their spatial context. We describe the generation and analysis of spatial transcriptomics data from six pancreas samples from healthy donors. Our analysis revealed high expression of INS within islets. However, we also identified a bleed of highly abundant islet genes (e.g., INS, GCG) into surrounding tissue areas. Through computational analyses, we successfully corrected for this bleed. We then identify genes which are spatially differentially expressed in the Type 2 Diabetes samples. We provide these data for researchers to study the organization of the pancreas and islets.
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Project description:Epigenetic processes such as DNA methylation play a key role in regulating tissue-specific and temporally-appropriate patterns of gene expression during development. Our knowledge about temporal changes to the epigenome in the developing human pancreas is limited. In this study we quantified levels of DNA methylation at over 800,000 sites in 112 human fetal pancreatic samples (51 male and 61 female) spanning from 6 to 21 post conception weeks (pcw). We found dramatic changes in DNA methylation across human pancreas development, with >22% of all methylation sites displaying significant changes across developmental age, with the majority of these sites showing stable levels of DNA methylation in the mature pancreas. Sites associated with developmental changes in DNA methylation during fetal pancreas development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across pancreas development. Weighted gene correlation network analysis (WGCNA) revealed modules of co-methylated loci associated with developmental age were enriched for genes involved in maturity onset diabetes of the young (MODY) and other metabolic phenotypes. A comparison with developmentally-dynamic patterns of DNA methylation in the developing human brain revealed significant tissue specific differences between the fetal pancreas and the fetal brain. Our data confirms the prenatal period to be a time of dynamic epigenetic changes. To our knowledge, this is the most extensive study of DNA methylation patterns in human fetal pancreatic development.
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Project description:Spatial localization is a key determinant of cellular fate and behavior, but spatial RNA assays traditionally rely on staining for a limited number of RNA species. In contrast, single-cell RNA-seq allows for deep profiling of cellular gene expression, but established methods separate cells from their native spatial context. Here we present Seurat, a computational strategy to infer cellular localization by integrating single-cell RNA-seq data with in situ RNA patterns. We applied Seurat to spatially map 851 single cells from dissociated zebrafish (Danio rerio) embryos, inferring a transcriptome-wide map of spatial patterning. We confirmed Seurat’s accuracy using several experimental approaches, and used it to identify a set of archetypal expression patterns and spatial markers. Additionally, Seurat correctly localizes rare subpopulations, accurately mapping both spatially restricted and scattered groups. Seurat will be applicable to mapping cellular localization within complex patterned tissues in diverse systems. We generated single-cell RNA-seq profiles from dissociated cells from developing zebrafish embryos (late blastula stage - 50% epiboly)
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Project description:A PDX1 cistrome and single-cell transcriptome resource of the developing pancreas
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