Developmental genes targeted for epigenetic variation between twin-twin transfusion syndrome children

Carmen J Marsit, Devin C Koestler, Debra Watson-Smith, Charlotte M Boney, James F Padbury, Francois Luks

Epigenetic 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. We 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. These 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.