DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation

Abstract

BackgroundThe association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome.MethodsWe investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing.ResultsAt a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF-associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors.ConclusionsTo our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0413-5) contains supplementary material, which is available to authorized users.

Changes in DNA methylation and imprinting disorders in E9.5 mouse fetuses and placentas derived from vitrified eight‐cell embryos

“…These disorders may impair embryonic and fetal development as well as placental function, thus increasing the risk of pregnancy-related disease (Bloise, Feuer, & Rinaudo, 2014;Burton, Fowden, & Thornburg, 2016;Castillo-Fernandez et al, 2017). In addition, our previous research confirmed that histomorphological alterations involving defects in placental layer segregation can be found in ART placentas at E18.5 in mice, resulting in reduced fetal weight, which may be attributed to perturbed genomic imprinting (Chen et al, 2015).…”

DNA methylation signatures in cord blood of ICSI children

“…A recent more comprehensive 450K methylation array study ( Estill et al ., 2016 ) on air-dried blood spots (Guthrie cards) from 76 children conceived by ICSI, 18 by intrauterine insemination, and 43 controls revealed numerous differences, in particular at metastable epialleles between ICSI and spontaneously conceived children. A single genome-wide significant DMR (upstream of TNP1 ) between 47 IVF and 60 control twins was detected using methylated cord blood DNA immunoprecipitation ( Castillo-Fernandez et al ., 2017 ).…”

The Present and Future of Embryo Cryopreservation

“…Differences in DNA methylation between IVF and non-IVF twins on a genomewide scale and their results show evidence for epigenetic modifications that may in part reflect parental subfertility [63].…”