Abnormal methylation of KCNQ1OT1 and differential methylation of H19 imprinting control regions in human ICSI embryos

Khoueiry, Rita; Ibala-Romdhane, Samira; Al-Khtib, Mohamed; Blachère, Thierry; Lornage, Jacqueline; Guérin, J. F.; Lefèvre, Annick

doi:10.1017/s0967199411000694

Cited by 19 publications

(30 citation statements)

References 30 publications

(37 reference statements)

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“…Interestingly, data in support for such a genome-wide abnormality of DNA methylation in ART pregnancies is scarce, 18,20 as most available studies have focused on specific loci related to imprinted genes. [12][13][14][15][16][17][18][19] Katari et al, 20 using a custom-designed methylation array platform that examined methylation differences in placenta and cord blood samples from ART (N D 10) and naturally conceived (N D 13) pregnancies. The authors analyzed a total of 1,536 CpG sites, most of which were located in the promoters of 736 selected genes.…”

Section: Discussionmentioning

confidence: 99%

“…While some of these studies found that ART is associated with abnormal DNA methylation in human gametes, embryos, [12][13][14] placentas, 15 and umbilical cord samples, 16 other studies concluded that this association is not significant. [17][18][19] These apparently conflicting data may be attributed, at least in part, to methodological limitations of some of these studies, such as the inclusion of mixed populations in the study group (e.g., ovulation induction, IVF, and ICSI) and lack of information regarding potential confounders (e.g., indication for ART, treatment protocol, use of cleavage stage embryos vs. blastocysts, and use of frozen vs. fresh embryos).…”

Section: Introductionmentioning

confidence: 99%

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Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

et al. 2015

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Data linking assisted reproductive technologies (ART) with aberrant DNA methylation is limited and inconclusive. In addition, most studies to date have analyzed only a small number of CpG sites and focused on methylation changes in placentas, while data on cord blood are scarce. Our aim was to compare DNA methylation in cord blood samples from ART (N D 10) and control pregnancies (N D 8) using a genome-wide approach with the Illumina Ò Infinium Human Methylation27 array, which interrogates 27,578 CpG sites. A total of 733 (2.7%) of the CpG sites were significantly differentially methylated between the 2 groups (P < 0.05), with an overall relative hypomethylation in the ART group (P < 0.001). Differences in DNA methylation were more pronounced for CpG sites in certain types of genomic locations and were related to baseline methylation levels and distance from CpG islands and transcription start sites. ART was associated with significantly higher variation in DNA methylation, suggesting that differences in DNA methylation between cases and controls may result from stochastic (or random) genome-wide changes in DNA methylation in ART pregnancies. We identified 24 candidate genes with 2 or more CpG sites that were significantly different between the IVF and control groups. The current study provides support for the hypothesis that ART or associated subfertility may be associated with genome-wide changes in DNA methylation, and these changes appear to be, at least in part, due to epigenetic instability in ART pregnancies. Further studies are required in order to determine the extent to which such ART-related epigenetic instability may have phenotypic consequences.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

et al. 2015

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“…Whether the observed methylation status of the blastocyst is considered as a normal phenotype for these embryos remains to be answered, but if we consider this phenomenon as a divergence from the norm, numerous explanations can be provided that include: 1) paternally-derived altered methylation [35][36][37] , 2) maternally-derived altered methylation [38] , 3) reduced maintenance of DNA methylation [29,39] , 4) Non-rigid and dynamic methylation statuses of DMR [40][41][42] , 5) reduced or altered methylation due to ART procedure [30,43] , and 6) altered methylation due to technical issues. Each of these propositions requires to be evaluated in the context of new experiments.…”

Section: Discussionmentioning

confidence: 99%

“…The clones with >50% of the CpGs methylated are considered as hyper-methylated, and strands lacked nine or more methylated CpGs were considered to be hypo-methylated [28][29][30] . Using these gauges, the percentage of hyper-methylated clones of H19/IGF2 DMR in the blastocysts was 43.75±5.1%, while this value for the lymphocyte was 50% (Fig.…”

