Martine De Rycke Team

Epigenetics and genomic imprinting, safety of assisted reproductive technologies

The general aims of our studies are to gain a more detailed insight into the influence of assisted reproductive technologies (ART) on the epigenome through comparative analysis of epigenetic patterns in human gametes and embryos and in blood and placenta samples from ART or from spontaneous pregnancies.

Background

The different epigenetic modifications such as the DNA methylation at CpG dinucleotides, histone modifications and chromatin remodelling cooperate to regulate gene expression and mediate phenotype characteristics. The two critical periods of genome-wide epigenetic reprogramming during gametogenesis and in the early embryo coincide with the time windows of ART. The small subset of imprinted genes, which have a crucial role in embryonic and placental growth, are reset in the gametes but escape the second reprogramming wave after fertilisation. There is concern that certain aspects of ART may interfere with epigenetic reprogramming and with imprinting in particular.

Most data on imprinting and epigenetic mechanisms have been derived from mice. Data from mice show that ovarian hormonal stimulation can interfere with imprint acquisition in oocytes and imprint maintenance in the embryos, while imprint acquisition for in vitro matured oocytes seems a robust process with no or minor defects. Data from animal models also indicate that embryo culture media may induce epigenetic defects that can influence birth weight. Data from human studies are limited, but they indicate that ovarian hormonal stimulation, embryo culture systems as well as underlying subfertility are contributing risk factors for epigenetic defects.

Previous work from our lab has focused on reprogramming of three imprinted genes and revealed germ-line imprints, time of resetting and imprint maintenance in the human embryo (De Rycke et al. 2002; De Rycke, 2003; Geuns et al., 2003; Geuns et al., 2007a and 2007b).

More recent work focused on expression of the DNA methyltransferase family in control of DNA methylation in gametes and among human preimplantation embryos. Comparison of expression patterns in embryos of good morphological quality with a correct developmental timing and embryos which are delayed or of poor morphological quality indicates that aberrant or failed expression of the epigenetic machinery is connected with preimplantation developmental failure in ART (Petrussa et al., 2014). A similar comparison between fresh and frozen/thawed embryos showed that a slow-freezing DMSO cryopreservation protocol does not seem to interfere with DNA methylation epigenetic reprogramming (De Munck et al., 2015).

Current and future research

5hmeC has only very recently been recognized as an epigenetic mark. The balance between 5hmeC and 5meC in the early embryo is linked with cell-differentiation processes such as pluripotency and lineage commitment. Current research focuses on genome-wide DNA methylation (5meC) and hydroxymethylation (5hmeC) patterns in preimplantation embryos, and is highly relevant, since global patterns and organisation are crucial for development in mammals, and alterations can lead to disturbances or arrest of preimplantation embryonic development.

We also investigate whether the epigenetic profile (DNA methylation) is influenced after various ART protocols, in particular after ICSI with in vitro matured oocytes, as compared to spontaneous pregnancies.

Publications

De Rycke M, Liebaers I, Van Steirteghem A. Epigenetic risks related to assisted reproductive technologies: risk analysis and epigenetic inheritance. Hum Reprod. 17(10):2487-94. Review (2002)

Geuns E, De Rycke M, Van Steirteghem A, Liebaers I. Methylation imprints of the imprint control region of the SNRPN-gene in human gametes and preimplantation embryos. Hum Mol Genet. 12:2873-9 (2003)

De Rycke M. Imprinting. Adv Exp Med Biol. 544:159-68 (2003)

Geuns E, Hilven P, Van Steirteghem A, Liebaers I, De Rycke M. Methylation analysis of KvDMR1 in human oocytes. J Med Genet. 44:144-7 (2007)

Geuns E, De Temmerman N, Hilven P, Van Steirteghem A, Liebaers I, De Rycke M Methylation analysis of the intergenic differentially methylated region of DLK1-GTL2 in human. Eur J Hum Genet. 15:352-61 (2007)

Anckaert E, De Rycke M, Smitz J. Culture of oocytes and risk of imprinting defects. Hum Reprod Update. 19(1):52-66 (2013)

Petrussa L, Van de Velde H, De Rycke M. Dynamic regulation of DNA methyltransferases in human oocytes and preimplantation embryos after assisted reproductive technologies. Mol Hum Reprod. 20(9):861-74 (2014)

De Munck N, Petrussa L, Verheyen G, Staessen C, Vandeskelde Y, Sterckx J, Bocken G, Jacobs K, Stoop D, De Rycke M, Van de Velde H. Chromosomal meiotic segregation, embryonic developmental kinetics and DNA (hydroxy)methylation analysis consolidate the safety of human oocyte vitrification. Mol Hum Reprod. 21(6):535-44 (2015)

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Department of Embryology and Genetics • ©2015 • http://emge.vub.ac.be
VUB • Faculty of Medicine & Pharmacy • Laarbeeklaan 103 • B-1090 Brussel, Belgium
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