GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in beta cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA417512 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6266350.fastq.gz | Fastqsanger.gz | |||
| SRR6266351.fastq.gz | Fastqsanger.gz | |||
| SRR6266352.fastq.gz | Fastqsanger.gz | |||
| SRR6266353.fastq.gz | Fastqsanger.gz | |||
| SRR6266354.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:We find that GLP-1 signaling-activated PKA directly phosphorylates menin at serine 487 residue, relieving menin mediated suppression of insulin expression in beta cells and islets of diabetic GK rat. Mechanistically, GLP-1-induced PKA activation leads to menin Ser487 phosphorylation, and phosphorylated menin gains increased binding affinity to cytoskeleton proteins such as beta actin and myosin. Sequestration of Ser487 phosphorylated menin from the Ins1 gene promoter leads to reduced binding of menin-associating repressive epigenetic regulators such as SUV39H1 and HDAC1 at the locus, resulting in increased Ins1 transcription. Our results have linked GLP-1 signaling to physiologically suppression of menin function in repressing insulin expression, and uncovered a potential step to modulate menin phosphorylation to improve T2D therapy.
2019-02-13 | GSE106653 | GEO
Project description:Pancreatic β-cells have the key homeostatic function of releasing insulin to keep blood glucose in the normal range. It is not fully understood how β-cell mass is determined. Ablation of a nuclear receptor, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), in mouse pancreatic β-cells results in glucose intolerance and 50% fewer β-cells during the postnatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces β-catenin thus upregulating target genes like cyclin D1. Beta-cell expansion triggered by glucagon-like peptide 1 (GLP-1) is known to be mediated by β-catenin controlling cyclin D1. We show that in the absence of COUP-TFII, exendin-4, an agonist of the GLP-1 receptor, does not fully induce cyclin D1 expression, while overexpression of β-catenin induces cyclin D1. A marked decrease in cyclin D1 expression is detected in islets isolated from transgenic mice lacking both GLP-1 receptor and gastric inhibitory peptide receptor. COUP-TFII is therefore required for GLP-1 activation of the β-catenin-dependent pathway in pancreatic β-cells to increase β-cell number. To understand the molecular mechanisms by which COUP-TFII controls β-cell mass, we determined the RNA profile of COUP-TFII knockdown β-cells using Affymetrix oligonucleotide microarrays. Computational analysis identified clusters of genes shared by different gene regulatory Networks that are up or down regulated namely genes involved in Wnt/β-catenin signaling, insulin signaling and lipid/carbohydrate metabolism. We determined the RNA profile of COUP-TFII knockdown β-cells (832/13 INS-1 cells transfected with COUP-TFII specific siRNA) with respect to control cells (832/13 INS-1 cells transfected with scrambled siRNA) using Affymetrix expression analysis technical manual 701025Rev.5 (Affymetrix, Santa Clara, California, USA). Briefly, 1 mg of total cellular mRNA was reverse transcribed into cDNA (SuperScript Choice System Invitrogen, Carlsbad, CA) using oligo-dT primers and a T7 RNA polymerase promoter site. The cDNA was in vitro transcribed and biotin-labeled for microarray analysis using the Affymetrix IVT labeling kit. The concentration of labelled cRNA was measured using a NanoDrop ND-1000 spectrophotometer. Labeled cRNA was fragmented in a fragmentation buffer for 35 min at 94°C. The quality of labeled and fragmented cRNA was analyzed using the Agilent bioanalyzer 2100 (Van Lommel et al, 2006). Fragmented cRNA was hybridized to the rat 230 2.0 array (Affymetrix) during 16h at 45°C. Arrays were washed and stained in a fluidics station (Affymetrix) and scanned using the Affymetrix 3000 GeneScanner.
2011-10-06 | E-GEOD-30526 | biostudies-arrayexpress
Project description:Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances alpha-cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which alpha-cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increases alpha-cell GLP-1 expression in a beta cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide is translationally relevant in human islets through application of a new scRNA-sequencing technology, DART-seq. We find that the effect of liraglutide to increase alpha-cell PC1/3 mRNA expression occurs in a sub-cluster of alpha-cells and is associated with increased expression of other beta-cell-like genes, which we confirm by IHC. Finally, we find that the effect of liraglutide to increase bi-hormonal insulin+ glucagon+ cells is mediated by the beta-cell GLP-1R in mice. Together, our data validate a new high-sensitivity method for scRNA-sequencing in human islets and identify a novel GLP-1 mediated pathway regulating human alpha-cell function.
