Dataset Information

Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals.

ABSTRACT: Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted MEST promoter and the paternally imprinted MEG3 intergenic (IG) differentially methylated region (DMR) in fetal cord blood, adult blood, and visceral adipose tissue. Epimutations were defined as paternal or maternal alleles with >50% aberrantly (de)methylated CpG sites, showing the wrong methylation imprint. The epimutation rates (range 2-66%) of the paternal MEST and the maternal MEG3 IG DMR allele, which should be completely unmethylated, were significantly higher than those (0-15%) of the maternal MEST and paternal MEG3 alleles, which are expected to be fully methylated. This hypermethylation of the non-imprinted allele (HNA) was independent of parental origin. Very low epimutation rates in sperm suggest that HNA occurred after fertilization. DBS with Illumina (MiSeq) technology confirmed HNA for the MEST promoter and the MEG3 IG DMR, and to a lesser extent, for the paternally imprinted secondary MEG3 promoter and the maternally imprinted PEG3 promoter. HNA leads to biallelic methylation of imprinted genes in a considerable proportion of normal body cells (somatic mosaicism) and is highly variable between individuals. We propose that during development and differentiation maintenance of differential methylation at most imprinting control regions may become to some extent redundant. The accumulation of stochastic and environmentally-induced methylation errors on the non-imprinted allele may increase epigenetic diversity between cells and individuals.

SUBMITTER: Haertle L

PROVIDER: S-EPMC5576652 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals.

Haertle Larissa L Maierhofer Anna A Böck Julia J Lehnen Harald H Böttcher Yvonne Y Blüher Matthias M Schorsch Martin M Potabattula Ramya R El Hajj Nady N Appenzeller Silke S Haaf Thomas T

PloS one 20170830 8

Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted MEST promoter and the paternally imprinted MEG3 intergenic (IG) diffe ...[more]

PMID: 28854270

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Project description:BACKGROUND:Imprinted genes, which are expressed in a parent of origin-specific manner, are thought to mediate the genetic priorities of each parent in pregnancy. Recently we reported that some fetal imprinted gene variants are associated with maternal glucose concentrations and blood pressures in pregnancy. We suggest that the conflict between the effects of paternal and maternal transmitted genes starts at conception and may already be evident in measures of maternal metabolism in early pregnancy, before gestational diabetes is manifest. METHODS:Lipid fractions in maternal non-fasting serum collected around week 15 of pregnancy were profiled using direct infusion mass spectrometry in a subset Discovery Cohort (n =?200) of women from the Cambridge Baby Growth Study using direct infusion mass spectrometry. Associations between 151 haplotype-tag fetal polymorphisms in 16 imprinted genes and lipids were determined using partial least squares discriminant analysis. Variable importance in projection scores were used to identify those lipid species that contribute most to the underlying variation in the lipid profile and the concentrations of these species tested for associations with fetal imprinted gene alleles using linear regression. In an internal Validation Cohort (n =?567 women from the same cohort) the lipid fraction was profiled using liquid chromatography-mass spectrometry and tested for associations with the same fetal imprinted gene variants as above, followed by meta-analysis of associations from the Discovery and Validation Cohorts. RESULTS:The most significant associations were between a monounsaturated triglyceride (44:1) and both paternally-transmitted fetal H19 rs7950932 (R =?0.14, p =?2.9?×?10-?3, n =?386) and maternally-transmitted fetal FAM99A rs7131362 (R =?0.18, p =?6.2?×?10-?3, n =?351; association with maternal-untransmitted allele R =?0.08, p =?0.07, n =?328). This same triglyceride isoform was also associated with subsequent week 28 fasting glucose concentrations (R = 0.09, p = 9.9 × 10-?3, n = 673) and homeostasis model assessment of insulin resistance (R = 0.09, p = 0.01, n = 664). CONCLUSIONS:Fetal imprinted genes may influence maternal circulating clinically relevant triglyceride concentrations early in pregnancy.

Dataset Information

Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals.

Publications

Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals.

Similar Datasets

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