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Title: Genome-wide alterations in polycomb-regulated epigenomic modifications in embryonic osteoblasts following exposure to maternal obesity in rats

Author
item CHEN, JINRAN - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHANG, JIAN - Arkansas Children'S Nutrition Research Center (ACNC)
item LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: 7/15/2014
Publication Date: 11/15/2014
Citation: Chen, J., Zhang, J., Lazarenko, O.P., Blackburn, M.L., Ronis, M.J., Badger, T.M., Shankar, K. 2014. Genome-wide alterations in polycomb-regulated epigenomic modifications in embryonic osteoblasts following exposure to maternal obesity in rats [abstract]. Journal of Bone and Mineral Research. 28(Suppl 1). SA0098. Available at http://www.asbmr.org/education/AbstractDetail?aid=4ee5e652-e828-4ae7-aab8-706722968c43.

Interpretive Summary:

Technical Abstract: Nutritional status during intrauterine and early postnatal life impacts the risk of chronic diseases, presumably via epigenetic mechanisms. However, evidence on the impact of gestational events on regulation of bone development is sparse. Recently we showed that bone development is inhibited in gestational day 18.5 (E18.5) embryos from rat dams made obese by feeding a high-fat diet (HFD). In these studies, female Sprague-Dawley rats were fed either a low-fat AIN-93G control diet or a HFD (45% fat calories) for 10 wk starting at 6 wk of age. Fetal rat osteogenic calvarial cells (FOCCs) from HFD-fed obese dams showed impaired osteogenic potential, decreased expression of osteogenic markers, and higher levels of PPAR' relative to cells from dams fed AIN-93G. More importantly, this impairment was associated with diminished mRNA/protein expression and increased promoter methylation of the osteogenic regulator HoxA10, suggesting involvement of mechanisms regulating DNA and repressive histone methylation. DNA methylation is intricately linked to histone methyltransferase (HMT) activity, especially the repressive mark H3K27me3. Since establishment of H3K27me3 is exclusively mediated via the polycomb (PcG) HMT, Enhancer of zeste homolog 2 (Ezh2), we examined this pathway. Recent studies have also shown that suppression of Ezh2 via CDK1 promotes osteogenesis. FOCCs from obese rat dams showed significantly increased mRNA and protein expression of Ezh2. Conversely, CDK1 expression and phosphorylation of Ezh2 (an inactivation event) were significantly lower in FOCCs from obese rat dams. In line with these results, H3K27me3 abundance in FOCCs from embryos of obese dams was significantly higher compared to cells from control dams. Analysis of genome-wide localization of the repressive histone mark H3K27me3 via ChIP-seq identified 338 genes with at least 2-fold increase in H3K27me3 in FOCCs from obese dams. Enrichment of GO terms for these genes revealed that appendage morphogenesis and bone development biological processes were signficantly enriched. Transcriptional regulation of these genes was confirmed using real-time PCR. Of these genes, H3K27me3 of IGF1 promoter was found to be increased, and H3K27me3 of BMP4 promoter was decreased, suggesting altered differentiation potential toward either osteoblasts or adipocytes. These results suggest that maternal obesity may affect fetal skeletal development through epigenetic regulation of polycomb-regulated genes, which may contribute to low bone mass in the offspring later in life.