Section: Percentages Of Hyper-methylated Clones Of H19/igf2 Dmrmentioning

confidence: 99%

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

Derakhshan-Horeh¹,

Abolhassani²,

Jafarpour³

et al. 2017

IBJ

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Backgrund: Imprinted genes are a unique subset of few genes, which have been differentially methylated region (DMR) in a parental origin-dependent manner during gametogenesis, and these genes are highly protected during pre-implantation epigenetic reprogramming. Several studies have shown that the particular vulnerability of imprinting genes during suboptimal pre-and peri-conception micro-environments often is occurred by assisted reproduction techniques (ART). This study investigated the methylation status of H19/IGF2 DMR at high-quality expanding/expanded human blastocysts donated by healthy individuals to evaluate the risks linked to ART. Method: Methylation levels of H19/IGF2 DMR were analyzed by bisulfite conversion and sequencing at 18 CpG sites (CpGs) located in this region. Result: The overall percentage of methylated CpGs and the proportion of hyper-methylated clones of H19/IGF2 DMR in analyzed blastocysts were 37.85±4.87% and 43.75±5.1%, respectively. For validation of our technique, the corresponding methylation levels of peripheral human lymphocytes were defined (49.52±1.86% and 50%, respectively). Conclusion: Considering the absence of in vivoproduced human embryos, it is not possible to conclude that the methylation found in H19/IGF2 DMR is actually normal or abnormal. Regarding the possible risks associated with ART, the procedures should be optimized in order to at least reduce some of the epigenetic risks.

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“…The altered methylation of imprinted genes leads to improper gene dosage during embryonic development and has been associated with several pathologies, including cancers and neurological disorders (Reed and Leff, 1994;Orstavik, 1999;Feinberg, 2004;Demars and Gicquel, 2012;Brioude et al, 2013;McCann et al, 1996;Takai et al, 2001). Recent studies have suggested that assisted reproductive technologies (ARTs), such as superovulation, in vitro fertilisation and embryo culture, favour acquisition of imprinting errors, which can lead to diseases and developmental defects (DeBaun et al, 2003;Gicquel et al, 2003;Maher et al, 2003;Orstavik et al, 2003;Borghol et al, 2006;Bowdin et al, 2007;Khoueiry et al, 2008;Grace and Sinclair, 2009;Chen et al, 2010;Ibala-Romdhane et al, 2011;Khoueiry et al, 2013). During the early stages of embryonic stem cells (ESCs) isolation from pre-implantation stage embryos, embryonic cells are subject to intense in vitro manipulation and environmental changes that may impact the epigenetic status and irreversibly alter the capacity to generate ESC lines or to exhibit the full differentiation potential of genuine ESCs.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic status of H19/IGF2 and SNRPN imprinted genes in aborted and successfully derived embryonic stem cell lines in non-human primates

et al. 2016

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The imprinted genes of primate embryonic stem cells (ESCs) often show altered DNA methylation. It is unknown whether these alterations emerge while deriving the ESCs. Here we studied the methylation patterns of two differentially methylated regions (DMRs), SNRPN and H19/IGF2 DMRs, during the derivation of monkey ESCs. We show that the SNRPN DMR is characteristically methylated at maternal alleles, whereas the H19/IGF2 DMR is globally highly methylated, with unusual methylation on the maternal alleles. These methylation patterns remain stable from the early stages of ESC derivation to late passages of monkey ESCs and following differentiation. Importantly, the methylation status of H19/IGF2 DMR and the expression levels of IGF2, H19, and DNMT3B mRNAs in early embryo-derived cells were correlated with their capacity to generate genuine ESC lines. Thus, we propose that these markers could be useful to predict the outcomes of establishing an ESC line in primates.

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Abnormal methylation of KCNQ1OT1 and differential methylation of H19 imprinting control regions in human ICSI embryos

Cited by 19 publications

References 30 publications

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

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

Epigenetic status of H19/IGF2 and SNRPN imprinted genes in aborted and successfully derived embryonic stem cell lines in non-human primates

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