Pdx1 overexpression sensitizes to IL-1b-induced apoptosis
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE40642 | GEO | 2012/09/20
SECONDARY ACCESSION(S): PRJNA174461
REPOSITORIES: GEO
Similar Datasets
Project description:Cytokines have been shown to play a key role in the destruction of beta cells. In the rat insulinoma cell line (INS-1ab) overexpressing pancreatic duodenum homeobox 1 (Pdx1) increases sensitivity to Interleukin 1b (IL-1b). To elucidate mechanisms of action underlying Pdx1 driven potentiation of beta-cell sensitivity to IL-1β, we performed a microarray analysis of INS-1ab cells with and without Pdx1 overexpression exposed to IL-1β between 2h and 24h. INS-1ab cells were cultured with or without 500 ng/ml doxycycline (+/- DOX). After 24 h, 40 ng/ml IL-1b was either added or not (+/- IL-1b). Cells were harvested either 2h, 4h, 6h, 12h or 24h after addition of IL-1b. Four biological replicates for each of the eight groups.
2012-09-20 | E-GEOD-40642 | biostudies-arrayexpress
Project description:In order to identify genes that are regulated by Pdx1, MIN6 insulinoma cells were transduced with adenovirus expressing a short hairpin RNA directed against murine Pdx1 (AdshPdx1) or luciferase (AdshLuc) or not transduced at all (untreated). RNA was harvested and reverse transcribed. Reduced expression of Pdx1 and established Pdx1 targets was confirmed. The RNA was then submitted for labeling and hybridization to the PancChip cDNA microarray.
2010-01-01 | E-MTAB-132 | biostudies-arrayexpress
Project description:Constitutive Kras and NF-kappaB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms of constitutive NF-kappaB activation in KrasG12D-induced PDAC are not yet understood. Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kappaB activation and completely suppressed PDAC development in KrasG12D and KrasG12D;Ink4a/Arf mutant mice, demonstrating a genetic link between IKK2/beta and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1alpha, which in turn activates NF-kappaB and its target genes IL-1alpha and p62, to initiate IL-1alpha/p62 feedforward loops for inducing and sustaining NF-kappaB activity. Furthermore, IL-1alpha overexpression correlates with Kras mutation, constitutive NF-kappaB activity, and poor survival in PDAC patients. Therefore, our findings establish a pathway linking duel feedforward loops of IL-1alpha/p62 through which IKK2/beta/NF-kappaB is activated by KrasG12D. To study Kras-induced inflammatory responses and to identify differentially expressed genes between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice, cDNA microarray analysis was performed.
2012-01-24 | E-GEOD-27478 | biostudies-arrayexpress
Project description:The aim of this experiment was to use highthroughput chromatin immunoprecipitation followed by hybridization to promoter microarrays to obtain a comprehensive list of sites in the genome that are physically occupied by Pdx1. Chromatin was prepared from Min6 insulinoma cells and immunoprecipitated with Pdx1 or control antiserum. The precipitated chromatin was then purified, amplified and directly sequenced using Illumina technology.
2009-12-02 | E-MTAB-134 | biostudies-arrayexpress
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-10-30 | GSE246507 | GEO
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-04-03 | GSE214674 | GEO
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-04-03 | GSE214676 | GEO
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-04-03 | GSE214675 | GEO
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-10-27 | GSE246297 | GEO
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-04-03 | GSE214677 | GEO