Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

Abstract

Data linking assisted reproductive technologies (ART) with aberrant DNA methylation is limited and inconclusive. In addition, most studies to date have analyzed only a small number of CpG sites and focused on methylation changes in placentas, while data on cord blood are scarce. Our aim was to compare DNA methylation in cord blood samples from ART (N D 10) and control pregnancies (N D 8) using a genome-wide approach with the Illumina Ò Infinium Human Methylation27 array, which interrogates 27,578 CpG sites. A total of 733 (2.7%) of the CpG sites were significantly differentially methylated between the 2 groups (P < 0.05), with an overall relative hypomethylation in the ART group (P < 0.001). Differences in DNA methylation were more pronounced for CpG sites in certain types of genomic locations and were related to baseline methylation levels and distance from CpG islands and transcription start sites. ART was associated with significantly higher variation in DNA methylation, suggesting that differences in DNA methylation between cases and controls may result from stochastic (or random) genome-wide changes in DNA methylation in ART pregnancies. We identified 24 candidate genes with 2 or more CpG sites that were significantly different between the IVF and control groups. The current study provides support for the hypothesis that ART or associated subfertility may be associated with genome-wide changes in DNA methylation, and these changes appear to be, at least in part, due to epigenetic instability in ART pregnancies. Further studies are required in order to determine the extent to which such ART-related epigenetic instability may have phenotypic consequences.

Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants

“…The health risks and disease phenotypes observed in ART-conceived children in part may result from underlying epigenetic aberrations presented by parental infertility or ART itself. However, evidence for concerted epigenetic changes in the ART population (23)(24)(25)(26)(27)(28) is countered by a number of studies asserting that the epigenome of ART-conceived offspring is essentially unchanged (29)(30)(31)(32).…”

“…The first described CpG methylation in the promoter regions of 736 select genes, primarily associated with imprinting and growth regulation, from 10 IVF and 13 in vivo-conceived children (23). The second used an Illumina Infinium Human Methylation27 Beadchip array and observed 733 CpG sites of differential methylation when cord blood of 8 IVF and 10 naturally conceived children were compared (26). However, these studies did not address the impact of infertility, the primary reason why ART was prescribed, nor provide a genomewide assessment of the epigenetic effects of ART.…”

A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies

“…Such comparisons have been performed in multiple laboratories, initially targeting small numbers of imprinted genes (reviewed by Batcheller et al 2011; systematic review and meta-analysis by Lazaraviciute et al 2014;Nelissen et al 2014;Whitelaw et al 2014;Melamed et al 2015), under the assumption that imprinted genes might be more susceptible to effects of epigenetic disruption (Table 2), and in a modest numbers of patients.…”

DOHaD et programmation pré- et péri-conceptionnelle

“…Outre l'atteinte métabolique, la mobilité spermatique Enfin, l'impact sur l'embryon des nouvelles procédures comme la maturation ovocytaire in vitro ou la vitrification ovocytaire 6 , n'a pas été évalué. [18,19]. Elles concernent des gènes impliqués dans des maladies métaboliques chroniques [42] et pourraient également être à l'origine de la diminution du développement trophoblastique et du poids foetal (IGF-2/H19, gènes soumis à l'empreinte [5]).…”

“…Le lien entre ces modifications épigénétiques et l'activation transcriptionnelle du génome embryonnaire n'est pas totalement élucidé. Toutefois, l'augmentation artificielle de l'acétylation des histones, comme l'inhibition de leur déméthyla-tion, perturbent l'activation du génome embryonnaire, montrant que la dynamique des modifications épigénétiques participe à cette [18,19]. Ces perturbations épigénétiques initiales, mémorisées par le génome embryonnaire, pourraient expliquer les effets de l'environnement de l'embryon préimplantatoire observés à long terme (voir plus loin).…”