ArticleDiabetologia2011
Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat.
Article in Diabetologia, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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66 citing papers in PubMed, 130 citations in OpenAlex.
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- Organ transformation by environmental disruption of protein integrity and epigenetic memory in Drosophila.PLoS biology · 2024Article
- Pharmacoepigenetics in type 2 diabetes: is it clinically relevant?Diabetologia · 2022Article
- Developmental origins of adult diseases.Medical review (2021) · 2022Review
- Epigenetics of type 2 diabetes mellitus and weight change - a tool for precision medicine?Nature reviews. Endocrinology · 2022Review
- Maternal antagonism of Glp1 reverses the adverse outcomes of sleeve gastrectomy on mouse offspring.JCI insight · 2022Article
- Identification of Novel Regulatory Regions Induced by Intrauterine Growth Restriction in Rat Islets.Endocrinology · 2022Article
- Maternal obesity and ovarian failure: is leptin the culprit?Animal reproduction · 2022Article
- Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells.Frontiers in endocrinology · 2022Review
- DNA Methylation GrimAge and Incident Diabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.Diabetes · 2021Observational
- Neonatal IL-4 exposure decreases adipogenesis of male rats into adulthood.American journal of physiology. Endocrinology and metabolism · 2021Article
- Immune dysfunction in developmental programming of type 2 diabetes mellitus.Nature reviews. Endocrinology · 2021Review
- Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Review
- Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress.Cellular and molecular life sciences : CMLS · 2020Review
- Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats.Cells · 2020Article
- Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling.Scientific reports · 2020Article
- Early overnutrition reduces Pdx1 expression and induces β cell failure in Swiss Webster mice.Scientific reports · 2019Article
- Review
- Prenatal Malnutrition-Induced Epigenetic Dysregulation as a Risk Factor for Type 2 Diabetes.International journal of genomics · 2019Review
6 more citing papers are in PubMed but not listed here.
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5 authors at 3 institutions in 1 country.
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Abstract
aims/hypothesisThe 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.
methodsIUGR 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.
resultsPhosphorylation 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/
interpretationThese 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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