Dynamic Reprogramming of the Methylome during Preimplantation Embryo Development

A range of stresses to the gametes and early embryo create a predisposition to a life-long increased risk of chronic diseases. Perturbation to epigenetic reprogramming during early development is a fundamental cause of this disease burden. Using an epigenetically sensitive marker gene in the mouse, Avy, we show that creation of embryos by assisted reproductive technologies creates a 4-fold increased risk of inheritance of the epi-mutation. Efforts to understand the molecular basis for these errors has been limited by a range of conflicting models of the nature of the reprogramming of the epi-genome during early development. Immune-based assay approaches have been particularly problematic. We report that much of this controversy stems from a high, yet variable, levels of epitope masking of both methylcytosine and the DNA methyltransferase enzymes within the nucleus of the embryo. Changes in the extent of this masking at key embryonic transitions give the artefactual impression of larger changes then actually exist. The development of techniques for the reliable epitope retrieval of methylCpG and DNMT has allowed us to redefine the pattern of global dynamic reprogramming of the methylome during early embryo development. This new modelling provides a basis for the investigation of the molecular basis for the developmental origins of disease.