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Med14 phosphorylation shapes genomic response to GLP-1 agonist [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE299280 | GEO | 2025/06/17

REPOSITORIES: GEO

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Med14 phosphorylation shapes genomic response to GLP-1 agonist [snRNA-seq]

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.

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Project description:The CREB family of transcription factors stimulates cellular gene expression following phosphorylation at a conserved serine (Ser133 in CREB1) in response to cAMP and other extracellular signals. In order to characterize CREB target genes in various tissues, we give a cAMP agonist, forskolin (FSK), to cell lines or primary cultures and monitor the gene expression. To eliminate CREB-independent effects of FSK on cellular gene expression, we employed a dominant negative form of CREB called A-CREB, which dimerizes selectively with and blocks the DNA binding activity of CREB but not other bZIP family members. Therefore, genes that are induced by cAMP and the induction was blocked by A-CREB treatment likely represents CREB target genes. Notes:; 1) In HEK293T cells, besides the Control+FSK+(FSK-ACREB) experiments, a different set of experiments showing FSK effect on 1hr and 4hr is included. The two sets of data in HEK293T were generated at different times with different batch of cells, and comparison should be limited within each set. The cAMP induced genes at 1hr, however, was similar between the two sets. 2) These is no ACREB data for pancreatic islets or hepatocytes. For hepatocytes, however, we have included fasting liver and refed liver in additional to FSK treated primary hepatocytes. During fasting, glucagon induces cAMP increase in the liver and CREB is activated. Therefore, a more reliable list of CREB target genes in hepatocytes can be obtained by selecting those genes are that induced both during fasting and in FSK treated primary culture.

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Characterize CREB target genes in different tissue types

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CREB Coactivators CRTC2 and CRTC3 Modulate Bone Marrow Hematopoiesis

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