A Study of the Placental Methylome of Dichorionic and Monochorionic Monozygotic Twin Pairs to Establish a Timeline of Epigenetic Programming

Rationale: The developmental origins of health and disease (DoHaD) hypothesis, states that antenatal and early life exposure to a suboptimal environment can predispose for adverse health outcomes in adult life, such as cardiometabolic disease. Modification of the epigenome, and more specifically the methylome, seems a plausible mechanism for this. It has been shown that a suboptimal early environment, such as famine during the periconception period, can perturb DNA methylation signatures of the offspring. Furthermore, the preimplantation period is likely to represent a critical window for the establishment of optimal DNA methylation as epigenetic reprogramming takes place during this time. The precise influence of environmental factors during this time is incompletely understood; human studies of the preimplantation period are complicated by an inaccessibility of samples and the high variability of the environment induced by maternal factors. Here, the study of monozygotic twins can be employed. Although monozygotic twins are genetically identical, they can differ phenotypically, for example in birth weight. Phenotype and methylome differences attributable to genetic and maternal differences can be ruled out, meaning that intra-pair differences must be a result of variation in their prentatal environment. Furthermore, the moment of splitting defines the point from which twins can experience environmental differences. The timing of the moment of splitting is variable amongst twins and can be inferred from chorionicity, allowing a time-line of early environmental influences to be established. Monozygotic twins can remain discordant for growth and health outcomes throughout life, implying the prenatal establishment of a regulatory program with effects that persist into adulthood.