title: Epigenetic imprinting during assisted reproductive technologies: The effect of temporal and cumulative fluctuations in methionine cycling on the DNA methylation state.
abstract: Assisted reproductive technology (ART) exposes gametes and embryos to an artificial environment that does not resemble the conditions of natural conception, and therefore might change epigenetic regulation of genes that are imprinted during development. In the present review, we discuss the relationship between susceptibility of specific genes to receive an altered epigenetic composition during ART processes, possibly via alterations in the biochemical folate and methionine cycle. We provide a comprehensive view of the current state of epigenetic patterning in ART-conceived healthy children and in Angelman syndrome (AS) and Beckwith-Wiedemann syndrome (BWS) patients. We illustrate that similar genes--that is, MEST, KCNQ1OT1, and IGF2--possess an altered DNA methylation profile in animal models, ART-conceived healthy children, and AS and BWS patients. The developmental stage at which these genes receive their epigenetic imprint appears to coincide with the specific moment that ART takes place. We highlight that ART procedures affect physiological levels of enzymes and substrates involved in the folate and methionine cycle thereby altering the DNA methylation state. Moreover, although the DNA methylation rate appears to be robust: (i) temporal imbalances coinciding with defined moments of epigenetic imprinting of specific genes affect the eventual DNA methylation state of those genes and (ii) cumulative ART effects on methionine and folate cycling can alter DNA methylation rates. These observations underscore the necessity to further investigate consequences of ART treatments on the epigenetic profile.
authors.affiliation: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: Hoeijmakers
authors.affiliation: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Hermannus
authors.initials: H
authors.lastname: Kempe
authors.affiliation: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Pernette J
authors.initials: PJ
authors.lastname: Verschure
mesh_terms: D017204:Angelman Syndrome / Q000196:embryology / Q000473:pathology; D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000196:embryology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008715:Methionine / Q000378:metabolism*; D027724:Reproductive Techniques, Assisted
chemical_list: D008715:Methionine
keywords: Angelman syndrome; Beckwith-Wiedemann syndrome; DNA methylation; homocysteine; methionine; 5-methyltetrahydrofolate