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Diabetologia

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01.10.2011 | Article

Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat

verfasst von: S. E. Pinney, L. J. Jaeckle Santos, Y. Han, D. A. Stoffers, R. A. Simmons

Erschienen in: Diabetologia | Ausgabe 10/2011

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Abstract

Aims/hypothesis

The abnormal intrauterine milieu of intrauterine growth retardation (IUGR) permanently alters gene expression and function of pancreatic beta cells leading to the development of diabetes in adulthood. Expression of the pancreatic homeobox transcription factor Pdx1 is permanently reduced in IUGR islets suggesting an epigenetic mechanism. Exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) analogue, given in the newborn period increases Pdx1 expression and prevents the development of diabetes in the IUGR rat.

Methods

IUGR was induced by bilateral uterine artery ligation in fetal life. Ex-4 was given on postnatal days 1–6 of life. Islets were isolated at 1 week and at 3–12 months. Histone modifications, PCAF, USF1 and DNA methyltransferase (Dnmt) 1 binding were assessed by chromatin immunoprecipitation (ChIP) assays and DNA methylation was quantified by pyrosequencing.

Results

Phosphorylation of USF1 was markedly increased in IUGR islets in Ex-4 treated animals. This resulted in increased USF1 and PCAF association at the proximal promoter of Pdx1, thereby increasing histone acetyl transferase (HAT) activity. Histone H3 acetylation and trimethylation of H3K4 were permanently increased, whereas Dnmt1 binding and subsequent DNA methylation were prevented at the proximal promoter of Pdx1 in IUGR islets. Normalisation of these epigenetic modifications reversed silencing of Pdx1 in islets of IUGR animals.

Conclusions/interpretation

These studies demonstrate a novel mechanism whereby a short treatment course of Ex-4 in the newborn period permanently increases HAT activity by recruiting USF1 and PCAF to the proximal promoter of Pdx1 which restores chromatin structure at the Pdx1 promoter and prevents DNA methylation, thus preserving Pdx1 transcription.

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Barker DJ (1999) The fetal origins of type 2 diabetes mellitus. Ann Intern Med 16:322–324

Simmons RA, Templeton L, Gertz S, Niu H (2001) Intrauterine growth retardation leads to type II diabetes in adulthood in the rat. Diabetes 50:2279–2286PubMedCrossRef

Simmons RA, Suponitsky-Kroyter I, Selak MA (2005) Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure. J Biol Chem 280:28785–28791PubMedCrossRef

Stoffers DA, Desai BM, Ng DD, Simmons RA (2003) Neonatal exendin-4 prevents the development of diabetes mellitus in the intrauterine growth retarded rat. Diabetes 52:734–740PubMedCrossRef

Simmons RA (2007) Developmental origins of diabetes: the role of epigenetic mechanisms. Curr Opin Endocrinol Diabetes Obes 14:13–16PubMedCrossRef

Brissova M, Blaha M, Spear C et al (2005) Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis. Am J Physiol Endocrinol Metab 288:E707–E714PubMedCrossRef

Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR (2004) PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 114:828–836PubMed

Holland AM, Gonez LJ, Naselli G, MacDonald RJ, Harrison LC (2005) Conditional expression demonstrates the role of the homeodomain transcription factor Pdx1 in maintenance and regeneration of beta-cells in the adult pancreas. Diabetes 54:2586–2595PubMedCrossRef

Jonsson J, Gonez LJ, Naselli G, MacDonald RJ, Harrison LC (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606–609PubMedCrossRef

10.

Offield MF, Jetton TL, Labosky PA et al (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122:983–995PubMed

11.

Hui H, Perfetti R (2002) Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Eur J Endocrinol 146:129–141PubMedCrossRef

12.

Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12:1763–1768PubMedCrossRef

13.

Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106–110PubMedCrossRef

14.

Park JH, Stoffers DA, Nicholls RD, Simmons RA (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118:2316–2324PubMedCrossRef

15.

Stoffers DA, Kieffer TJ, Drucker DJ, Bonner-Weir S, Habener JF, Egan JM (2000) Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49:741–748PubMedCrossRef

16.

Song WJ, Schreiber WE, Zhong E et al (2008) Exendin-4 stimulation of cyclin A2 in beta-cell proliferation. Diabetes 57:2371–2381PubMedCrossRef

17.

Movassat J, Beattie GM, Lopez AD, Hayek A (2002) Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells. J Clin Endocrinol Metab 87:4775–4781PubMedCrossRef

18.

Perfetti R, Zhou J, Doyle ME, Egan JM (2000) Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 141:4600–4605PubMedCrossRef

19.

Cheung E, Mayr P, Coda-Zabetta F, Woodman PG, Boam DS (1999) DNA-binding activity of the transcription factor upstream stimulatory factor 1 (USF1) is regulated by cyclin-dependent phosphorylation. Biochem J 344:145–152PubMedCrossRef

20.

Galibert MD, Carreira S, Goding CR (2001) The USF1 transcription factor is a novel target for the stress-responsive p38 kinase and mediates UV-induced tyrosinase expression. EMBO J 20:5022–5031PubMedCrossRef

21.

Xiao Q, Kenessey A, Ojamaa K (2002) Role of USF1 phosphorylation on cardiac alpha-myosin heavy chain promoter activity. Am J Physiol 283:H213–H219

22.

