Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Compromised oocyte quality and assisted reproduction contribute to sex-specific effects on offspring outcomes and epigenetic patterning

ABSTRACT: Clinical studies have revealed an increased incidence of growth and genomic imprinting disorders in children conceived using Assisted Reproductive Technologies (ART), and aberrant DNA methylation has been implicated. We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1∆1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1∆1o/+ females only when combined with ART. Together, maternal oocyte Dnmt1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ARTs in a sex-specific manner and plays a role in mediating poor embryonic outcome.

ORGANISM(S): Mus musculus

PROVIDER: GSE85200 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA336545

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Placental abnormalities are associated with specific windows of embryo culture in a mouse model

Project description:Assisted Reproductive Technologies (ART) employ gamete/embryo handling and culture in vitro to produce offspring. ART pregnancies have increased risk of low birth weight, abnormal placentation, pregnancy complications, and imprinting disorders. We and others have previously shown that embryo culture induces low birth weight, abnormal placental morphology, and lower levels of DNA methylation in placentas in a mouse model of ART. We hypothesized that these adverse effects are linked to a subtle disruption of specific biological processes during preimplantation development. To test this hypothesis, we performed embryo culture for several discrete periods of preimplantation development and assessed fetal and placental outcomes at term. We observed a reduction in fetal:placental ratio in two distinct windows of preimplantation embryo development, while placental morphological abnormalities and reduced imprinting control region methylation were associated with culture prior to the morula stage. We also provide evidence that extended culture to the blastocyst stage induces additional placental DNA methylation changes compared to embryos transferred at the morula stage, and that female concepti exhibited a higher loss of DNA methylation than males. Altogether, this study identifies specific developmental windows of susceptibility and potential targets for embryo culture optimization.

2022-04-11 | GSE193271 | GEO

Higher Incidence of Embryonic Defects in Mouse Offspring Conceived with Assisted Reproduction from Fathers with Sperm Epimutations

Project description:Assisted reproductive technologies (ART) account for 1-6% of live births in developed countries. While most children conceived using ART are healthy, increases in birth and genomic imprinting defects have been reported; such abnormal outcomes have been attributed to underlying parental infertility and/or the ART used. Here, we assessed whether paternal genetic and lifestyle factors, that are associated with male infertility and affect the sperm epigenome, can influence ART outcomes. We examined how paternal factors, Dnmt3L haploinsufficiency and/or diet-induced obesity, in combination with ART (superovulation, in vitro fertilization, embryo culture and embryo transfer), could adversely influence embryo development and DNA methylation patterning in mice. While male mice fed high-fat diets (HFD) gained weight and showed perturbed metabolic health, their sperm DNA methylation was minimally affected by the diet. In contrast, Dnmt3L haploinsufficiency induced a marked loss of DNA methylation in sperm; notably, regions affected were associated with neurodevelopmental pathways and enriched in young retrotransposons, sequences that can have functional consequences in the next generation. Following ART, placental imprinted gene methylation and growth parameters were impacted by one or both paternal factors. For the embryos conceived by natural conception, the abnormality rates were similar for WT and Dnmt3L+/- fathers. In contrast, paternal Dnmt3L+/- genotype, as compared to WT fathers, resulted in a 3-fold increase in the incidence of morphological abnormalities in embryos generated by ART. Together, the results indicate that embryonic morphological and epigenetic defects associated with ART may be exacerbated in offspring conceived by fathers with sperm epimutations.

2023-12-05 | GSE234855 | GEO

Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice [BS-seq]

Project description:Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA methylation. In mammals, evidence supports similar trans- and inter-generational effects although the underlying mechanisms are incompletely understood. Here a luciferase knock-in reporter mouse for the imprinted Dlk1 locus was generated to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet (HFD) in pregnancy provoked sustained re-expression of the normally silent maternal Dlk1 allele in offspring (a loss of imprinting) and increased DNA methylation at the sDMR. In the next generation heterogeneous Dlk1 mis-expression was seen exclusively among animals born to F1-exposed females. Oocytes from these females showed altered gene and miR expression without changes in DNA methylation, and correct imprinting was restored in subsequent generations. Our results illustrate how diet impacts the foetal epigenome, disturbing canonical and non-canonical imprinting mechanisms to modulate the properties of two successive generations of offspring.

