Integrated analysis of genome-wide DNA methylation and gene expression data provide a regulatory network in intrauterine growth restriction

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Abstract

Intrauterine growth restriction (IUGR), a serious complication of perinatal period, results in metabolic and brain disorders. However, the exact cause of IUGR remains unclear. Recently, some evidences indicated that epigenetic modification plays an important role in IUGR. Hence, in this study the methylation status and gene expression profiles of IUGR were compared to investigate the changes in epigenetic regulation and gene expression induced by IUGR. DNA samples extracted from blood samples of infants with IUGR and controls appropriate for gestational age (AGA) were analyzed with Illumina Human Methylation 450 k array to identify differences in genome-wide DNA methylation, and results were verified by Mass ARRAY. Moreover, an IUGR rat model was established by maternal malnutrition method, and gene expression profiles associated with progressive DNA methylation changes in brain tissue were detected using microarray Affymetrix Rat Gene 2.0ST. Based on DNA methylation array, 2265 genes are differentially methylated between IUGR and AGA 1338 genes in the promoter region. Genes with differentially methylated CpG loci in the promoter region enriched in 10 pathways.1311 differentially expressed genes were obtained by Microarray. 36 significantly enriched pathways were identified. After comparing DNA methylation data with gene expression data, 49 genes showed a negative correlation between DNA methylation and gene expression. 27 commonly enriched pathways were identified, which involved sugar, fat and protein metabolism, diseases of the nervous system, cancer, and immunomodulation and endocrine regulation. These findings suggest the epigenetic regulatory mechanisms on corresponding gene expression which may play a role in the adult-onset diseases induced by IUGR.

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