title: Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine Philadelphia, Philadelphia, PA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Pinney
authors.forename: L J
authors.initials: LJ
authors.lastname: Jaeckle Santos
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.forename: D A
authors.initials: DA
authors.lastname: Stoffers
authors.forename: R A
authors.initials: RA
authors.lastname: Simmons
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D000077270:Exenatide; D005317:Fetal Growth Retardation / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D018398:Homeodomain Proteins; D010455:Peptides; D015534:Trans-Activators; D051720:Upstream Stimulatory Factors; C497182:Usf1 protein, rat; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D000077270:Exenatide; D051548:Histone Acetyltransferases