Abstract
BackgroundEpigenetic mechanisms provide an interface between environmental factors and the genome and are influential in various diseases. These mechanisms, including DNA methylation, influence the regulation of development, differentiation, and establishment of cellular identity. Here, we performed high-throughput methylome profiling to determine whether differential patterns of DNA methylation correlate with Down syndrome (DS).Materials and methodsWe extracted DNA from the chorionic villi cells of five normal and five DS fetuses at the early developmental stage (12–13 weeks of gestation). Methyl-capture sequencing (MC-Seq) was used to investigate the methylation levels of CpG sites distributed across the whole genome to identify differentially methylated CpG sites (DMCs) and regions (DMRs) in DS. New functional annotations of DMR genes using bioinformatics tools were predicted.ResultsDNA hypermethylation was observed in DS fetal chorionic villi cells. Significant differences were evident for 4,439 DMCs, including hypermethylation (n = 4,261) and hypomethylation (n = 178). Among them, 140 hypermethylated DMRs and only 1 hypomethylated DMR were located on 121 genes and 1 gene, respectively. One hundred twenty-two genes, including 141 DMRs, were associated with heart morphogenesis and development of the ear, thyroid gland, and nervous systems. The genes were significantly associated with DS and various diseases, including hepatopulmonary syndrome, conductive hearing loss, holoprosencephaly, heart diseases, glaucoma, and musculoskeletal abnormalities.ConclusionsThis is the first study to compare the whole-epigenome DNA methylation pattern of the chorionic villi cells from normal and DS fetuses at the early developmental-stage using MC-seq. Overall, our results indicate that the chorionic villi cells of DS fetuses are hypermethylated in all autosomes and suggested that altered DNA methylation may be a recurrent and functionally relevant downstream response to DS in human cells. This study provides basic information for future research focused on the pathophysiology of the DS and its potential effects, as well as the role DNA methylation plays in the early developmental stage of DS fetuses.
Highlights
Epigenetic mechanisms provide an interface between environmental factors and the genome and are influential in various diseases
DNA hypermethylation was observed in Down syndrome (DS) fetal chorionic villi cells
Our results indicate that the chorionic villi cells of DS fetuses are hypermethylated in all autosomes and suggested that altered DNA methylation may be a recurrent and functionally relevant downstream response to DS in human cells
Summary
Epigenetic mechanisms provide an interface between environmental factors and the genome and are influential in various diseases. The estimated incidence of DS, the most prevalent genetic cause of developmental disabilities, is generally between 1 in 1000 to 1 in 1100 live births worldwide according to the World Health Organization [2] It is characterized by over 80 clinical features that include mental retardation, stereotypical facial features, poor muscle tone, and short stature of various penetrance, and is associated with an increased risk of congenital heart disease, diabetes, leukemia, and other diseases [3]. In our prior transcriptome analysis using chorionic villi cells in the early developmental stage of DS fetuses, we reported gene expression changes on all chromosomes, not on only HSA21 [10]. These results suggest that genes are embedded in temporally and spatially highly coordinated regulatory networks. The functional consequences of epigenetic changes, which occur at a much higher rate than DNA sequence changes (4.46 × 10–4 versus 7 × 10–9) [11], may significantly contribute to the clinical phenotype variation of DS
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