NEUROD1 dependent gene regulation in murine pancreatic endocrine cells and human stem cell derived insulin producing cells
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ABSTRACT:
PROVIDER: PRJNA507422 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8247830.fastq.gz | Fastqsanger.gz | |||
| SRR8247840.fastq.gz | Fastqsanger.gz | |||
| SRR8247831.fastq.gz | Fastqsanger.gz | |||
| SRR8247841.fastq.gz | Fastqsanger.gz | |||
| SRR8247832.fastq.gz | Fastqsanger.gz |
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Project description:NEUROD1 is a transcription factor that helps maintain a mature phenotype of pancreatic β cells. Disruption of Neurod1 during pancreatic development causes severe neonatal diabetes; however, the exact role of NEUROD1 in the differentiation programs of endocrine cells is unknown. Here, we report a crucial role of the NEUROD1 regulatory network in endocrine lineage commitment and differentiation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that Neurod1 inactivation triggers a downregulation of endocrine differentiation transcription factors and upregulation of non-endocrine genes within the Neurod1-deficient endocrine cell population, disturbing endocrine identity acquisition. Neurod1 deficiency altered the H3K27me3 histone modification pattern in promoter regions of differentially expressed genes, which resulted in gene regulatory network changes in the differentiation pathway of endocrine cells, compromising endocrine cell potential, differentiation, and functional properties.
2023-08-17 | GSE236559 | GEO
Project description:The purpose of this study was to identify genes regulated by Neurod1 during murine pancreatic endocrine cell differentiation.
2018-11-28 | GSE122992 | GEO
Project description:The purpose of this study was to identify genes regulated by NEUROD1 in insulin expressing cells differentiated from human embryonic stem cells.
2018-11-28 | GSE122991 | GEO
Project description:While diabetes incidence is gradually rising worldwide, novel therapeutical approaches are required in the search for a replacement of dysfunctional endocrine tissue, especially beta-cells. A promising potential lies in direct cellular reprogramming of similar cell types sharing common multipotent progenitors. With the knowledge of molecular mechanisms determining the endocrine cell fate commitment and endocrine lineage differentiation, other endocrine cells contained within the islets of Langerhans or closely related cells could be trans- or dedifferentiated either in situ or in vitro with their subsequent transplantation into the patient. NEUROD1 is a transcription factor situated on the base of the gene regulatory network of the developing endocrine precursors, directly downstream of endocrine lineage master regulator NEUROG3. While NEUROG3 initiates a rapid cascade of chromatin reorganization in numerous bivalent promoters resulting in spatiotemporal gene expression leading to differentiation of all endocrine cell subtypes from pancreatic multipotent progenitors, the role of NEUROD1 has yet to be clarified. Notably, NEUROD1 can induce neuronal program through pioneering and chromatin remodelling in other cell types. In this study, we performed advanced molecular and phenotypic analyses in early endocrine-specific Neurod1-deficient mouse model, including RNA and CUT&Tag sequencing and lightsheet microscopy, to gain insight into the NEUROD1-regulated transcription network driving endocrine lineage cell fate commitment. Besides a postnatal diabetic phenotype, disrupted endocrine differentiation and associated altered islet architecture, we observed an apparent elevation in the non-endocrine gene expression pattern and uncovered alterations in the epigenetic landscape of characteristic genes, specifically in the H3K4me3 and H3K27me3 distribution. Therefore, we provide evidence that NEUROD1 is critical player responsible for the establishment of the endocrine cell identity, which further affects endocrine development and may serve as a potent proendocrine reprogramming driver.
