Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner

Market-Velker, Brenna A.; Zhang, Liyue; Magri, Lauren S.; Bonvissuto, Anne C.; Mann, Mellissa R.W.

doi:10.1093/hmg/ddp465

Cited by 292 publications

(255 citation statements)

References 57 publications

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“…Our results showed losses of methylation on the normally hypermethylated allele of imprinted genes but not gain of methylation on the normally hypomethylated allele in ART-generated offspring. These results are consistent with a study by Market-Velker et al (17) that analyzed offspring from mice subjected to ovarian stimulation, but contrast with the pattern of aberrant hypermethylation observed by Turan et al (18) in human tissues from offspring generated by ART.…”

Section: Discussionsupporting

confidence: 92%

“…B6(CAST7) mice possess a chromosome 7 from the Mus musculus castaneus (Cast) strain on a C57BL/6 (B6) background. B6(CAST7) females were crossed with DBA males and the ensuing F1 progeny carried several previously characterized strain-specific polymorphisms that were used to distinguish the parental alleles of imprinted genes on chromosome 7 (17,23,24). Because of the significant labor involved in generating mice by ICSI and analyzing allelespecific DNA methylation and expression patterns, our study was limited to examining six mice (three male, three female) conceived through natural reproduction and six mice (three male, three female) created through the use of ICSI.…”

Section: Methodsmentioning

confidence: 99%

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Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming

Waal

Yamazaki

Ingale

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The use of assisted reproductive technologies (ART) has become increasingly common worldwide and is now responsible for 2-3% of children born in developed countries. Multiple reports have suggested that ART-conceived children are more likely to develop rare epigenetic disorders such as Beckwith-Wiedemann Syndrome or Angelman Syndrome, both of which involve dysregulation of imprinted genes. Anecdotal reports suggest that animals produced with ART that manifest apparent epigenetic defects typically do not transmit these epimutations to subsequent generations when allowed to breed naturally, but this hypothesis has not been directly studied. We analyzed allele-specific DNA methylation and expression at three imprinted genes, H19, Snrpn, and Peg3, in somatic cells from adult mice generated with the use of intracytoplasmic sperm injection (ICSI), a type of ART. Epimutations were detected in most of the ICSI-derived mice, but not in somatic cells of their offspring produced by natural mating. We examined germ cells from the ICSI mice that exhibited epimutations in their somatic cells and confirmed normal epigenetic reprogramming of the three imprinted genes analyzed. Collectively, these results confirm that ART procedures can lead to the formation of primary epimutations, but while such epimutations are likely to be maintained indefinitely in somatic cells of the ART-derived individuals, they are normally corrected in the germ line by epigenetic reprogramming and thus, not propagated to subsequent generations.gametogenesis | transgenerational inheritance E arly embryos and germ cells are unique in that they must undergo extensive epigenetic reprogramming to reestablish developmental potency during each generation. This reprogramming entails erasure of most inherited epigenetic modifications followed by the acquisition and subsequent maintenance of new epigenetic profiles (1). Genomic imprinting is an epigenetic phenomenon found in eutherian and metatherian mammals (2) that results in parent-of-origin-specific, monoallelic expression of a subset of genes (3). This functional asymmetry of imprinted genes is conferred through differential DNA methylation patterns established during gametogenesis in each parent that distinguish the maternal and paternal alleles in the ensuing offspring (4, 5). These regions are known as differentially methylated regions (DMRs), and the differential methylation profiles at these genetic elements play an important role in regulating allele-specific expression of imprinted genes (3).Because the epigenome is distinct in each cell type and is readily reversible by developmental reprogramming, it is particularly susceptible to disruption by environmental influences (6). Such epigenetic defects are known as "epimutations" and can be of two types-primary epimutations or secondary epimutations (7). Primary epimutations result from a direct disruption of an epigenetic parameter such as DNA methylation that is then propagated through DNA replication to subsequent cells. Secondary epimutations result...

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming

Waal

Yamazaki

Ingale

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Other reports suggest that proper acquisition of methylation can be perturbed by superovulation; loss of methylation was detected in oocytes at several maternally methylated ICRs (human MEST, mouse Peg3, Snrpn and Kcnq1ot1 ICRs) and gain of methylation was detected at a paternally methylated ICR (human and mouse H19 ICRs) (Table 1). 89,90 A number of studies report that BWS and AS cases are overrepresented in children born through ART. 42,[91][92][93][94][95] However, other studies did not find evidence for increased risk for these diseases, 96,97 and the relationship between ART and imprinting disorders remains to be established.…”

Section: Molar Pregnancy Infertility Assisted Reproductive Technolomentioning

confidence: 99%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.

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“…Such a gain of maternal methylation and a loss of paternal methylation at H19DMR have been recently documented in mouse blastocysts and were attributed to superovulation induced imprinting disorders. 17 The authors did not give information on the imprint in the oocytes themselves. On the other hand, we found almost no residual methylation on the maternal allele of control human blastocysts while Market-Velker et al 17 showed an average methylation of the maternal allele of H19 of up to 15% in mouse blastocysts obtained from spontaneously ovulated female, demonstrating one more time the discrepancies existing between species at the level of epigenome regulation.…”

mentioning

confidence: 99%

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

et al. 2011

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ART is suspected to generate increased imprinting errors in the lineage. Following an intra cytoplasmic sperm injection (ICSI) procedure, a certain number of embryos fail to develop normally and imprinting disorders may be associated to the developmental failure. To evaluate this hypothesis, we analysed the methylation profile of H19DMR, a paternally imprinting control region, in high-graded blastocysts, in embryos showing developmental anomalies, in the matching sperm and in oocytes of the concerned couples when they were available. Significant hypomethylation of the paternal allele was observed in half of the embryos, independently of the stage at which they were arrested (morula, compacted morula, pre blastocyst or BC-graded blastocysts). Conversely, some embryos showed significant methylation on the maternal allele, whereas few others showed both hypomethylation of the paternal allele and abnormal methylation of the maternal allele. The matching sperm at the origin of the embryos exhibited normal methylated H19 patterns. Thus, hypomethylation of the paternal allele in the embryos does not seem inherited from the sperm but likely reflects instability of the imprint during the demethylating process, which occurred in the early embryo. Analysis of a few oocytes suggests that the defect in erasure of the paternal imprint in the maternal germ line may be responsible for the residual methylation of the maternal allele in some embryos. None of these imprinting alterations could be related to a particular stage of developmental arrest; compared with high-grade blastocysts, embryos with developmental failure are more likely to have abnormal imprinting at H19 (Po0.05).

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Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner

Cited by 292 publications

References 57 publications

Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming

Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

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