High Frequency of Imprinted Methylation Errors in Human Preimplantation Embryos

Abstract

Assisted reproductive technologies (ARTs) represent the best chance for infertile couples to conceive, although increased risks for morbidities exist, including imprinting disorders. This increased risk could arise from ARTs disrupting genomic imprints during gametogenesis or preimplantation. The few studies examining ART effects on genomic imprinting primarily assessed poor quality human embryos. Here, we examined day 3 and blastocyst stage, good to high quality, donated human embryos for imprinted SNRPN, KCNQ1OT1 and H19 methylation. Seventy-six percent day 3 embryos and 50% blastocysts exhibited perturbed imprinted methylation, demonstrating that extended culture did not pose greater risk for imprinting errors than short culture. Comparison of embryos with normal and abnormal methylation didn’t reveal any confounding factors. Notably, two embryos from male factor infertility patients using donor sperm harboured aberrant methylation, suggesting errors in these embryos cannot be explained by infertility alone. Overall, these results indicate that ART human preimplantation embryos possess a high frequency of imprinted methylation errors.

Clinical and molecular analyses of Beckwith–Wiedemann syndrome: Comparison between spontaneous conception and assisted reproduction techniques

“…Specifically, idiopathic male infertility has been strongly associated with methylation defects in H19/IGF2 :IG‐DMR and MEST imprinting loci [Poplinski et al, ], which could potentially explain the increase of methylation defects in children born by ART. In contrast, another study showed that embryos from male factor infertility patients using donor sperm harbored aberrant methylation, suggesting errors in these embryos cannot be explained by infertility alone [White et al, ]. This suggested that ART human preimplantation embryos possess a high frequency of imprinted methylation errors.…”

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

“…Interestingly, recent work has shown that high-quality human embryos generated from ART exhibit a high degree of DNA methylation errors in imprinted loci (50). Enrichment of imprinted genes was observed in the set of differentially methylated genes when comparing ICSI (FH and FZ) with the IUI control (Supplemental Table 8), with hypomethylated genes contributing strongly to this enrichment (Supplemental Tables 9 and 10 and Supplemental File 3).…”

Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome

“…The cause for the absence or loss of methylation at KvDMR1 is not clear but presumably results from improper establishment and/or maintenance during oogenesis or failure of maintenance after fertilization. KvDMR1 may be particularly susceptible to epigenetic disruption, as evidenced by frequent disruption of methylation following assistedreproductive technologies (Amor and Halliday, 2008;Weksberg et al, 2007;White et al, 2015).…”