Abstract
BackgroundLow birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes.ResultsOverall, co-twins show very similar genome-wide DNA methylation profiles. Since observed differences are almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3,153 are differentially methylated between the heavy and light co-twins at nominal significance, of which 45 show sensible absolute mean β-value differences. Deep bisulfite sequencing of eight such loci reveals that differences remain in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicates no significant intra-pair differences.ConclusionsSevere intra-uterine growth differences observed within these monozygotic twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies.
Highlights
Low birth weight is associated with an increased adult metabolic disease risk
A genome-wide DNA methylation study performed on CD34+ hematopoietic stem cells from cord blood of five intra-uterine growth restricted (IUGR) neonates and five gestational age and gendermatched controls [16] identified among others significant methylation differences at the hepatocyte nuclear factor 4 alpha (HNF4A) gene, which is involved in monogenic diabetes
Results of the Wilcoxon signed-rank test of the 8 selected methylation variable position (MVP) performed on the Infinium and the deep bisulfite sequencing (DBS) data in the 16 MZ twins discordant for birth weight are presented. aInfinium data are expressed as mean b-value ± standard deviation (SD). bHeavy versus light calculated using a Wilcoxon signed-rank test. cDBS
Summary
Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes Both observational human and experimental animal studies have confirmed that low birth weight is associated with an increased risk of metabolic diseases, like type 2 diabetes (T2D) [1,2,3]. Genetic factors are likely to contribute [4,5], studies assessing the association between low birth weight and T2D precursors in monozygotic (MZ) twins showed that the twin who was lighter at birth had a more adverse metabolic profile in adulthood compared to its genetically identical co-twin, who was heavier at birth [6,7,8,9,10]. A genome-wide DNA methylation study performed on CD34+ hematopoietic stem cells from cord blood of five intra-uterine growth restricted (IUGR) neonates and five gestational age and gendermatched controls [16] identified among others significant methylation differences at the HNF4A gene, which is involved in monogenic diabetes
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