The promoter methylomes of monochorionic twin placentas reveal intrauterine growth restriction-specific variations in the methylation patterns.

Zhiming He,Qun Fang,Fei Gao,Tong Wang,Yu Gao,Huijuan Luo,Hanlin Lu,Junwen Wang

doi:10.1038/srep20181

Abstract

Intrauterine growth restriction (IUGR) affects the foetus and has a number of pathological consequences throughout life. Recent work has indicated that variations in DNA methylation might cause placental dysfunction, which may be associated with adverse pregnancy complications. Here, we investigated the promoter methylomes of placental shares from seven monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR) using the healthy twin as an ideal control. Our work demonstrated that the IUGR placental shares harboured a distinct DNA hypomethylation pattern and that the methylation variations preferentially occurred in CpG island shores or non-CpG island promoters. The differentially methylated promoters could significantly separate the IUGR placental shares from the healthy ones. Ultra‐performance liquid chromatography/tandem mass spectrometry (UPLC‐MS/MS) further confirmed the genome‐wide DNA hypomethylation and the lower level of hydroxymethylation statuses in the IUGR placental shares. The methylation variations of the LRAT and SLC19A1 promoters, which are involved in vitamin A metabolism and folate transportation, respectively, and the EFS promoter were further validated in an additional 12 pairs of MC twins with sIUGR. Although the expressions of LRAT, SLC19A1 and EFS were not affected, we still speculated that DNA methylation and hydroxymethylation might serve a functional role during in utero foetal development.

Highlights

Responses by changing the DNA methylation statuses[10,11]
DNA imprinting has been widely studied in Intrauterine growth restriction (IUGR) placentas[2,14,15,16,17] and the results showed that the loss of IGF2 imprinting could be involved in the pathophysiology of foetal growth restriction and placental insufficiency[15]
Consistent with a previous report[18], our results indicated that the IUGR-associated placental shares harboured a distinct DNA hypomethylation pattern in promoters and the methylation variations preferentially occurred in CpG island (CGI) shores or non-CGI containing promoters

Summary

Introduction

Responses by changing the DNA methylation statuses[10,11]. All of these observations shed light on the possibility that variations in the DNA methylation patterns that affect placental development or function might lead to placental insufficiency, foetal growth restriction and death[8,12,13]. The liquid hybridization capture-based bisulfite sequencing (LHC-BS) is our recently developed method, which employed designed probes to capture the native genomic DNA of interest using a liquid hybridization system, followed by bisulfite treatment and high throughput sequencing to investigate the methylation levels of genomic regions This strategy was used here to study the promoter methylomes of placental shares from MC twins with selective intrauterine growth restriction (sIUGR)[26,27]. We found that the promoters for LRAT, SLC19A1, which are involved in vitamin A metabolism and folate transportation, respectively, and EFS were abnormally methylated in the IUGR placental shares These findings indicated that DNA methylation and hydroxymethylation in placental tissues might serve a functional role in in utero foetal development

Methods

Results

Conclusion