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Review
. 2009 Jun;56(3):449-66, Table of Contents.
doi: 10.1016/j.pcl.2009.03.004.

Developmental origins of adult disease

Rebecca A Simmons  1
Affiliations
Review

Developmental origins of adult disease

Rebecca A Simmons. Pediatr Clin North Am. 2009 Jun.

Abstract

Intrauterine growth retardation (IUGR) has been linked to development of type 2 diabetes in adulthood. Using a rat model, we tested the hypothesis that uteroplacental insufficiency disrupts the function of the electron transport chain in the fetal beta-cell and leads to a debilitating cascade of events. The net result is progressive loss of beta-cell function and eventual development of type 2 diabetes in the adult. Studies in the IUGR rat demonstrate that an abnormal intrauterine environment induces epigenetic modifications of key genes regulating beta-cell development; experiments directly link chromatin remodeling with suppression of transcription. Future research will be directed at elucidating the mechanisms underlying epigenetic modifications in offspring.

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Figures

Figure 1
Figure 1. Summary of epigenetic changes at Pdx1 in IUGR rats during the development of type 2 diabetes
In pancreatic ß-cells (top), the Pdx1 proximal promoter is normally found in an unmethylated (white circles) open chromatin state allowing access to transcription factors such as USF-1 and associated with nucleosomes characterized by acetylated (Ac, blue octagons) histones H3 and H4 and with trimethylated H3K4 (Me, green hexagons). In IUGR fetal and 2 week islets (middle) histone acetylation is progressively lost through association with a mSin3A-HDAC1-DNMT1 repressor complex, with trimethylated H3K4 disappearing and dimethylated H3K9 (Me, red hexagons) appearing after birth. IUGR adult islets are characterized by inactive chromatin with dimethylated H3K9 and extensive DNA methylation (red circles) locking in the transcriptionally silent state of Pdx1.
See this image and copyright information in PMC

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