Abstract
BackgroundGenomic imprinting is an important epigenetic process involved in regulating placental and foetal growth. Imprinted genes are typically associated with differentially methylated regions (DMRs) whereby one of the two alleles is DNA methylated depending on the parent of origin. Identifying imprinted DMRs in humans is complicated by species- and tissue-specific differences in imprinting status and the presence of multiple regulatory regions associated with a particular gene, only some of which may be imprinted. In this study, we have taken advantage of the unbalanced parental genomic constitutions in triploidies to further characterize human DMRs associated with known imprinted genes and identify novel imprinted DMRs.ResultsBy comparing the promoter methylation status of over 14,000 genes in human placentas from ten diandries (extra paternal haploid set) and ten digynies (extra maternal haploid set) and using 6 complete hydatidiform moles (paternal origin) and ten chromosomally normal placentas for comparison, we identified 62 genes with apparently imprinted DMRs (false discovery rate <0.1%). Of these 62 genes, 11 have been reported previously as DMRs that act as imprinting control regions, and the observed parental methylation patterns were concordant with those previously reported. We demonstrated that novel imprinted genes, such as FAM50B, as well as novel imprinted DMRs associated with known imprinted genes (for example, CDKN1C and RASGRF1) can be identified by using this approach. Furthermore, we have demonstrated how comparison of DNA methylation for known imprinted genes (for example, GNAS and CDKN1C) between placentas of different gestations and other somatic tissues (brain, kidney, muscle and blood) provides a detailed analysis of specific CpG sites associated with tissue-specific imprinting and gestational age-specific methylation.ConclusionsDNA methylation profiling of triploidies in different tissues and developmental ages can be a powerful and effective way to map and characterize imprinted regions in the genome.
Highlights
Genomic imprinting is an important epigenetic process involved in regulating placental and foetal growth
The parallel observations in humans are ovarian teratomas, which are a rare form of tumour that consists of a variety of embryonic tissues or organs but no placental tissues, and complete hydatidiform moles (CHMs), which consist of abnormal placental growth characterized by trophoblast hyperplasia but no embryonic structures
It was previously suggested that DNA methylation may be less important in regulating imprinting in placental tissue as compared to foetal tissue, we recently demonstrated that the DNA methylation status of many known imprinted differentially methylated region (DMR) is strictly maintained in triploid placentas and can be used to distinguish diandric from digynic triploidy [19]
Summary
Genomic imprinting is an important epigenetic process involved in regulating placental and foetal growth. Imprinted genes are typically associated with differentially methylated regions (DMRs) whereby one of the two alleles is DNA methylated depending on the parent of origin. Imprinted genes are thought to be important to placental and foetal growth and development and may help regulate growth in response to maternal and foetal signals in utero [2]. The importance of imprinted genes for placental and foetal development was initially demonstrated in mice by observations that parthenogenetic embryos (maternal origin, digynic diploid) could show embryonic differentiation but failed to form extraembryonic components [6]. The parental conflict theory developed to explain the evolution of imprinted genes [8] suggests that paternally expressed genes tend to promote growth of the offspring at the expense of the mother, while maternally expressed genes act as growth-limiting factors to conserve maternal resources [8]
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