PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dataset 2]
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PROVIDER: PRJNA839336 | ENA |
REPOSITORIES: ENA
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Project description:Diabetes is a major chronic disease with an excessive healthcare burden on society. A coding variant (p.Arg192His) in the transcription factor PAX4 is uniquely and reproducibly associated with altered risk for type 2 diabetes (T2D) in East Asian populations, whilst rare PAX4 alleles have been proposed to cause monogenic diabetes8. In mice, Pax4 is essential for beta cell formation but neither the role of diabetes-associated variants in PAX4 nor PAX4 itself on human beta cell development and/or function are known. Here, we demonstrate that non-diabetic carriers of either the PAX4 p.Arg192His or a newly identified p.Tyr186X allele exhibit decreased pancreatic beta cell function. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content and altered hormone gene expression. Deletion of PAX4 in isogenic human induced pluripotent stem cell (hiPSC)-derived beta-like cells resulted in de-repression of alpha cell gene expression whilst in vitro differentiation of hiPSCs from carriers of PAX4 p.192His and p.186X alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content. In silico and in vitro studies showed that these PAX4 alleles cause either reduced PAX4 expression or function. Correction of the diabetes-associated PAX4 alleles reversed these phenotypic changes. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function and its contribution to type 2 diabetes risk.
2023-08-05 | GSE203264 | GEO
Project description:Diabetes is a major chronic disease with an excessive healthcare burden on society. A coding variant (p.Arg192His) in the transcription factor PAX4 is uniquely and reproducibly associated with altered risk for type 2 diabetes (T2D) in East Asian populations, whilst rare PAX4 alleles have been proposed to cause monogenic diabetes8. In mice, Pax4 is essential for beta cell formation but neither the role of diabetes-associated variants in PAX4 nor PAX4 itself on human beta cell development and/or function are known. Here, we demonstrate that non-diabetic carriers of either the PAX4 p.Arg192His or a newly identified p.Tyr186X allele exhibit decreased pancreatic beta cell function. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content and altered hormone gene expression. Deletion of PAX4 in isogenic human induced pluripotent stem cell (hiPSC)-derived beta-like cells resulted in de-repression of alpha cell gene expression whilst in vitro differentiation of hiPSCs from carriers of PAX4 p.192His and p.186X alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content. In silico and in vitro studies showed that these PAX4 alleles cause either reduced PAX4 expression or function. Correction of the diabetes-associated PAX4 alleles reversed these phenotypic changes. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function and its contribution to type 2 diabetes risk.
2023-08-05 | GSE202206 | GEO
Project description:PAX4 loss of function alters human endocrine cell development and influences diabetes risk.
| PRJNA839330 | ENA
Project description:PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dateset 1]
| PRJNA835054 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-08-05 | GSE203265 | GEO
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:Validation dataset of 298 ER-positive patients treated with tamoxifen for 5 years. All patients in this dataset have ER+ breast cancer and were uniformly treated with tamoxifen for 5 years. The objective of the study was to correlate levels of genomic markers to outcomes (relapse free survival) in this cohort of uniformly treated patients.
2010-08-13 | GSE17705 | GEO
Project description:Validation dataset of 298 ER-positive patients treated with tamoxifen for 5 years. All patients in this dataset have ER+ breast cancer and were uniformly treated with tamoxifen for 5 years. The objective of the study was to correlate levels of genomic markers to outcomes (relapse free survival) in this cohort of uniformly treated patients. Tissue samples were processed and profiled by two different labs (MD Anderson Cancer Center and Jules Bordet Institute).
2010-08-13 | E-GEOD-17705 | biostudies-arrayexpress
Project description:Strategies to enhance islet b-cell survival and regeneration while refraining inflammation through manipulation of molecular targets would provide means to stably replenish the deteriorating functional b-cell mass detected in both Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM). Herein we report that over expression of the islet enriched transcription factor Pax4 refrains development of hyperglycemia in the RIP-B7.1 mouse model of T1DM through reduced insulitis, decreased b-cell apoptosis correlating with diminished DNA damage and increased proliferation. Transcriptomics revealed up regulation of genes involved in immunomodulation, cell cycle and ER homeostasis in islets over expressing Pax4 as compared to the T2DM-linked mutant variant Pax4R129W. Pax4 but not Pax4R129W protected islets from thapsigargin-mediated ER-stress apoptosis. Collectively, Pax4 is a critical signaling hub coordinating regulation of distinct molecular pathways resulting in improved b-cell fitness whereas Pax4R129W sensitizes to death under stress. More importantly we highlight potential common pharmacological targets for the treatment of DM. 4 groups of 3 samples each. Primary isolated islets of langerhans from either Pax4/rtTA or Pax4R121W/rtTA mice treated or not with Doxicycline.
2016-07-03 | E-GEOD-62846 | biostudies-arrayexpress
Project description:Stop Codon Context Influences Genome-Wide Stimulation of Termination Codon Readthrough by Aminoglycosides [Dataset 3]
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