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

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 β-cell chromatin structure. Stimulation of INS-1(832/13) β-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 β-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. 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 β-cell chromatin structure. Stimulation of INS-1(832/13) β-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 β-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. The gastrointestinal incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) 2The abbreviations used are: GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HAT, histone acetyltransferase; HDAC, histone deacetylase; H3AT, histone H3 acetyltransferase; PKA, protein kinase A; MSK-1, mitogen- and stress-activated kinase-1; CREB, cAMP-response element-binding protein; phospho-CREB, phosphorylated cAMP-response element-binding protein; CBP, CREB-binding protein; ANOVA, analysis of variance; SAPK, stress-activated protein kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; BSA, bovine serum albumin; TORC2, cAMP-responsive CREB coactivator 2. 2The abbreviations used are: GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HAT, histone acetyltransferase; HDAC, histone deacetylase; H3AT, histone H3 acetyltransferase; PKA, protein kinase A; MSK-1, mitogen- and stress-activated kinase-1; CREB, cAMP-response element-binding protein; phospho-CREB, phosphorylated cAMP-response element-binding protein; CBP, CREB-binding protein; ANOVA, analysis of variance; SAPK, stress-activated protein kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; BSA, bovine serum albumin; TORC2, cAMP-responsive CREB coactivator 2. and glucagon-like peptide-1 (GLP-1), exert pleiotropic effects on pancreatic islets that include the potentiation of glucose-stimulated insulin secretion, expansion of β-cell mass via induction of β-cell proliferation, and reduction of β-cell apoptosis (1Brubaker P.L. 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Chem. 2005; 280: 22297-22307Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 8Kim S.J. Nian C. Widenmaier S. McIntosh C.H.S. Mol. Cell Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (108) Google Scholar). Recently, members of two classes of incretin-related compounds have been approved by the FDA for the treatment of type 2 diabetes, the incretin mimetic exenatide (Byetta™) and the DPP-IV inhibitor sitagliptin (Januvia™), resulting in a burgeoning interest in this class of hormones. Although significant progress has been made in incretin biology over the past few years, there is relatively little known about their mode of action in gene regulation. In the current study we examined the possible involvement of GIP and GLP-1 in β-cell chromatin modification. Eukaryotic chromatin is composed of an octamer of four core histones (H2A, H2B, H3, and H4) around which 147 bp of DNA are wrapped. Chromatin can exert a regulatory effect on gene transcription by modulating accessibility of transcription factors to target genes (9Workman J.L. Kingston R.E. Annu. Rev. Biochem. 1998; 67: 545-579Crossref PubMed Scopus (956) Google Scholar). Different post-translational modifications in the N termini of the histones have been identified, including acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation, deamination, and proline isomerization, and these modifications have direct effects on gene expression (10Strahl B.D. Allis C.D. Nature. 2000; 403: 41-45Crossref PubMed Scopus (6448) Google Scholar, 11Berger S.L. Curr. Opin. Genet. Dev. 2002; 2: 142-148Crossref Scopus (973) Google Scholar, 12Bernstein B.E. Schreiber S.L. Chem. Biol. 2002; 9: 1167-1173Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Histone acetyltransferases (HATs) are involved in the acetylation of histone N termini, resulting in chromatin adopting an “open” conformation, whereas histone deacetylase (HDAC) generally promotes a “closed” conformation, by reversing the process (13Marmorstein R. Cell Mol. Life Sci. 2001; 58: 693-703Crossref PubMed Scopus (128) Google Scholar, 14Gregory P.D. Wagner K. Hörz W. Exp. Cell Res. 2001; 265: 195-202Crossref PubMed Scopus (224) Google Scholar, 15Cress W.D. Seto E. J. Cell Physiol. 