Assisted reproduction treatment and epigenetic inheritance

Abstract

Background: The subject of epigenetic risk of assisted reproduction treatment (ART), initiated by reports on an increase of children with the Beckwith-Wiedemann imprinting disorder, is very topical. Hence, there is a growing literature, including mouse studies.

Methods: In order to gain information on transgenerational epigenetic inheritance and epigenetic effects induced by ART, literature databases were searched for papers on this topic using relevant keywords.

Results: At the level of genomic imprinting involving CpG methylation, ART-induced epigenetic defects are convincingly observed in mice, especially for placenta, and seem more frequent than in humans. Data generally provide a warning as to the use of ovulation induction and in vitro culture. In human sperm from compromised spermatogenesis, sequence-specific DNA hypomethylation is observed repeatedly. Transmittance of sperm and oocyte DNA methylation defects is possible but, as deduced from the limited data available, largely prevented by selection of gametes for ART and/or non-viability of the resulting embryos. Some evidence indicates that subfertility itself is a risk factor for imprinting diseases. As in mouse, physiological effects from ART are observed in humans. In the human, indications for a broader target for changes in CpG methylation than imprinted DNA sequences alone have been found. In the mouse, a broader range of CpG sequences has not yet been studied. Also, a multigeneration study of systematic ART on epigenetic parameters is lacking.

Conclusions: The field of epigenetic inheritance within the lifespan of an individual and between generations (via mitosis and meiosis, respectively) is growing, driven by the expansion of chromatin research. ART can induce epigenetic variation that might be transmitted to the next generation.

Figure 1

Characteristics of a chromatin domain. Schematic representation of the covalent and structural features that define a certain chromatin domain. Different contributing factors are highlighted in shaded boxes. The dashed line represents a separation between two adjacent domains. Figure from Margueron and Reinberg (2010).

Figure 2

Imprinting in the germline. Erasure, establishment and maintenance of methylation imprints at imprinting control regions during germ cell and embryonic development. Imprinting control regions (IC1) and IC2 are shown as examples. Grey indicates modification and white indicates no modification at the corresponding alleles. Parental chromosomes are marked according to their sex in blue (male) or red (female). The reading in the developing embryo is indicated by arrows. Figure from Reik and Walter (2001).

Figure 3

Chronology of mouse germ cell development and the main epigenetic events that occur. PGCs first emerge at embryonic Day 7.25 (E7.25) after which they migrate to the gonad where they enter the process of sex differentiation and eventually develop into full-grown gametes. Green bars indicate the developmental stage and yellow bars indicate the epigenetic processes occurring at these points in the germ line. MSCI stands for meiotic sex chromosome inactivation. Figure from Sasaki and Matsui (2008).

Figure 4

Epigenetic state of the imprinted Igf2/H19 domain on the maternal and paternal genome. On the paternal chromosome, the H19 gene and the adjacent DMR are methylated preventing H19 expression and the binding of the insulator CTCF, thus allowing enhancers access to the Igf2 gene promoting its expression. In the absence of DMR methylation on the maternal chromosome, bound CTCF prevents enhancer activity reaching Igf2, effectively silencing the gene. Instead, enhancer activity is limited to the unmethylated H19 gene resulting in its expression on the maternally contributed chromosome. Figure from Reik and Murrell (2000).

Figure 5

(A) Methylation reprogramming in the germ line. PGCs in the mouse become demethylated early in development, between E7.5 and E13.5. Remethylation begins in prospermatogonia in male germ cells, and after birth in growing oocytes. (B) Methylation reprogramming in preimplantation embryos. The paternal genome (blue) is demethylated by an active mechanism immediately after fertilization. The maternal genome (red) is demethylated by a passive mechanism. Both are remethylated around the time of implantation to different extents in embryonic (EM) and extraembryonic (EX) lineages. Methylated imprinted genes and some repeat sequences (dashed line) do not become demethylated. Unmethylated imprinted genes (dashed line) do not become methylated. Figure from Reik et al. (2001).

Figure 6

Overview of the results of studies on the effect of ART on methylation and expression of imprinted genes. (A) Overview of mouse data. (B) Overview of human data. A/C = Amnion/Chorion, Bl = Blastocyst, E = embryo with the age, Ex = Expression which indicates either the level of expression or the allelic expression, ET = embryo transfer, GV = germinal vesicle oocyte, M = methylation, MI = oocyte in meiosis I, MII = oocyte in meiosis II, P = placenta with the age, UCB = umbilical cord blood. The numbers refer to the studies: 1. Sato et al. (2007), 2. Market-Velker et al. (2010a), 3. Fauque et al. (2007), 4. Fortier et al. (2008), 5. Rivera et al. (2008), 6. Doherty et al. (2000), 7. Mann et al. (2004), 8. Li et al. (2005), 9. Market-Velker et al. (2010b), 10. Khosla et al. (2001), 11. Fauque et al. (2010a), 12. Geuns et al. (2003), 13. Geuns et al. (2007b), 14. Khoueiry et al. (2008), 15. El-Maarri et al. (2001), 16. Borghol et al. (2006), 17. Geuns et al. (2007a) 18. Chen et al. (2010), 19. Ibala-Romdhane et al. (2011), 20. Gomes et al. (2009), 21. Tierling et al. (2010), 22. Turan et al. (2010), 23. Zechner et al. (2010), 24. Zhang et al. (2010), 25. Katari et al. (2009).