Abstract
Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.
Highlights
IntroductionTo elucidate the mechanisms by which intrauterine growth restriction (IUGR) results in the development of diabetes, we have developed a rat model of uteroplacental insufficiency induced by bilateral uterine artery ligation, which reduces the blood supply and critical substrates to the fetus [3,5]
Poor fetal growth with low birth weight due to intrauterine growth restriction (IUGR) is strongly associated with increased risk of adulthood type 2 diabetes (T2D) in human and animal studies [1,2,3,4].To elucidate the mechanisms by which IUGR results in the development of diabetes, we have developed a rat model of uteroplacental insufficiency induced by bilateral uterine artery ligation, which reduces the blood supply and critical substrates to the fetus [3,5]
We have demonstrated that alterations of histone modifications in key transcription factor binding motifs and genes are associated with changes in expression of key genes, suggesting that these epigenetic modifications contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats
Summary
To elucidate the mechanisms by which IUGR results in the development of diabetes, we have developed a rat model of uteroplacental insufficiency induced by bilateral uterine artery ligation, which reduces the blood supply and critical substrates to the fetus [3,5]. This adverse intrauterine milieu impairs the development of pancreatic islets in the fetus and causes permanent β-cell dysfunction [3,5]. By 10 weeks of age, β-cell mass is reduced and IUGR rats have developed mild-fasting hyperglycemia and exhibit diminished glucose- and leucine-stimulated insulin secretion [3,6,7,8]
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