Med14 phosphorylation shapes genomic response to GLP-1 agonist [ATAC-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1273749 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33979770_1.fastq.gz | Fastqsanger.gz | |||
| SRR33979770_2.fastq.gz | Fastqsanger.gz |
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Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299399 | GEO
Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299281 | GEO
Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299280 | GEO
Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299282 | GEO
Project description:Med14 phosphorylation shapes genomic response to GLP-1 agonist [RNA-seq]
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Project description:Med14 phosphorylation shapes genomic response to GLP-1 agonist [snRNA-seq]
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Project description:Med14 phosphorylation shapes genomic response to GLP-1 agonist [ChIP-seq]
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Project description:the changes of cardiac proteomics in diabetic cardiomyopathy mice treated with GLP-1 receptor agonist
2021-09-10 | PXD028452 |
Project description:Drugs to improve obesity-linked metabolic dysfunction are on the rise, with GLP-1:GIP co-agonism being effective in the management of obesity and type 2 diabetes, and with Lanifibranor (Lani), a nuclear acting small molecule triple agonist at the peroxisome proliferator-activated receptors alpha, gamma and delta (PPAR , , ) being in phase 3 development for the treatment of metabolic dysfunction-associated steatohepatitis. Seeking to further improve the metabolic efficacy of GLP-1:GIP co-agonism, we here report the design and preclinical evaluation of an unimolecular quintuple agonist, which synergistically combines the body weight and blood glucose lowering effects of GLP-1:GIP co-agonism with the insulin sensitizing effects of Lani through its targeted delivery into only cells that express the receptor for either GIP or GLP-1. In vitro, GLP-1:GIP:Lani is indistinguishable from its GLP-1:GIP backbone in GIPR and GLP-1R signaling and equally stimulates insulin secretion in isolated murine islets. In vivo, however, GLP-1:GIP:Lani is much superior to GLP-1:GIP co-agonism or Semaglutide to decrease body weight, food intake, and hyperglycemia in obese and insulin resistant mice through synergistic incretin and PPAR action in key glucoregulatory tissues. The superior metabolic action of GLP-1:GIP:Lani is demonstrated in mice with genetic (db/db) and diet-induced obesity (DIO), is accelerated in DIO mice with adipose-specific overexpression of GIPR and is absent in DIO double-incretin receptor knock-out mice. Collectively, our data suggest that this novel quintuple polyagonist holds unprecedented therapeutic value to treat obesity and type 2 diabetes.
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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