2000; 184: 1-16Crossref PubMed Scopus (573) Google Scholar). Histone H2B has been shown to be acetylated at lysine residues 5, 12, 15, and 20 (16Cheung P. Allis C.D. Sassone-Corsi P. Cell. 2000; 103: 263-271Abstract Full Text Full Text PDF PubMed Scopus (816) Google Scholar, 17Thorne A.W. Kmiciek D. Mitchelson K. Sautiere P. Crane-Robinson C. Eur. J. Biochem. 1990; 193: 701-713Crossref PubMed Scopus (123) Google Scholar), whereas histone H3 is acetylated at lysines 9, 14, 18, and 23 (18Hansen J.C. Tse C. Wolffe A.P. Biochemistry. 1998; 37: 17637-17641Crossref PubMed Scopus (213) Google Scholar, 19Hendzel M.J. Wei Y. Mancini M.A. Van Hooser A. Ranalli T. Brinkley B.R. Bazett-Jones D.P. Allis C.D. Chromosoma. 1997; 106: 348-360Crossref PubMed Scopus (1490) Google Scholar). Among these sites, acetylation of H3 at Lys-9 has been considered to play a dominant role in histone deposition and chromatin assembly (18Hansen J.C. Tse C. Wolffe A.P. Biochemistry. 1998; 37: 17637-17641Crossref PubMed Scopus (213) Google Scholar, 19Hendzel M.J. Wei Y. Mancini M.A. Van Hooser A. Ranalli T. Brinkley B.R. Bazett-Jones D.P. Allis C.D. Chromosoma. 1997; 106: 348-360Crossref PubMed Scopus (1490) Google Scholar). Additionally, phosphorylation at serine 10 and 28 and threonine 1 has been shown to be tightly regulated for chromosome condensation during cell cycle progression (19Hendzel M.J. Wei Y. Mancini M.A. Van Hooser A. Ranalli T. Brinkley B.R. Bazett-Jones D.P. Allis C.D. Chromosoma. 1997; 106: 348-360Crossref PubMed Scopus (1490) Google Scholar, 20Goto H. Tomono Y. Ajiro K. Kosako H. Fujita M. Sakurai M. Okawa K. Iwamatsu A. Okigaki T. Takahashi T. Inagaki M. J. Biol. Chem. 1999; 274: 25543-25549Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 21Preuss U. Landsberg G. Scheidtmann K.H. Nucleic Acids Res. 2003; 31: 878-885Crossref PubMed Scopus (152) Google Scholar). In the present study, we have shown that GIP and GLP-1 induce core histone H3 protein modifications through the regulation of histone H3 acetyltransferase (H3AT) and 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. 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 (TORC2) in the nucleus. Incretin-mediated post-translational modification of core histones is therefore likely to be an important component of their effects on gene transcription in β-cells. Cell Culture—INS-1 β-cells (clone 832/13) were kindly provided by Dr. C. B. Newgard (Duke University Medical Center, Durham, NC). INS-1 cells were cultured in 11 mm glucose RPMI 1640 (Sigma Laboratories, Natick, MA) supplemented with 2 mm glutamine, 50 μm β-mercaptoethanol, 10 mm HEPES, 1 mm sodium pyruvate, 10% fetal bovine serum, 100 unit/ml penicillin G-sodium, and 100 μg/ml streptomycin sulfate. Cell passages 45–70 were used. In incretin stimulation experiments a peptide concentration of 100 nm was used, because previous studies have demonstrated near-maximal β-cell responses at this concentration (7Kim S.J. Winter K. Nian C. Tsuneoka M. Koda Y. McIntosh C.H.S. J. Biol. Chem. 2005; 280: 22297-22307Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 8Kim S.J. Nian C. Widenmaier S. McIntosh C.H.S. Mol. Cell Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (108) Google Scholar). Islet Isolation—Male C57BL/6 mice (12 weeks old, Charles River) were anesthetized by intraperitoneal injection of pentobarbital (30–40 mg/kg). Islets were isolated by collagenase digestion and dispersed to single cells as described previously (22MacDonald P.E. Ha X.F. Wang J. Smukler S.R. Sun A.M. Gaisano H.Y. Salapatek A.M. Backx P.H. Wheeler M.B. Mol. Endocrinol. 