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Epigenetics and nutrition – nature versus nurture

Rebecca Simmons
Published in : HAMDAN MEDICAL JOURNAL ; Vol 5, No 3 (2012)
DOI : 10.7707/hmj.v5i3.210

Abstract


It is becoming increasingly apparent that the in utero environment in which a fetus grows and develops may have long-term effects on subsequent health and survival. 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. Beta-cell function is markedly impaired in IUGR offspring in very early life. This is accompanied by a reduction in beta-cell proliferation and neogenesis. Expression of the pancreatic and duodenal homeobox 1 (Pdx1) transcription factor is permanently reduced in IUGR and epigenetic modifications are responsible for this decrease. Pdx1 encodes a homeobox transcription factor critically important for beta-cell function and development. Expression of Pdx1 is permanently reduced in IUGR beta-cells and epigenetic modifications are responsible for this. The fetal IUGR state is characterized by loss of upstream stimulatory factor 1 (USF1) binding at the proximal promoter of Pdx1, with deacetylation of histones H3 and H4 due to recruitment of histone deacetylase 1 (HDAC1) and the co-repressor mSin3A. After birth, histone 3 lysine 4 (H3K4) is demethylated and histone 3 lysine 9 (H3K9) is methylated. During the neonatal period, the reduction in Pdx1 expression and these epigenetic changes can be reversed by HDAC inhibition. Finally, once diabetes occurs, DNA methylation of the cytosine-phosphate-guanine (CpG) island in the proximal promoter ensues, resulting in permanent silencing of the Pdx1 locus.


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