Corre S, Primot A, Baron Y, Le Seyec J, Goding C, Galibert MD (2009) Target gene specificity of USF1 is directed via p38 mediated phosphorylation dependent acetylation. J Biol Chem 284:18851–18862PubMedCrossRef

23.

Sayasith K, Lussier JG, Sirois J (2005) Role of upstream stimulatory factor phosphorylation in the regulation of the prostaglandin G/H synthase-2 promoter in granulosa cells. J Biol Chem 280:28885–28893PubMedCrossRef

24.

Haring M, Offermann S, Danker T (2007) Chromatin immunoprecipitation: optimization, quantitative analysis and data normalization. Plant Methods 3:1–16CrossRef

25.

Jaskelioff M, Peterson CL (2003) Chromatin and transcription: histones continue to make their marks. Nat Cell Biol 5:395–399PubMedCrossRef

26.

Liang G, Lin JC, Wei V et al (2004) Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc Natl Acad Sci USA 101:7357–7362PubMedCrossRef

27.

Nightingale KP, Gendreizig S, White DA, Bradbury C, Hollfelder F, Turner BM (2007) Cross talk between histone modifications in response to HDAC inhibitors: MLL4 links histone H3 acetylation and histone H3K4 methylation. J Biol Chem 282:4408–4416PubMedCrossRef

28.

Vakoc CR, Sachdeva MM, Wang H, Blobel GA (2006) Profile of histone lysine methylation across transcribed mammalian chromatin. Mol Cell Biol 26:9185–9195PubMedCrossRef

29.

Qian J, Kaytor EN, Towle HC, Olson LK (1999) Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic ß-cells. Biochem J 341:315–322PubMedCrossRef

30.

Sharma S, Leonard J, Lee S, Chapman HD, Leiter EH, Montminy MR (1996) Pancreatic islet expression of the homeobox factor STF-1 (Pdx-1) relies on an E-box motif that binds USF. J Biol Chem 271:2294–2299PubMedCrossRef

31.

Gerrish K, van Velkinburgh JC, Stein R (2004) Conserved transcriptional regulatory domains of the pdx-1 gene. Mol Endo 18:533–548CrossRef

32.

Gannon M, Gamer LW, Wright CV (2001) Regulatory regions driving developmental and tissue-specific expression of the essential pancreatic gene pdx1. Dev Biol 238:185–201PubMedCrossRef

33.

Doyle ME, Egan JM (2007) Mechanisms of action of GLP-1 in the pancreas. Pharmocol Ther 113:546–593CrossRef

34.

Bannister AJ, Kouzarides T (1996) The CBP co-activator is a histone acetyltransferase. Nature 384:641–643PubMedCrossRef

35.

Rodolosse A, Campos ML, Rooman I, Lichtenstein M, Reak FX (2009) p/CAF modulates the activity of the transcription factor p48/Ptf1a involved in pancreatic acinar differentiation. Biochem J 418:463–473PubMedCrossRef

36.

Bird AP, Wolffe AP (1999) Methylation-induced repression-belts, braces, and chromatin. Cell 99:451–454PubMedCrossRef

37.

Li H, Rauch T, Chen ZX, Szabo PE, Riggs AD, Pfeifer GP (2006) The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem 281:19489–19500PubMedCrossRef

38.

Huang S, Li X, Yusufzai TM, Qiu Y, Felsenfeld G (2007) USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier. Mol Cell Biol 22:7991–8002CrossRef

39.

Pikaart MJ, Recillas-Targa F, Felsenfeld G (1998) Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. Genes Dev 12:2852–2862PubMedCrossRef

40.

Buteau J, Roduit R, Susini S, Prentki M (1999) Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 42:856–864PubMedCrossRef

41.

Wong RHF, Chang I, Hudak CSS, Hyun S, Kwan H, Sul HS (2009) A role of DNA-PK for metabolic gene regulation in response to insulin. Cell 136:1056–1072PubMedCrossRef

42.

Litt MD, Simpson M, Gaszner M, Allis CD, Felsenfeld G (2001) Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus. Science 293:2453–2455PubMedCrossRef

43.

Noma K, Grewal SI (2002) Histone H3 lysine 4 methylation is mediated by Set1 and promotes maintenance of active chromatin states in fission yeast. Proc Natl Acad Sci USA 99:16438–16445PubMedCrossRef

44.

Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138:1736–1741PubMedCrossRef

45.

Bonner-Weir S (2000) Perspective: postnatal pancreatic beta cell growth. Endocrinology 141:1926–1929PubMedCrossRef

46.

Kaung HL (1994) Growth dynamics of pancreatic islet cell populations during fetal and neonatal development of the rat. Dev Dyn 200:163–175PubMedCrossRef

47.

Bachman KE, Park BH, Rhee I et al (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3:89–95PubMedCrossRef

48.

Kouzarides T (2002) Histone methylation in transcriptional control. Curr Opin Genet Dev 12:198–209PubMedCrossRef

Titel: Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat
verfasst von: S. E. Pinney
L. J. Jaeckle Santos
Y. Han
D. A. Stoffers
R. A. Simmons
Publikationsdatum: 01.10.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 10/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2250-1

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Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat

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