Abstract
BackgroundGenome-wide studies have begun to link subtle variations in both allelic DNA methylation and parent-of-origin genetic effects with early development. Numerous reports have highlighted that the placenta plays a critical role in coordinating fetal growth, with many key functions regulated by genomic imprinting. With the recent description of wide-spread polymorphic placenta-specific imprinting, the molecular mechanisms leading to this curious polymorphic epigenetic phenomenon is unknown, as is their involvement in pregnancies complications.ResultsProfiling of 35 ubiquitous and 112 placenta-specific imprinted differentially methylated regions (DMRs) using high-density methylation arrays and pyrosequencing revealed isolated aberrant methylation at ubiquitous DMRs as well as abundant hypomethylation at placenta-specific DMRs. Analysis of the underlying chromatin state revealed that the polymorphic nature is not only evident at the level of allelic methylation, but DMRs can also adopt an unusual epigenetic signature where the underlying histones are biallelically enrichment of H3K4 methylation, a modification normally mutually exclusive with DNA methylation. Quantitative expression analysis in placenta identified two genes, GPR1-AS1 and ZDBF2, that were differentially expressed between IUGRs and control samples after adjusting for clinical factors, revealing coordinated deregulation at the chromosome 2q33 imprinted locus.ConclusionsDNA methylation is less stable at placenta-specific imprinted DMRs compared to ubiquitous DMRs and contributes to privileged state of the placenta epigenome. IUGR-associated expression differences were identified for several imprinted transcripts independent of allelic methylation. Further work is required to determine if these differences are the cause IUGR or reflect unique adaption by the placenta to developmental stresses.
Highlights
Genome-wide studies have begun to link subtle variations in both allelic Deoxyribonucleic acid (DNA) methylation and parent-of-origin genetic effects with early development
Aberrant methylation at ubiquitous differentially methylated regions (DMRs) is associated with intrauterine growth restriction (IUGR) Using the Illumina Infinium Human Methylation450 BeadChip arrays (HM450k) array platform, we initially profiled ubiquitous imprinted DMRs in 67 placenta samples
We identified isolated gain-of-methylation (GOM) at two DMRs associated with the MEST and MCTS2 genes in a control biopsy (PL35) and an IUGR placenta (PL37), respectively
Summary
Genome-wide studies have begun to link subtle variations in both allelic DNA methylation and parent-of-origin genetic effects with early development. Numerous reports have highlighted that the placenta plays a critical role in coordinating fetal growth, with many key functions regulated by genomic imprinting. With the recent description of wide-spread polymorphic placenta-specific imprinting, the molecular mechanisms leading to this curious polymorphic epigenetic phenomenon is unknown, as is their involvement in pregnancies complications. IUGR is clinically associated with increased umbilical or uterine artery resistance in prenatal Doppler measures, indicative of anomalies in placental vasculature. Often pregnancies complicated by IUGR or PE are accompanied by prematurity, since early elective delivery is warranted to limit fetal distress [3]. IUGR babies have immediate medical problems requiring extensive stay in neonatal units but are at increased risk of common comorbidities later in life, including hypertension, type 2-diabetes, and heart disease through the effects of fetal programming [4]
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