The expression order determines the pioneer functions of Ngn3 and NeuroD1 in pancreatic endocrine differentiation
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PROVIDER: PRJNA1129023 | ENA |
REPOSITORIES: ENA
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Project description:This study investigates the roles of Ngn3 and NeuroD1 in pancreatic endocrine differentiation. Using a new mouse model, we mapped NGN3 binding sites by CUT&RUN and demonstrated its pioneering role in making chromatin accessible by scATAC-seq. According to conditional knock-out and over-expression experiments and scRNA-seq, we domonstrated that NGN3's pioneering function was dose tolerance, with low doses sufficing, while NeuroD1, as a conventional TF, has no significant pioneer effects under normal phenomena. But when NGN3 was absent, NeuroD1 can alternatively acted as a pioneer factor, and sequential expression of NeuroD1 ahead of Ngn3 predominantly drives α-cell generation.
2025-02-15 | GSE270915 | GEO
Project description:This study investigates the roles of Ngn3 and NeuroD1 in pancreatic endocrine differentiation. Using a new mouse model, we mapped NGN3 binding sites by CUT&RUN and demonstrated its pioneering role in making chromatin accessible by scATAC-seq. According to conditional knock-out and over-expression experiments and scRNA-seq, we domonstrated that NGN3's pioneering function was dose tolerance, with low doses sufficing, while NeuroD1, as a conventional TF, has no significant pioneer effects under normal phenomena. But when NGN3 was absent, NeuroD1 can alternatively acted as a pioneer factor, and sequential expression of NeuroD1 ahead of Ngn3 predominantly drives α-cell generation.
2025-02-15 | GSE271546 | GEO
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:This experiment used RNA-Seq technology to explore gene expression in mouse Ngn3^GFP/+ [het] FACS sorted pancreatic cells at E15.5 (commited endocrine progenitor cells) and in Ngn3^GFP/GFP [null] at E15.5 (defective endocrine progenitor cells). This experiment is designed to understand the gene expression alteration in the endocrine lineage at different embryonic days. The aim is to understand both Ngn3 dependent and independent gene expression profiles so as to reveal the instructive signals that specfy the collective endocrine islet cell fate or specific islet cell type.
2015-10-01 | E-MTAB-3352 | biostudies-arrayexpress
Project description:The basic helix-loop-helix transcription factor Neurogenin3 (Ngn3/Neurog3) is expressed in endocrine progenitor cells in the embryonic mouse pancreas. Ngn3 controls endocrine cell fate decisions. Ngn3 deficient mice do not develop any pancreatic endocrine cells, including insulin producing beta cells, and die postnatally from diabetes. Therefore, the characterization of gene expression in Ngn3-expressing cells and their progeny is of particular interest for the development of novel strategies for cell replacement therapies in type-1 diabetes. Here we describe two studies. In the first study (8 assays) we used mice where the EYFP (Enhanced Yellow fluorescent Protein) is expressed under the control of Ngn3 regulatory elements (knock add on strategy). EYFP-positive, Ngn3-expressing cells, were FACS sorted from embryonic pancreas at day 15.5 (E15.5), as well as EYFP-negative cells. In the second study (6 assays) we compared wild-type and Ngn3 mutant pancreas at E15.5. All samples were hybridized to Affymetrix GeneChip Mouse Genome 430.2.0 array.
2009-12-03 | E-CBIL-48 | biostudies-arrayexpress
Project description:NGN3 is a transcription factor whose transient expression during pancreatic development is vital for the generation of endocrine pancreatic cells, including beta cells. NGN3 stabilisation has been shown to induce exocrine-to-endocrine cell plasticity in the murine pancreas, making it a viable target for therapies aiming to replenish beta cells after immune-mediated destruction in type 1 diabetes patients. Here, we set out to identify new interactors of NGN3 that could play a role in its post-translational regulation. We transfected HEK293A cells with HA-tagged NGN3 and carried out immunoprecipitation of the HA-tag, followed by analysis of co-immunoprecipitated interactors via LC-MS/MS.
2023-03-27 | PXD033691 | Pride
Project description:Expression of the proendocrine gene neurogenin 3 (Ngn3) is required for the development of pancreatic islets. In order to better characterize the molecular events regulated by Ngn3 during development, we have determined the expression profile of differentiating murine embryonic stem cells (mESCs) uniformly induced to overexpress Ngn3. An ESC line was created that allows for the induction of Ngn3 by adding doxycycline (Dox) to the culture medium. Genome-wide microarray analysis was performed to identify genes regulated by Ngn3 in a variety of both undifferentiated and differentiated conditions. Characterization of pancreatic developmental markers during embryoid body (EB) formation revealed an optimum context for Ngn3 induction. Neuroendocrine genes including neurogenic differentiation 1 (NeuroD1) and single minded 1 (Sim1) were found to be significantly upregulated. Genes regulated by Ngn3 independent of the context were analyzed using systematic gene ontology tools and revealed Notch signaling as the most significantly regulated signaling pathway (p=0.009). This result is consistent with the hypothesis that Ngn3 expression makes the cell competent for Notch signaling to be activated and conversely, more sensitive to Notch signaling inhibition. Indeed, EBs induced to express Ngn3 were significantly more sensitive to gamma-secretase inhibitor-mediated Notch signaling inhibition (p<0.0001). Moreover, we find that Ngn3 induction in differentiating ESCs results in significant increases in insulin, glucagon, and somatostatin transcription. Keywords: Ngn3 induction, embryonic stem cell differentiation
2006-07-01 | GSE3653 | 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: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