Response to comment on: Gleicher N et al., 2016. Reprod biol endocrinol Sep 5;14(1):54

Gleicher, Norbert; Vidali, Andrea; Braverman, Jeffrey; Kushnir, Vitaly A.; Barad, David H.; Hudson, C.; Wu, Yan-Guang; Wang, Qi; Zhang, Lin

doi:10.1186/s12958-017-0241-x

Cited by 7 publications

(8 citation statements)

References 6 publications

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“…In our gene expression data AR is expressed in GV and expression drops until it is undetectable in MII oocytes. AR expression is important in early follicle maturation and in knockout mouse models, females have many phenotypes associated with reduced fertility 42 . AR is also important for germinal vesicle breakdown, the process by which the GV oocyte resumes meiosis to become the mature MII oocyte 42 .…”

Section: Resultsmentioning

confidence: 99%

“…AR expression is important in early follicle maturation and in knockout mouse models, females have many phenotypes associated with reduced fertility 42 . AR is also important for germinal vesicle breakdown, the process by which the GV oocyte resumes meiosis to become the mature MII oocyte 42 . TMEFF2 is also a gene potentially regulated by proximal hypermethylated LINE1 elements (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

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Single-cell analysis of Non-CG methylation dynamics and gene expression in human oocyte maturation

Jayavelu

Battle

et al. 2019

Preprint

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Oocyte maturation is a coordinated process that is tightly linked to reproductive potential. A better understanding of gene regulation during human oocyte maturation will not only answer an important question in biology, but also facilitate the development of in vitro maturation technology as a fertility treatment. We generated single-cell transcriptome and use previously published single-cell methylome data from human oocytes at different maturation stages to investigate how genes are regulated during oocyte maturation, focusing on the potential regulatory role of non-CG methylation.DNMT3B, a gene encoding a key non-CG methylation enzyme, is one of the 1000 genes upregulated in mature oocytes, which may be at least partially responsible for the increased non-CG methylation as oocytes mature. Non-CG differentially methylated regions (DMRs) between mature and immature oocytes have multiple binding motifs for transcription factors, some of which bind with DNMT3B and may be important regulators of oocyte maturation through non-CG methylation. Over 98% of non-CG DMRs locate in transposable elements, and these DMRs are correlated with expression changes of the nearby genes. Taken together, this data indicates that global non-CG hypermethylation during oocyte maturation may play an active role in gene expression regulation, potentially through the interaction with transcription factors. KEY WORDSDNA methylation, oocyte maturation, gene expression 1 3 proximity of LINE1 elements to the AR gene. When we looked in the UCSC genome browser, there are cluster of non-CG hypermethylated LINE1 elements upstream of the AR gene ( Figure 4). In our gene expression data AR is expressed in GV and expression drops until it is undetectable in MII oocytes. AR expression is important in early follicle maturation and in knockout mouse models, females have many phenotypes associated with reduced fertility 42 . AR is also important for germinal vesicle breakdown, the process by which the GV oocyte resumes meiosis to become the mature MII oocyte 42 . TMEFF2 is also a gene potentially regulated by proximal hypermethylated LINE1 elements ( Figure 4). TMEFF2 is upregulated in early oocyte development in the primordial/primary follicle stage 43 and in our data we observed downregulation of TMEFF2 from GV to MII. Therefore non-CG hypermethylation in the MII stage oocyte could be a means to suppress LINE1 elements that help regulate the expression of early oocyte maturation genes. DISCUSSIONWhile many studies have looked at the genetic and epigenetic contributions of the oocyte to embryonic development, less focus has been on regulatory factors during oocyte maturation. Here we used RNA-seq and WGBS data generated in single-cell oocytes at three different timepoints of oocyte maturation. We use oocytes from patients undergoing ART and therefore one major limitation of our study is the potential heterogeneity of the patients samples. In our three timepoints we observed less RNA transcripts and general downregulation of gene expression as the oocyt...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Single-cell analysis of Non-CG methylation dynamics and gene expression in human oocyte maturation

Jayavelu

Battle

et al. 2019

Preprint

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“…A current diagnosis of mosaicism assigned to an embryo is, therefore, not only based on an incorrect definition of mosaicism but on the incorrect biological understanding what mosaicism at preimplantation stages really represents. As has been well documented [ 12 ], simply mathematically, a 5–6 cell trophectoderm biopsy cannot represent the complete embryo in all its cellular and chromosomal diversity.…”