2001; 15: 1423-1435Crossref PubMed Scopus (160) Google Scholar). Dispersed islets were cultured in RPMI 1640 supplemented with 5 mm glucose, 0.25% HEPES, 7.5% fetal bovine serum, 100 units/ml penicillin G-sodium, and 100 μg/ml streptomycin sulfate. Preparation of Nuclear Extracts—Nuclear proteins were isolated as described by Schreiber et al. (23Schreiber E. Matthias P. Muller M.M. Schaffner W. Nucleic Acids Res. 1989; 17: 6419Crossref PubMed Scopus (3903) Google Scholar). Briefly, cells were washed with phosphate-buffered saline and disrupted with 200 μl of ice-cold buffer A (10 mm HEPES, pH 7.9, 10 mm KCl, 1.5 mm MgCl2, 1 mm EDTA, 1 mm dithiothreitol, 0.1% Nonidet P-40, and protease inhibitors). Following centrifugation, the resulting pellet was re-suspended in 20 μl of buffer B (20 mm HEPES, pH 7.9, 400 mm NaCl, 1 mm EDTA, 1 mm dithiothreitol, 20% glycerol, and protease inhibitors) and incubated on ice for 10 min. After clarification of the mixture by centrifugation, the supernatant (nuclear extract) was collected and subjected to Western blot analysis or enzyme activity assay. Western Blot Analysis—Protein samples were separated on a 13% SDS/PAGE gel and transferred onto nitrocellulose membranes (Bio-Rad Laboratories). Probing of the membranes was performed with acetyl-histone H3 (Lys-9), acetyl-histone H3 (Lys-18), acetyl-histone H3 (Lys-23), phospho-histone H3 (Ser-10), histone 3, and HDAC1, -2, -3, -4, -5, and -7 antibodies (Cell Signaling Technology, Beverly, MA). Immunoreactive bands were visualized by enhanced chemiluminescence (Amersham Biosciences) using horseradish peroxidase-conjugated IgG secondary antibodies. Confocal Microscopy—INS-1 cells were treated with GIP or GLP-1 (100 nm) for 24 h. Following treatment, immunocytochemical staining was performed using antibodies against acetyl-histone Lys-9, acetyl-histone Lys-18, or phospho-histone H3 and insulin and visualized with secondary and cells were using a were using the HDAC, H3AT, and HDAC and were used to enzyme activity of HDAC, H3AT, and MSK-1, to the activity is as activity to protein treatment, nuclear were and acetylated histones H3 at Lys-9, Lys-18, or phosphorylated histone H3 at were using protein A and histone H3 Lys-9, Lys-18, or histone H3 The were by and with or was and were by 100 of was used in the to Bcl-2 whereas 10 of was used in the The and used for the of Bcl-2 were as the and cycle was used as a of are as with the of experiments in the was using analysis of with as in the of on Histone H3 in effects of GIP and GLP-1 on the post-translational modification of histone H3 in INS-1 β-cells were first shown in 1 and GIP and GLP-1 (100 nm) treatment increased acetylation of histone H3 at Lys-9 and and phosphorylation at whereas there were significant in acetylation of histone H3 at of histone H3 at Lys-9 and and phosphorylation at demonstrated responses to GIP or GLP-1 staining of INS-1 β-cells the effects of incretins on histone H3 by Western histone modification were with dispersed mouse Both incretins increased acetylation of histone H3 at Lys-9 and and phosphorylation at the there were significant in acetylation of histone H3 at of on the of and effects of GIP and GLP-1 on protein or activity of chromatin-modifying enzymes were shown in 2 and there were significant in the protein of class 1 HDAC1, -2, and or the class 2 -5, and -7 Exp. 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In the current study, INS-1 β-cells were treated with GIP or GLP-1 (100 nm) for 24 and nuclear were with antibodies against histone H3 acetylated at Lys-9 or Lys-18, or phosphorylated at by for CREB or Both GIP and GLP-1 increased direct interactions between and with histone H3 acetylated at Lys-9 or Lys-18, or phosphorylated at functional of incretin-mediated histone H3 acetylation on target gene incretin-mediated Bcl-2 gene transcription was in the or of of INS-1 cells with GIP or GLP-1 (100 nm) for 24 resulted in to in Bcl-2 with and incretin-mediated Bcl-2 gene transcription was greatly reduced by inhibitor Incretin-mediated histone H3 modification is therefore likely to be an important of CREB-related transcription in pancreatic β-cells. of chromatin an important role in the regulation of gene transcription in post-translational modifications of core histone nuclear proteins have been to be with the and of target genes. including acetylation, phosphorylation, and methylation, are to of or activity T. 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