Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat
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.
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.
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.
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.
- blah 125_2011_2250_MOESM1_ESM.pdf (47KB)
- blah 125_2011_2250_MOESM2_ESM.pdf (37KB)
- blah 125_2011_2250_MOESM3_ESM.pdf (56KB)
- blah 125_2011_2250_MOESM4_ESM.pdf (40KB)
- blah 125_2011_2250_MOESM5_ESM.pdf (41KB)
- blah 125_2011_2250_MOESM6_ESM.pdf (41KB)
- blah 125_2011_2250_MOESM7_ESM.pdf (64KB)
- blah 125_2011_2250_MOESM8_ESM.pdf (138KB)
- Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat
Volume 54, Issue 10 , pp 2606-2614
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Beta cell
- Intrauterine growth retardation
- Industry Sectors
- Author Affiliations
- 1. Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine Philadelphia, Philadelphia, PA, USA
- 2. Biomedical Research Building II/III 1308, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA, 19104, USA
- 3. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- 4. Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, USA