Section: Why a Correct Definition Of Mosaicism Is Essential?mentioning

confidence: 99%

“…As noted earlier, the assumption that a single trophectoderm biopsy correctly reflects ploidy of the complete blastocyst-stage embryo is mathematically unsustainable [ 12 ]. Should a biopsy contain more than one cell lineage, it, furthermore, incorrectly assumes that NGS can accurately determine exact percentages of DNA for each cell lineage and that, whatever this percentage is, reflects the complete embryo and predicts its implantation, pregnancy and live birth potential [ 10 , 22 ].…”

Section: The Threshold Conceptmentioning

confidence: 99%

Commentary on two recently published formal guidelines on management of “mosaic” embryos after preimplantation genetic testing for aneuploidy (PGT-A)

Gleicher

Barad

Ben‐Rafael

et al. 2021

Reprod Biol Endocrinol

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Two professional societies recently published opinions on the clinical management of “mosaic” results from preimplantation genetic testing for aneuploidy (PGT-A) in human blastocyst-stage embryos in associations with in vitro fertilization (IVF). We here point out three principal shortcomings: (i) Though a most recent societal opinion states that it should not be understood as an endorsement of the use of PGT-A, any discussion of how PGT-A should be clinically interpreted for all practical purposes does offer such an endorsement. (ii) The same guideline derived much of its opinion from a preceding guidance in favor of utilization of PGT-A that did not follow even minimal professional requirements for establishment of practice guidelines. (iii) Published guidelines on so-called “mosaic” embryos from both societies contradict basic biological characteristics of human preimplantation-stage embryos. They, furthermore, are clinically unvalidated and interpret results of a test, increasingly seen as harmful to IVF outcomes for many infertile women. Qualified professional organizations, therefore, should finally offer transparent guidelines about the utilization of PGT-A in association with IVF in general.

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“…Sometimes, after comprehensive considerations and adequately counseling with patients, embryos with partial genetic problems have been transferred into uterus. Strange and interesting phenomena during the followup that those embryos have potential to produce healthy children were reported (2)(3)(4). Of note, TE biopsies were used for PGT in those studies for not damaging embryos, which were not direct to reflect the inner cell mass (ICM).…”

Section: Introductionmentioning

confidence: 99%

Chromosomal Concordance between the Baby Produced by Preimplantation Genetic Testing Embryo and the Trophectoderm Biopsy: a Retrospective Study

Yao¹,

Wang²,

Zeng³

et al. 2021

Preprint

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BackgroundChromosomal mosaicism and aneuploidies are routine phenomena throughout human pre- and post-implantation development. The benefit of implanting mosaicism or aneuploidies is still controversial. The purposes of the study are to investigate the developmental potential of embryos with chromosomally segmental or mosaic abnormalities, and whether precise Next Generation Sequencing (NGS) resolution would reduce the development of an abnormal embryo in preimplantation genetic testing (PGT) cycles.MethodsThe peripheral blood of 17 PGT babies were collected for single nucleotide polymorphism (SNP) array and were compared with trophectoderm (TE) biopsy results at different NGS resolutions.Results76.5% (13/17) of babies’ peripheral blood chromosome analysis was consistent with 10Mb TE biopsies and 58.8% (10/17) of babies’ analysis was consistent with 4Mb TE biopsies. 2 babies who had euploid TE showed abnormal peripheral blood chromosome analysis. 17.6% (3/17) embryos with aberrant TE biopsies produced healthy babies. Although the sensitivity of 10Mb was lower than 4Mb (25% vs. 50%), the specificity (100% vs. 76.9%), PPV (100% vs. 40%) and diagnostic accuracy (82.4% vs. 70.6%) of 10Mb showed better results than 4Mb.Conclusion(s)The chromosomal results between peripheral blood samples and TE biopsies of born babies are not completely congruent. Aneuploid and mosaic embryos have potential to produce healthy babies, whereas normal embryos also have chance to produce babies with chromosomal abnormalities. In spite of low sensitivity of both resolutions, 10Mb has higher specificity, PPV and diagnostic accuracy than 4Mb. It is suggested that TE biopsy be analyzed in both 10Mb and 4Mb resolutions to uncover severely adverse chromosomal aberrations but use 10Mb resolution to guide transfer.Trial registrationThe study was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2100042522).

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Response to comment on: Gleicher N et al., 2016. Reprod biol endocrinol Sep 5;14(1):54

Cited by 7 publications

References 6 publications

Single-cell analysis of Non-CG methylation dynamics and gene expression in human oocyte maturation

Single-cell analysis of Non-CG methylation dynamics and gene expression in human oocyte maturation

Commentary on two recently published formal guidelines on management of “mosaic” embryos after preimplantation genetic testing for aneuploidy (PGT-A)

Chromosomal Concordance between the Baby Produced by Preimplantation Genetic Testing Embryo and the Trophectoderm Biopsy: a Retrospective Study

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