2022-04-01 | GSE175537 | GEO

Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice [RNA-seq]

2022-04-01 | GSE175536 | GEO

Genome-wide maps of DNA methylome during oocyte aging and its transgenerational inheritance

Project description:The goals of this study are to compare genome-wide DNA methylation levels in young and aged oocytes,and to investigate the transgenerational inheritance of methylome profiles in oocytes during natural aging. We apply a novel protocol of rapamycin to overcome the DNA methylation drift associated with oocyte aging. 8-week-old female mice were injected intraperitoneally with rapamycin or vehicle for 40 weeks. At the end of the experiment, females (48 weeks, F0) were paired with young adult (~4 mo old) males to produce F1 offspring (OF1 and ORaF1). An F2 generation (OF2 and ORaF2) resulted from mating F1 female at 44~48 weeks of age with young adult males. To generate YF1 and YF2 as normal control (offspring of young mother), we mated females (~8 weeks) with young adult males. Then we collect oocytes (F0,F1 and F2 generations)，sperm ( F1 and F2 generations) and hippocampus (F1 female offspring) from different groups to investigate the transgenerational inheritance of DNA methylome profiles associated with oocyte aging by the single cell whole-genome methylation sequencing (sc-WGBS). We found that oocytes from aged mother exhibited increased DNA methylation levels in CpG sites. Maternal aging related methylome changes can be inherited transgenerationally though oocyte to the germ line of F1 and F2 offspring. The application of rapamycin during the course of oocyte aging could reverse these DNA methylation alterations, and it can ameliorate several neurobehavioral aging trails that were in observed in aged oocyte offspring. WGBS-seq on DNA from hippocampal tissue revealed a number of differentially methylated (P<0.05) genes in OF1 and ORaF1 compared with YF1, and some of the enriched pathways were associated with aging process, such as PI3K-Akt signaling pathway (akin to transcriptional alterations above), MAPK signaling and Ras signaling pathway .

2022-12-31 | GSE164139 | GEO

Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

Project description:Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR). How allele-specific DNA methylation at ICR is regulated is largely unknown. Mammalian N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins. Mutation of human Naa10p is linked to severe developmental defects and mental retardation, including the Ogden syndrome. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorder and maternal-effect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses reveal global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-null embryos and ES cells. Naa10p regulates global DNA methylation by stimulating DNA methyltransferase 1 (Dnmt1) activity, while maintaining imprinted allele methylation by binding to GCXGXG and recruits Dnmt1. Clinical mutation of Naa10p disrupts its H19-ICR binding and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated human diseases to defective DNA methylation and genomic imprinting.

2017-09-29 | GSE83206 | GEO

A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes as well as failure of epigenetic reprogramming and zygotic genome activation in embryos [scRNA-seq]

Project description:Maternal inactivation of genes encoding components of the sub-cortical maternal complex (SCMC) and its associated member PADI6 generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multi-locus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a Padi6 missense variant that was identified in a family with Beckwith-Wiedemann syndrome and MLID. If homozygous in female mice this variant resulted in interruption of embryo development at the 2-cell stage. Single-cell multi-omic analyses demonstrated defective maturation of Padi6-mutant oocytes and incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, up-regulation of maternal decay genes and developmental delay in 2-cell embryos developing from Padi6-mutant oocytes, but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced level of UHRF1 in oocytes and abnormal localization of DNMT1 and UHRF1 in both oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue the developmental arrest of mutant embryos. Taken together, this study demonstrates that PADI6 controls both nuclear and cytoplasmic oocyte processes that are necessary for pre-implantation epigenetic reprogramming and ZGA.

2023-10-18 | GSE245423 | GEO

A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes as well as failure of epigenetic reprogramming and zygotic genome activation in embryos [WGS]

2023-10-18 | GSE245425 | GEO

A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes as well as failure of epigenetic reprogramming and zygotic genome activation in embryos [scBS-seq]

2023-10-18 | GSE245424 | GEO

Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

Project description:Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), of which the underlying mechanism remains largely unclear. Mammalian N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins. Mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorder and maternaleffect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and ES cells. Mechanistically, Naa10p facilitates the binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates and recruits Dnmt1 to ICRs of the imprinted allele during S phase. Moreover, the clinical lethal Ogden syndrome-associated mutation of Naa10p disrupts its binding to H19-ICR and Dnmt1 recruitment. Our study thus links Naa10p mutationassociated human disease to defective DNA methylation and genomic imprinting.

2017-10-05 | GSE102224 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data