2020-12-24 | GSE163744 | GEO
Project description:Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating ? cell function, with menin suppressing, and GLP-1 promoting, ? cell function. However, little is known as to whether or how GLP-1 pathway represses menin function. Here, we show that GLP-1 signaling-activated protein kinase A (PKA) directly phosphorylates menin at the serine 487 residue, relieving menin-mediated suppression of insulin expression and cell proliferation. Mechanistically, Ser487-phosphorylated menin gains increased binding affinity to nuclear actin/myosin IIa proteins and gets sequestrated from the Ins1 promoter. This event leads to reduced binding of repressive epigenetic histone modifiers suppressor variegation 3-9 homologue protein 1 (SUV39H1) and histone deacetylases 1 (HDAC1) at the locus and subsequently increased Ins1 gene transcription. Ser487 phosphorylation of menin also increases expression of proproliferative cyclin D2 and ? cell proliferation. Our results have uncovered a previously unappreciated physiological link in which GLP-1 signaling suppresses menin function through phosphorylation-triggered and actin/myosin cytoskeletal protein-mediated derepression of gene transcription.
| S-EPMC6400573 | biostudies-literature
Project description:We developed an engraftment strategy to examine age-associated human islet cell replication and found that Ex-4, an agonist of GLP-1R, stimulates human β cell proliferation in juvenile, but not adult islets. We showed that this β cell proliferative response to Ex-4 requires Cn/NFAT signaling.
2017-10-18 | GSE100660 | GEO
Project description:ABSTRACT Background: The control of the functional pancreatic b-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how b-cell mass is determined. Methodology/principal findings: Conditional chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-deficient mice were generated and crossed with mice expressing Cre under the control of pancreatic duodenal homeobox 1 (pdx1) gene promoter. Ablation of COUP-TFII in pancreas resulted in glucose intolerance. Beta-cell number was reduced at 1 day and 3 weeks postnatal. Together with a reduced number of insulin-containing cells in the ductal epithelium and normal b-cell proliferation and apoptosis, this suggests decreased b-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured b-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the b-catenin gene and its target genes such as cyclin D1 and axin 2. Moreover, induction of these genes by glucagon-like peptide 1 (GLP-1) via b-catenin was impaired in absence of COUP-TFII. The expression of two other target genes of GLP-1 signaling, GLP-1R and PDX-1 was significantly lower in mutant islets compared to control islets, possibly contributing to reduced b-cell mass. Finally, we demonstrated that COUP-TFII expression was activated by the Wnt signaling-associated transcription factor TCF7L2 (T-cell factor 7-like 2) in human islets and rat b-cells providing a feedback loop. Conclusions/significance: Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases b-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the b-catenin-dependent pathwayand its expression is under the control of TCF7L2.
2011-10-07 | GSE30526 | GEO
Project description:Ets1 suppresses the expression of key TFH genes to block TFH differentiation
| PRJNA434187 | ENA
Project description:To determine the translational status of mRNAs in glp-4 mutant animals, we analyzed total and polysomal RNA levels by tiling arrays A total of 8 samples was analyzed (quadruplicates of glp-4_total and glp-4_polysomal, respectively)
2015-01-08 | E-GEOD-62860 | biostudies-arrayexpress
Project description:Aim: The purpose of this RNAseq study is to gain insight into the effect that Glucagon Like Peptide-1(GLP-1) or BMS-21 (11 amino acid GLP-1 mimetic) has on the transcriptomic profile of an insulin secreting pancreatic beta cell line INS-1 at 1h and 6h. Methods: The mRNA-focussed libraries (constructed using TruSeq RNA Library Prep Kit v2) of GLP-1 or BMS-21 treated INS-1 cells at 1h or 6h were generated by sequencing, in quadruplicate, using an Illumina Hiseq2000. De-multiplexing and FASTQ sequence data was generated using the Illumina CASAVA1.8.2 pipeline. The sequence reads that passed quality filters were analyzed at the transcript level using the following. Alignment using TopHat (2.0.12) + Bowtie (2.2.3.0) to the illumina rat iGenome (build 75 - Rnor_5.0 (GCA_000001895.3)), reads summarised using Subread-feature counts (1.4.6) and differential gene analysis using DESeq2 (1.6.3) within Rstudio (0.98.945). Results: GLP-1 treatment of INS-1 cells induced many transcriptomic changes in gene expression at both 1h and 6h relative to control at 1h and 6h. At 1h following GLP-1 treatment there were 674 genes differentially expressed (470 up-regulated and 204 down-regulated, p-adj <0.05). Further, at 6h following exposure to GLP-1 treatment there were 3192 genes differently expressed (1709 up-regulated and 1,483 down-regulated, p-adj <0.05). Comparison of GLP-1 and BMS-21 treatments revealed highly similar transcriptomic profiles at both the 1h and 6h timepoints. Conclusion: GLP-1 has a varied effect on the transcriptomic profile of INS-1 cells.
2018-07-28 | GSE102003 | GEO
Project description:glp-4 adults vs mixed stage reference Keywords: other
2003-12-31 | GSE715 | GEO