Glucose-dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 Modulate β-Cell Chromatin Structure

Cuilan Nian,Su-Jin Kim,Christopher H.S. McIntosh

doi:10.1074/jbc.m809046200

Cuilan Nian, Su-Jin Kim + Show 1 more

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https://doi.org/10.1074/jbc.m809046200

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Abstract

Chromatin can exert a regulatory effect on gene transcription by modulating the access of transcription factors to target genes. In the present study, we examined whether nuclear actions of the incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, involve modulation of beta-cell chromatin structure. Stimulation of INS-1(832/13) beta-cells or dispersed mouse islets with glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 resulted in the post-translational modification of core H3 histones, through acetylation and phosphorylation. Both increased histone H3 acetyltransferase and reduced histone deacetylase activities contributed. Subsequent studies demonstrated that incretin-mediated histone H3 modifications involved activation of protein kinase A, p42/44 mitogen-activated protein kinase (MAPK), and p38 MAPK signaling modules, resulting in the activation of mitogen- and stress-activated kinase-1. Additionally, modification of histone H3 increased its association with the transcription factor, phosphorylated cAMP-response element-binding protein (phospho-CREB) and with cAMP-responsive CREB coactivator 2. Incretin-activated CREB-related Bcl-2 transcription was greatly reduced by a histone acetyltransferase inhibitor, demonstrating the functional importance of histone H3 modification. This appears to be the first demonstration of beta-cell chromatin modification in response to the incretins and the studies indicate that their regulatory effects involve coordinated nuclear interactions between specific signaling modules, chromatin-modifying enzymes and transcription factors.

Highlights

(GLP-1), exert pleiotropic effects on pancreatic islets that include the potentiation of glucose-stimulated insulin secretion, expansion of ␤-cell mass via induction of ␤-cell proliferation, and reduction of ␤-cell apoptosis [1,2,3,4,5,6,7,8]
We have shown that glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 induce core histone H3 protein modifications through the regulation of histone H3 acetyltransferase (H3AT) and histone deacetylase (HDAC) activity, and activation of protein kinase A (PKA), p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and mitogen- and stress-activated kinase-1 (MSK-1) signaling modules are involved in this process
INS-1 (832/13) cells were serum-starved in 3 mM glucose RPMI containing 0.1% BSA overnight and stimulated for 24 h with 100 nM GIP in the presence or absence of inhibitors of PKA, p42/44 MAPK, p38 MAPK, and SAPK/JNK

Summary

Introduction

(GLP-1), exert pleiotropic effects on pancreatic islets that include the potentiation of glucose-stimulated insulin secretion, expansion of ␤-cell mass via induction of ␤-cell proliferation, and reduction of ␤-cell apoptosis [1,2,3,4,5,6,7,8]. Multiple signaling modules are involved in incretin-mediated activation/inactivation of H3AT/HDAC, resulting in the post-translational modification of histone H3 core proteins.

Results

Conclusion