Epigenetics and Cell-Fate in Early Mammalian Development

The chromatin in stem cells and in cells of the early embryo displays unique features compared to the chromatin of differentiated cells, including the lack of ‘conventional’ heterochromatin. We propose that the transition from a totipotent state to a differentiated one is regulated by dramatic changes in chromatin states and chromatin organisation, in particular the formation of new heterochromatin.

We study the molecular players and the sequence of events that lead to the establishment of heterochromatin de novo in the embryo. We use the repetitive elements in the mouse genome, in particular retrotransposons and the major satellite repeats found in the pericentromeric chromatin, as a model for these studies. This research has direct implications for epigenetic reprogramming and for our understanding of how a more compact chromatin configuration progressively restricts cell fate determination and cellular plasticity.

Following fertilisation, the gametes undergo epigenetic reprogramming in order to revert to a totipotent state. The mechanism through which embryonic cells subsequently acquire their fate and the role of chromatin dynamics in this process are largely unknown.

The one-cell embryo – the zygote - undergoes a series of cell divisions resulting in the formation of the blastocyst. By this time point, the first differentiation event in the mammalian embryo has occurred; segregating the outer trophectoderm, which is developmentally restricted to extra-embryonic tissues, from the inner cell mass, which comprises the first pluripotent embryonic cells. We use a variety of approaches, including single cell approaches, to determine i) the chromatin components, ii) their dynamic changes, and iii) their role in the formation of the two first lineages of the mammalian embryo. In addition, we use the data generated to model quantitative changes underlying cell fate determination. This research will have an impact on our understanding of stem cell biology and cellular plasticity.

Totipotent cells are unique to the early embryo and are characterised by an extraordinary potential to form the extra-embryonic tissues as well as the embryo proper. Thus, totipotent cells display larger plasticity than pluripotent cells. Histone modifications and DNA methylation patterns are dramatically remodelled during early development.

Nuclear architecture has recently emerged as a key epigenetic factor, but a role for nuclear architecture in regulating reprogramming and totipotency during early development has not been established. We are interested in understanding how the genome organisation within the nucleus is shaped during the transitions from totipotency to pluripotency, and in determining whether this organisation has a functional impact on driving cellular plasticity and cell fate. Uncovering the molecular features that establish and maintain totipotency will have major implications for our ability to manipulate cell fate and cellular state. We anticipate that this knowledge will open up the road to establishing more efficient protocols for cellular reprogramming in regenerative medicine.