“It is important to think about reprogramming from the natural side, rather than only from the experimental side, because embryonic pluripotent stem cells and early embryos appear to have some capacity to reprogram their own epigenomes,” explains Wolf Reik, M.D., head of the epigenetics laboratory at the Babraham Institute.
Dr. Reik’s laboratory focuses on natural epigenetic reprogramming, a phenomenon that was first discovered a little over 10 years ago when several groups described genome-wide DNA-methylation loss that occurs subsequent to fertilization in the pre-implantation mouse embryo, up to the blastocyst stage.
“We have been trying to examine natural reprogramming from a mechanistic point of view and to understand its biological significance.” Investigators in Dr. Reik’s laboratory recently described the active demethylation of 5-methylcytosine to generate 5-hydroxymethylcytosine as a novel modification visualized in the paternal pronucleus of mouse, bovine, and rabbit zygotes. The conversion of 5-methylcytosine to 5-hydroxymethylcytosine in embryonic stem cells is mediated by TET1 and TET2, enzymes that are highly expressed in these cells.
In an analysis of the genome-wide pattern of methylation and hydroxymethylation during differentiation of murine embryonic stem cells, Dr. Reik’s team found decreased hydroxymethylation along with increased methylation and gene silencing at embryonic stem cell promoters. This indicates that 5-hydroxymethylcytosine plays important roles in genome-wide methylation reprogramming, and the balance between global hydroxymethylation and methylation appears to be tightly linked to the balance between pluripotency and lineage commitment.
Understanding epigenetic modifications during natural reprogramming has multiple clinical applications. Regenerative medicine is one area that will benefit, and assessing the epigenetic status of embryonic stem cells promises interventions to therapeutically change reprogramming when needed.
“A broader area is in common adult diseases in humans, where genetic explanations are still not satisfactory,” says Dr. Reik. While genetic variants were unveiled and characterized for many adult-onset complex human diseases, most frequently, a large part of the risk cannot be explained by genetic factors alone. “It is this area where knowledge about epigenetic variants, and how they contribute, and epigenetic modifiers, will be important.”
Epigenetics promises to unveil fundamental mechanistic details about natural and experimental cellular reprogramming during differentiation and development. Some of the most recent developments in this field underscore the central role of epigenetic and genetic factors that, in combination, shape these processes. A better understanding of the players and signaling pathways promises not only to unravel the mysteries that surround cellular reprogramming, but also to open important therapeutic avenues.