Genomic imprints as a model for the analysis of epigenetic stability during assisted reproductive technologies

Abstract

Gamete and early embryo development are important stages when genome-scale epigenetic transitions are orchestrated. The apparent lack of remodeling of differential imprinted DNA methylation during preimplantation development has lead to the argument that epigenetic disruption by assisted reproductive technologies (ARTs) is restricted to imprinted genes. We contend that aberrant imprinted methylation arising from assisted reproduction or infertility may be an indicator of more global epigenetic instability. Here, we review the current literature on the effects of ARTs, including ovarian stimulation, in vitro oocyte maturation, oocyte cryopreservation, IVF, ICSI, embryo culture, and infertility on genomic imprinting as a model for evaluating epigenetic stability. Undoubtedly, the relationship between impaired fertility, ARTs, and epigenetic stability is unquestionably complex. What is clear is that future studies need to be directed at determining the molecular and cellular mechanisms giving rise to epigenetic errors.

Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology

“…Supraphysiological levels of FSH as well as cryostorage, sperm centrifugation, and culture conditions can all negatively impact the genomic system. ART may also induce global instability at the epigenetic level, as supported by aberrant imprinted methylation arising from ART and, in addition, the timing of ART coincides with critical epigenetic events during gametogenesis and early embryogenesis including epigenetic reprogramming and maternal/paternal pronuclear genome modifications [Denomme and Mann 2012]. This implies that even if conception and pregnancy are achieved through ART, this success may come with stress-induced genomic alterations and later health complications in the embryo or later in life.…”

Methylation Status of H19/IGF2 Differentially Methylated Region in in vitro Human Blastocysts Donated by Healthy Couples

“…It has been well established that the parent-of-origin specific DNA methylation, known as genomic imprinting, is crucially important for normal embryonic development. Therefore, any interference with imprint acquisition and/or maintenance will result in ill or fatal phenotypes of the resultant embryos [6] . In human, most of the imprinted genes are arranged in clusters [7] .…”

“…Although assisted reproductive techniques (ARTs) are now well-established and globally applied, several epidemiological studies have shown the association of ART with the increased incidence rate of certain imprinting disorders such as BWS and RSS [19] . This phenomenon has been mainly attributed to the coincidence between gamete and embryo in vitro manipulations events and the normal pattern of epigenetic reprogramming, which begins at fertilization and continues during pre-implantation embryo development [6,20,21] . Despite several investigations in the gametic DMRs (gDMRs) in human pre-implantation embryos, there is still space for further studies.…”

Dysregulation of methylation and expression of imprinted genes in oocytes and reproductive tissues in mice of advanced maternal age

“…Knockout studies of maternally expressed genes result in fetal and placental overgrowth, whereas knockout of paternally expressed genes result in fetal and placental growth restriction [17]. Dysregulation of methylation patterns may be an indicator for epigenetic instability which could result in infertility [20]. There is a potential link between maternal age and imprinting disorders, such as Angelman syndrome and Beckwith-Wiedermann syndrome, as these disorders are more prevalent in the offspring from older women [20,21].…”

“…Dysregulation of methylation patterns may be an indicator for epigenetic instability which could result in infertility [20]. There is a potential link between maternal age and imprinting disorders, such as Angelman syndrome and Beckwith-Wiedermann syndrome, as these disorders are more prevalent in the offspring from older women [20,21]. Furthermore, maternal age has been associated with developmental abnormalities, including low birth weight in women [3,22,23] and mares [24].…”