Homo sapiens
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PROVIDER: PRJNA253125 | ENA |
REPOSITORIES: ENA
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Project description:PDX1 Binding in human embryonic stem cell derived pancreatic progenitor cells [ChIP-seq]
| PRJNA253175 | ENA
Project description:Objective: Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far. Methods: In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions. Results: ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions included important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B and MEIS1, which were activated during the differentiation process as revealed by the active mono-acetylated chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand for the Notch receptor, DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes. Conclusions: Our data provides stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.
2018-02-27 | GSE106813 | GEO
Project description:The pancreas of vertebrates is separately derived from both the dorsal and ventral endodermal domains. However, the difference between these two programs has been unclear. Here, using a pancreatic determination gene, Pdx1, driven GFP transgenic mouse strain, we identified Pdx1-GFP highly expressing cells (Pdx1high) and Pdx1-GFP lowly expressing cells (Pdx1low) in both embryonic dorsal Pdx1-expressing region (DPR) and ventral Pdx1-expressing region (VPR). We analyzed the transcriptomes of single Pdx1low and Pdx1high cells from the DPR and VPR. In the VPR, Pdx1low cells have an intermediate progenitor identity and can generate hepatoblasts, extrahepatobiliary cells, and Pdx1high pancreatic progenitor cells. In the DPR, Pdx1high cells are directly specified as pancreatic progenitors, whereas Pdx1low cells are precocious endocrine cells. Therefore, our study defines distinct road maps for dorsal and ventral pancreatic progenitor specification. The findings provide guidance for optimization of current β-cell induction protocols by following the in vivo dorsal pancreatic specification program.
2018-07-23 | GSE86225 | GEO
Project description:Identification of genes regulated by IPF1/PDX1 in early pancreatic progenitor cells, analysis of Ipf1/Pdx1 global null mutants e10.5 embryonic pancreatic buds compared to wt
2008-02-12 | E-MEXP-1047 | biostudies-arrayexpress
Project description:Knowledge of the genetic signatures of specific pancreatic cellular populations, both during development and in the adult animal, provides an objective basis for evaluating genetic signatures of cultured human embryonic stem cells (hESCs) and reprogrammed pancreatic mouse cells. Previous transcriptome profiling studies have utilized DNA microarrays, which have well-defined limitations, and few have utilized FACS-purified cell populations. To overcome both of these limitations we utilized a series of mice with fluorescent reporter alleles (Sox17, Pdx1, Ptf1a, Ngn3, Insm1) or transgene (Ins1) to isolate three biological replicates of 12 different pancreatic progenitor or adult cell populations between embryonic day 8.0 and post-natal day 60. These RNAs were then used to make 36 libraries which were sequenced to an average depth of 50 million reads each. After mapping these reads to mouse genome using a standardized analysis pipeline the resulting datasets were analyzed in several ways.
2021-02-19 | E-MTAB-2816 | biostudies-arrayexpress
Project description:Single cell-based studies have revealed tremendous cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degree of plasticity during organogenesis. The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including liver, pancreas, gallbladder, and extra-hepatic bile ducts. Experimental manipulation of various developmental signals in the mouse embryo underscored important cellular plasticity in this embryonic territory. This is also reflected in the existence of human genetic syndromes as well as congenital or environmentally-caused human malformations featuring multiorgan phenotypes in liver, pancreas and gallbladder. Nevertheless, the precise lineage hierarchy and succession of events leading to the segregation of an endoderm progenitor compartment into hepatic, biliary, and pancreatic structures are not yet established. Here, we combine computational modelling approaches with genetic lineage tracing to assess the tissue dynamics accompanying the ontogeny of the hepato-pancreato-biliary organ system. We show that a multipotent progenitor domain persists at the border between liver and pancreas, even after pancreatic fate is specified, contributing to the formation of several organ derivatives, including the liver. Moreover, using single-cell RNA sequencing we define a specialized niche that possibly supports such extended cell fate plasticity.
2021-07-01 | MODEL2105030001 | BioModels
Project description:Whole proteome profiling and quantification was performed on an isogenic Huntington disease (IsoHD) human embryonic stem cell (hESC) allelic panel. The IsoHD hESCs harbour 30, 45, 65 and 81 CAG repeats in the first exon of HTT. Whole proteome quantification was also performed on neural progenitor cells derived from the IsoHD hESC panel.
2019-02-14 | PXD006585 | JPOST Repository
Project description:Analysis of gene expression of Pdx-EGFP1+ pancreatic progenitors before or after co-culture at mRNA level. The hypothesis tested in the study was that the overall gene expression in Pdx1-EGFP+ does not alter after co-culture with endothelial cells. The result supported our hypothesis. Total RNA isolated from Pdx1-EGFP+ progenitors from the Pdx1-EGFP HUES8 cell-derived pancreatic progenitor population before (none) and after co-culture (AKT-HUVEC, MPEC, or BJ) Fig 2d in publication.
2014-12-04 | E-GEOD-63840 | biostudies-arrayexpress
Project description:Metabolism is vital to cellular function and tissue homeostasis during human lung development. In utero, embryonic pluripotent stem cells undergo endodermal differentiation towards a lung progenitor cell fate that can be mimicked in vitro using induced human pluripotent stem cells (hiPSCs) to study genetic mutations. To identify differences between wild type and surfactant protein B (SFTPB)-deficient cell lines during endoderm specification towards lung, we used an untargeted metabolomics approach to evaluate the developmental changes in metabolites. We found that the metabolites most enriched during the differentiation from pluripotent stem cell to lung progenitor cell, regardless of cell line, were sphingomyelins and phosphatidylcholines, two important lipid classes in fetal lung development. The SFTPB mutation had no metabolic impact on early endodermal lung development. The identified metabolite signatures during lung progenitor cell differentiation may be utilized as biomarkers for normal embryonic lung development.
2021-06-29 | ST002055 | MetabolomicsWorkbench