The hypomethylation of imprinted genes in IVF/ICSI placenta samples is associated with concomitant changes in histone modifications

Epigenetics. 2020 Dec;15(12):1386-1395. doi: 10.1080/15592294.2020.1783168. Epub 2020 Jun 23.


Although more and more children are born by Assisted Reproductive Technologies (ART), ART safety has not fully been demonstrated. Notably, ART could disturb the delicate step of implantation, and trigger placenta-related adverse outcomes with potential long-term effects, through disrupted epigenetic regulation. We have previously demonstrated that placental DNA methylation was significantly lower after IVF/ICSI than following natural conception at two differentially methylated regions (DMRs) associated with imprinted genes (IGs): H19/IGF2 and KCNQ1OT1. As histone modifications are critical for placental physiology, the aim of this study was to profile permissive and repressive histone marks in placenta biopsies to reveal a better understanding of the epigenetic changes in the context of ART. Utilizing chromatin immunoprecipitation (ChIP) coupled with quantitative PCR, permissive (H3K4me3, H3K4me2, and H3K9ac) and repressive (H3K9me3 and H3K9me2) post-translational histone modifications were quantified. The analyses revealed a significantly higher quantity of H3K4me2 precipitation in the IVF/ICSI group than in the natural conception group for H19/IGF2 and KCNQ1OT1 DMRs (P = 0.016 and 0.003, respectively). Conversely, the quantity of both repressive marks at H19/IGF2 and SNURF DMRs was significantly lower in the IVF/ICSI group than in the natural conception group (P = 0.011 and 0.027 for H19/IGF2; and P = 0.010 and 0.035 for SNURF). These novel findings highlight that DNA hypomethylation at imprinted DMRs following ART is linked with increased permissive/decreased repressive histone marks, altogether promoting a more permissive chromatin conformation. This concomitant change in epigenetic state at IGs at birth might be an important developmental event because of ART manipulations.

Keywords: in vitro fertilization; Assisted reproductive technologies; DNA methylation; epigenetics; histone modifications; placenta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation*
  • Female
  • Genomic Imprinting*
  • Histone Code*
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Male
  • Placenta / metabolism*
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism
  • Pregnancy
  • Sperm Injections, Intracytoplasmic / adverse effects*


  • Histones
  • IGF2 protein, human
  • KCNQ1OT1 long non-coding RNA, human
  • Potassium Channels, Voltage-Gated
  • Insulin-Like Growth Factor II

Grants and funding

This work was supported by Besançon and Dijon University Hospitals under grant [‘appel à projet Dijon-Besançon 2013’], by the Agence Nationale pour la Recherche under grant [‘ANR-17-CE12-0014’] and by the Fonds pour la santé des femmes. The Monk laboratory was supported by the Spanish Ministry of Economy and Competitiveness under grant [‘MINECO; BFU2014-53093-R’ and ‘BFU2017-85571-R’] and by the European Union Regional Development Fund (FEDER). AMS is a recipient of an FPI PhD studentship from MINECO.