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 induced by bilateral uterine artery ligation, we performed ChIP-Seq and RNA-Seq to assess the association of genome-wide histone modifications and gene dysregulation in islets from 2 and 10 week rats. IUGR induced significant changes in enrichment of H3K4me3 and H3K27me3 marks in both 2-week and 10-week islets, which were correlated with expression changes of multiple genes critical for normal islet function in IUGR islets. HOMER analysis showed that IUGR-induced histone mark changes were enriched at transcription factor binding motifs, such as Nkx2-1, Nkx2-5, FoxL2, Pax7, Sox4, Mitf, and Oct4-Sox2-Nanog. These transcription factors were also identified by Ingenuity Pathway Analysis of islet transcriptomes as top upstream regulators that regulate the changes in gene expression and biological activities. In addition, our ChIP-seq data revealed more than 1,000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. No expression or very low expression of these genes was consistent with a poised state of transcription. The poised state of many potential bivalent genes was altered by IUGR. Interestingly, 3 genes important for islet function, Acod1, FGF-21, and Serpina11, which were poised in 2-week control islets, lost their poised state in 10-week control islets, but gained bivalency in 10-week IUGR islets. In contrast, another 3 genes, Cdh16, Lrrc27, and Lrrc66, which were not poised in control 2-week islets, gained de novo bivalency in 10-week control islets, but lost their poised state in 10-week IUGR islets. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes which may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.
Y. Lien: None. X.M. Lu: None. Z. Wang: None. R.A. Simmons: None.
National Institutes of Health