2023-08-17 | GSE212083 | GEO
Project description:While diabetes incidence is gradually rising worldwide, novel therapeutical approaches are required in the search for a replacement of dysfunctional endocrine tissue, especially beta-cells. A promising potential lies in direct cellular reprogramming of similar cell types sharing common multipotent progenitors. With the knowledge of molecular mechanisms determining the endocrine cell fate commitment and endocrine lineage differentiation, other endocrine cells contained within the islets of Langerhans or closely related cells could be trans- or dedifferentiated either in situ or in vitro with their subsequent transplantation into the patient. NEUROD1 is a transcription factor situated on the base of the gene regulatory network of the developing endocrine precursors, directly downstream of endocrine lineage master regulator NEUROG3. While NEUROG3 initiates a rapid cascade of chromatin reorganization in numerous bivalent promoters resulting in spatiotemporal gene expression leading to differentiation of all endocrine cell subtypes from pancreatic multipotent progenitors, the role of NEUROD1 has yet to be clarified. Notably, NEUROD1 can induce neuronal program through pioneering and chromatin remodelling in other cell types. In this study, we performed advanced molecular and phenotypic analyses in early endocrine-specific Neurod1-deficient mouse model, including RNA and CUT&Tag sequencing and lightsheet microscopy, to gain insight into the NEUROD1-regulated transcription network driving endocrine lineage cell fate commitment. Besides a postnatal diabetic phenotype, disrupted endocrine differentiation and associated altered islet architecture, we observed an apparent elevation in the non-endocrine gene expression pattern and uncovered alterations in the epigenetic landscape of characteristic genes, specifically in the H3K4me3 and H3K27me3 distribution. Therefore, we provide evidence that NEUROD1 is critical player responsible for the establishment of the endocrine cell identity, which further affects endocrine development and may serve as a potent proendocrine reprogramming driver.
2023-08-17 | GSE212082 | GEO
Project description:Rna-seq transcriptome data for Neurod1-homozygous null and Neurod1-heterozygous null murine E17 pancreatic endocrine cells
| PRJNA507176 | ENA
Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
2022-01-29 | GSE163947 | GEO
Project description:We aimed to assess whether Wnt-modulation could contribute to mature hiPSC-derived insulin-producing cells in vitro. Building our hypothesis on our previous findings of Wnt activation in immature hiPSC-derived insulin-producing cells compared to adult human islets and with recent data reporting a link between Wnt/PCP and in vitro beta-cell maturation. In this study we stimulated hiPSC-derived insulin-producing cells with syntetic proteins including WNT3A, WNT4, WNT5A and WNT5B as well as inhibiting endogeneous Wnt signaling with Tankyrase inhibitor G007-LK.
2019-11-13 | PXD012081 | Pride
Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
2022-01-29 | GSE178726 | GEO
Project description:Objective: The developmental effects of mutations in genes associated with monogenic diabetes on human pancreas development is not well understood. More specifically, if insulin gene recessive mutations influence the human endocrine lineage segregation still needs to be investigated. Methods: We generated a novel knock-in H2B-Cherry reporter human induced pluripotent stem cell (iPSCs) line expressing no insulin upon differentiation to stem cell-derived (SC-) β cells in vitro. This cell line enabled us to have a model mimicking the extremely reduced insulin levels in patients with recessive insulin mutations. We combined immunostaining, Western blotting and proteomics analysis to characterize the SC-islets from this iPSC line. Furthermore, we leveraged FACS analysis and imaging to explore the impact of insulin shortage on human endocrine cell induction, composition and proliferation. Results: We found that lack of insulin hampers insulin receptor (IR) signaling in SC-islets but increases the IR sensitivity. Furthermore, insulin deficiency showed no effects on human endocrine lineage induction. However, lack of insulin skewed the SC-islet cell composition. We found an increased in SC-β cell number at the expense of SC-α cell differentiation in the absence of insulin. Finally, insulin shortage reduced the rate of SC-β cell proliferation but had no impact of the expansion of SC-α cells. Conclusions: We provided evidence of the developmental impacts of reduced insulin levels on human β cell characteristics and endocrine lineage formation. These findings help to better understand the pathomechanisms of recessive insulin mutations during embryonic development and also shed some lights on the possible physiological function of this hormone coordinating human islet cell composition and architecture during endocrinogenesis.
2024-01-17 | PXD045366 | Pride