Genome-Wide Analysis of DNA Methylation in Buccal Cells of Children Conceived through IVF and ICSI.
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ABSTRACT:
SUBMITTER: Ducreux B
PROVIDER: S-EPMC8701402 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
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Genome-Wide Analysis of DNA Methylation in Buccal Cells of Children Conceived through IVF and ICSI.
Ducreux Bastien B Frappier Jean J Bruno Céline C Doukani Abiba A Guilleman Magali M Simon Emmanuel E Martinaud Aurélie A Bourc'his Déborah D Barberet Julie J Fauque Patricia P
Genes 20211128 12
Early life periconceptional exposures during assisted reproductive technology (ART) procedures could alter the DNA methylation profiles of ART children, notably in imprinted genes and repetitive elements. At the genome scale, DNA methylation differences have been reported in ART conceptions at birth, but it is still unclear if those differences remain at childhood. Here, we performed an epigenome-wide DNA methylation association study using Illumina InfiniumEPIC BeadChip to assess the effects of ...[more]
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Project description:AIM:Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed. METHODS:Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array. RESULTS:Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways. CONCLUSION:High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.
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Project description:BackgroundIn vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception.Methods and findingsCausal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school.ConclusionsIn this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.
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Project description:With nearly ten million babies conceived globally, using assisted reproductive technologies, fundamental questions remain; e.g., How do the sperm and egg DNA unite? Does ICSI have consequences that IVF does not? Here, pronuclear and mitotic events in nonhuman primate zygotes leading to the establishment of polarity are investigated by multidimensional time-lapse video microscopy and immunocytochemistry. Multiplane videos after ICSI show atypical sperm head displacement beneath the oocyte cortex and eccentric para-tangential pronuclear alignment compared to IVF zygotes. Neither fertilization procedure generates incorporation cones. At first interphase, apposed pronuclei align obliquely to the animal-vegetal axis after ICSI, with asymmetric furrows assembling from the male pronucleus. Furrows form within 30° of the animal pole, but typically, not through the ICSI injection site. Membrane flow drives polar bodies and the ICSI site into the furrow. Mitotic spindle imaging suggests para-tangential pronuclear orientation, which initiates random spindle axes and minimal spindle:cortex interactions. Parthenogenetic pronuclei drift centripetally and assemble astral spindles lacking cortical interactions, leading to random furrows through the animal pole. Conversely, androgenotes display cortex-only pronuclear interactions mimicking ICSI. First cleavage axis determination in primates involves dynamic cortex-microtubule interactions among male pronuclei, centrosomal microtubules, and the animal pole, but not the ICSI site.
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Project description:Study questionDoes ICSI induce specific DNA methylation changes in the resulting offspring?Summary answerAlthough several thousand analyzed CpG sites (throughout the genome) displayed significant between-group methylation differences, both ICSI and spontaneously conceived children varied within the normal range of methylation variation.What is known alreadyChildren conceived by ART have increased risks for medical problems at birth and to the extent of present knowledge also in later life (i.e. impaired metabolic and cardiovascular functions). One plausible mechanism mediating these ART effects are epigenetic changes originating in the germ cells and/or early embryos and persisting during further development.Study design, size, durationWe compared the cord blood methylomes and candidate gene methylation patterns of newborns conceived through ICSI or spontaneously.Participants/materials, setting, methodsUmbilical cord bloods were obtained from healthy newborn singletons conceived spontaneously (53 samples), through ICSI (89) or IVF (34). Bisulfite-converted DNA samples of 48 ICSI and 46 control pregnancies were used for genome-wide analyses with Illumina's 450K methylation arrays. Candidate genes from the methylation screen were analyzed in all three groups by bisulfite pyrosequencing.Main results and the role of chanceAltogether, 4730 (0.11%) of 428 227 analyzed CpG sites exhibited significant between-group methylation differences, but all with small (β < 10%) or very small (β < 1%) effect size. ICSI children showed a significantly decreased DNA methylation age at birth, lagging approximately half a week behind the controls. ART-susceptible CpGs were enriched in CpG islands with low methylation values (0-20%) and in imprinting control regions (ICRs). Eighteen promoter regions (six in microRNA and SNORD RNA genes), four CpG islands (three in genes including one long non-coding RNA), and two ICRs contained multiple significant sites. Three differentially methylated regions were studied in more detail by bisulfite pyrosequencing. ATG4C and SNORD114-9 could be validated in an independent ICSI group, following adjustment for maternal age and other confounding factors. ATG4C was also significant in the IVF group.Large scale dataN/A.Limitations, reasons for cautionThe observed epigenetic effects are small and there are numerous potential confounding factors such as parental age and infertility. Although our study meets current standards for epigenetic screens, sample size is still two orders of magnitude below that of genome-wide association studies.Wider implications of the findingsOur study suggests an impact of ICSI on the offspring's epigenome(s), which may contribute to phenotypic variation and disease susceptibility in ART children. Epigenetic regulation of gene expression by different classes of non-coding RNAs may be a key mechanism for developmental programming through ART.Study funding/competing interest(s)This work was supported by a research grant (no. 692185) from the European Union (ERA of ART). There are no competing interests.
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Project description:BackgroundDNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.ResultsGood-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3.ConclusionsWe conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.
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Project description:The field of DNA methylation research is rapidly evolving, focusing on disease and phenotype changes over time using methylation measurements from diverse tissue sources and multiple array platforms. Consequently, identifying the extent of longitudinal, inter-tissue, and inter-platform variation in DNA methylation is crucial for future advancement. DNA methylation was measured in 375 individuals, with 197 of those having 2 blood sample measurements ~10 years apart. Whole-blood samples were measured on Illumina Infinium 450K and EPIC methylation arrays, and buccal samples from a subset of 58 participants were measured on EPIC array. The data were analyzed with the aims to examine the correlation between methylation levels in longitudinal blood samples in 197 individuals, examine the correlation between methylation levels in the blood and buccal samples in 58 individuals, and examine the correlation between blood methylation profiles assessed on the EPIC and 450K arrays in 83 individuals. We identified 136,833, 7674, and 96,891 CpGs significantly and strongly correlated (>0.50) longitudinally, across blood and buccal samples as well as array platforms, respectively. A total of 3674 of these CpGs were shared across all three sets. Analysis of these shared CpGs identified previously found associations with aging, ancestry, and 7016 mQTLs as well.
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Project description:Epidemiological data indicate that children conceived in vitro have a greater relative risk of low birth-weight, major and minor birth defects, and rare disorders involving imprinted genes, suggesting that epigenetic changes may be associated with assisted reproduction. We examined DNA methylation at more than 700 genes (1536 CpG sites) in placenta and cord blood and measured gene expression levels of a subset of genes that differed in methylation levels between children conceived in vitro versus in vivo. Our results suggest that in vitro conception is associated with lower mean methylation at CpG sites in placenta and higher mean methylation at CpG sites in cord blood. We also find that in vitro conception-associated DNA methylation differences are associated with gene expression differences at both imprinted and non-imprinted genes. The range of inter-individual variation in gene expression of the in vitro and in vivo groups overlaps substantially but some individuals from the in vitro group differ from the in vivo group mean by more than two standard deviations. Several of the genes whose expression differs between the two groups have been implicated in chronic metabolic disorders, such as obesity and type II diabetes. These findings suggest that there may be epigenetic differences in the gametes or early embryos derived from couples undergoing treatment for infertility. Alternatively, assisted reproduction technology may have an effect on global patterns of DNA methylation and gene expression. In either case, these differences or changes may affect long-term patterns of gene expression.
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