ISX-9 manipulates endocrine progenitor fate revealing conserved intestinal lineages in mouse and human
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ABSTRACT:
PROVIDER: PRJNA599344 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10841766_1.fastq.gz | Fastqsanger.gz | |||
| SRR10841766_2.fastq.gz | Fastqsanger.gz | |||
| SRR10841767_1.fastq.gz | Fastqsanger.gz | |||
| SRR10841767_2.fastq.gz | Fastqsanger.gz | |||
| SRR10841768_1.fastq.gz | Fastqsanger.gz |
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Project description:Objective: Enteroendocrine cells (EECs) survey the gut luminal environment and co-ordinate hormonal, immune and neuronal responses to it. They exhibit well characterized physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in human gut. The small molecule Isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation. Methods: We investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real time quantitative PCR, fluorescent activated cell sorting, immunostaining and single cell RNA sequencing. Results: ISX-9 increased the number of neurogenin3 (Ngn3) positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors which play roles in mouse EEC specification. Single cell analysis revealed induction of Pax4 expression in a developmentally late Ngn3+ population of cells and potentiation of genes associated with progenitors biased towards serotonin-producing enterochromaffin (EC) cells. This coincided with enrichment of organoids with functional EC cells which was partly dependent on stimulation of calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 overexpression, in ileal organoids, uncovered its importance as a component of early human endocrine specification and highlighted the potential existence of two major endocrine lineages, the early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains classical gut hormone cell types. Conclusion: Our data provide proof-of-concept for the controlled manipulation of specific endocrine lineages with small molecules, whilst also shedding new light on human EEC differentiation and its similarity to mouse. Given their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications.
2020-01-08 | GSE143221 | GEO
Project description:OBJECTIVE:Enteroendocrine cells (EECs) survey the gut luminal environment and coordinate hormonal, immune and neuronal responses to it. They exhibit well-characterised physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in the human gut. The small molecule isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation. METHODS:We investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real-time quantitative polymerase chain reaction (RT-qPCR), fluorescent-activated cell sorting, immunostaining and single-cell RNA sequencing. RESULTS:ISX-9 increased the number of neurogenin3-RFP (Ngn3)-positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors that play roles in mouse EEC specification. Single-cell analysis showed induction of Pax4 expression in a developmentally late Ngn3+ population of cells and potentiation of genes associated with progenitors biased toward serotonin-producing enterochromaffin (EC) cells. Further, we observed enrichment of organoids with functional EC cells that was partly dependent on stimulation of calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 overexpression, in ileal organoids, uncovered its importance as a component of early human endocrine specification and highlighted the potential existence of two major endocrine lineages, the early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains classical gut hormone cell types. CONCLUSION:Our data provide proof-of-concept for the controlled manipulation of specific endocrine lineages with small molecules, whilst also shedding new light on human EEC differentiation and its similarity to the mouse. Given their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications.
| S-EPMC7036449 | biostudies-literature
Project description:We investigated the cell identity and cell proportion in the intestinal organoids treated by Isoxazole-9 (Isx-9) using single-cell transcriptome analysis. Isx-9 enriches enteroendocrine cells without altering the cell identity of other lineages. To investigate the mechanism of this process, we performed RNA-seq and ATAC-seq of Isx-9 treated intestinal stem cells. Based on the gene expression pattern and differential peaks of open chromatin, we found that Isx-9 upregulated neuroendocrine related genes, and elevated the chromatin accessibility at the promoter region of enteroendocrine related transcription factors.
2023-09-05 | GSE183476 | GEO
Project description:The pancreatic islet contains multiple hormone+ endocrine lineages (alpha, beta, delta, PP and epsilon cells), but the developmental processes that underlie endocrinogenesis are poorly understood. Here, we generated novel mouse lines and combined them with various genetic tools to enrich all types of hormone+ cells for well-based deep single-cell RNA sequencing (scRNA-seq), and gene coexpression networks were extracted from the generated data for the optimization of high-throughput droplet-based scRNA-seq analyses. These analyses defined an entire endocrinogenesis pathway in which different states of endocrine progenitor (EP) cells sequentially differentiate into specific endocrine lineages in mice. Subpopulations of the EP cells at the final stage (EP4-early and EP4-late) show different potentials for distinct endocrine lineages. epsilon cells and an intermediate cell population were identified as distinct progenitors that independently generate both alpha and PP cells. Single-cell analyses were also performed to delineate the human pancreatic endocrinogenesis process. Although the developmental trajectory of pancreatic lineages is generally conserved between humans and mice, clear interspecies differences, including differences in the proportions of cell types and the regulatory networks associated with the differentiation of specific lineages, have been detected. Our findings support a model in which sequential transient progenitor cell states determine the differentiation of multiple cell lineages and provide a blueprint for directing the generation of pancreatic islets in vitro.
2021-04-20 | GSE139627 | GEO
Project description:We developed a strategy to generate cardiac progenitor cells from human induced pluripotent stem cells using a novel small molecule. mRNA-sequencing results showed different gene expression profile among undifferentiated human induced pluripotent stem cells(hiPSCs), DMSO and ISX-9 treated hiPSCs.In comparsion with DMSO treated cells or undifferentiated hiPSCs, ISX-9 upregulated the genes related to WNT and cytoskeleton remodeling and TGF-β signaling, which are involved in heart development and cardiac differentiation. In addition, the genes related to cardiac differentiation signaling pathways were upregulated by ISX-9 including development of PIP3 signaling in cardiomyocyte myocytes, muscle contraction and NF-AT hypertrophy signaling.
2017-12-30 | GSE95389 | GEO
Project description:We developed a strategy to generate cardiac progenitor cells from human induced pluripotent stem cells using a novel small molecule.miRNA-sequencing results showed different miRNA expression profile among undifferentiated human induced pluripotent stem cells(hiPSCs), DMSO and ISX-9 treated hiPSCs.In comparsion with DMSO treated cells, ISX-9 upregulated several myogenic miRNAs and cardiac hypertrophy related-miRNAs including miR-335, miR-21, miR-30c,miRNA-181a and miR-214.
2017-12-30 | GSE95390 | GEO
Project description:MCF7 cells were treated with ISX, a novel GLI1 inducing HDAC-inhibitor
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Project description:IMR32 neuroblastoma cells were treated with ISX, a novel GLI1 inducing HDAC-inhibitor
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Project description:IMR32 cells were treated with DMSO/ISX and open chromatin regions were assessed via ATACseq
2023-01-17 | E-MTAB-11633 | biostudies-arrayexpress
Project description:IMR32 cells were treated with DMSO/ISX and Histone code and MycN binding was assessed via ChIPseq.
2023-01-17 | E-MTAB-12344 | biostudies-arrayexpress