Abstract
BackgroundEpigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor. The donor twin in the TTTS syndrome can be profoundly growth restricted and there is likely a nutritional imbalance between the twins. The consequences of TTTS on fetal programming are unknown. This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent. As this condition and the resulting uteroplacental discordance can play a role in the epigenetic process, we sought to investigate the DNA methylation profiles of childhood survivors of TTTS (n = 14). We focused on differences in both global measures and genome-wide CpG specific DNA methylation between donor and recipient children in this pilot study in order to generate hypotheses for further research.ResultsWe identified significant hypomethylation of the LINE1 repetitive element in the peripheral blood of donor children and subtle variation in the genome-wide profiles of CpG specific methylation most prominent at CpG sites which are targets for polycomb group repressive complexes.ConclusionsThese preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.
Highlights
Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease
We examined how DNA methylation profiles in cases of Twin-twin transfusion syndrome (TTTS) are impacted by donor-recipient status, a model of extreme adverse and rich intrauterine conditions
Using a gene-set enrichment analysis approach, we found that loci with high donor-recipient interclass correlation coefficient (ICC) were significantly more likely (P = 0.0002) to be polycomb group target genes (PcG) [36,37] but were not significantly enriched for genes within CpG islands (P = 0.14)
Summary
Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Epidemiologic studies have clearly linked infant growth to antenatal environmental factors, including diet, xenobiotic exposures, stress and lifestyle factors, as a significant risk factor for long-term chronic disease, cardiovascular disease and metabolic syndromes [1,2,3] These studies, and a growing literature on the role of development on lifelong health, would suggest that a significant. Studies of specific candidate genes as well as genome-wide examinations of DNA methylation have demonstrated clear relationships to infant birthweight, supporting the role of DNA methylation in mediating these risks [7,8] This is relevant to correlations in genes involved in metabolism, growth and cardiovascular disease [9]
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