Reprogramming and Chromatin

There are hundreds of cell types in adult organism. Despite the fact that these cells have different functions, they all contain the same genetic material. The destiny of each cell in the body is set through a series of cell fate decisions that occur early in embryonic development. During this process numerous epigenetic marks (DNA and chromatin modifications) are added on genes in order to allow or permanently prevent their activation; this effectively leads to the restriction of the developmental potential of each cell. Consequently, in order to change the resulting cell fate, all the acquired epigenetic information needs to be erased and re-set. Such process (epigenetic reprogramming) normally occurs during embryonic development (at the onset of embryonic development in one cell embryo; and later on - in early embryonic germ cells). Additionally, similar process underlies regeneration and aberrant reversal of stable cell fate observed in cancer. Reprogramming processes can also be artificially induced in vitro, whereupon a somatic differentiated cell is changed to resemble cells of early embryos. Efficiency of this is, however, very low due to our lack of understanding of molecular mechanisms involved. The aim of our research is to unravel mechanisms underlying the natural reprogramming events that occur in mouse early embryos and germ cells. Investigation of the mechanisms operating during these processes will help us to understand regeneration and cancer and significantly improve our ability to manipulate cell fate in vitro.

The process of epigenetic reprogramming requires global resetting of epigenetic memory at the level of DNA methylation and chromatin modifications. This process leads to major shifts in gene expression profile and can lead to a change in cell fate. In mammals, under physiological conditions epigenetic reprogramming occurs in the course of development and potentially to some extent also as a part of the regenerative processes during wound healing. Aberrantly, similar processes that reverse cell fate decisions might be partially recapitulated during cellular dedifferentiation observed in cancer. In vitro, several reprogramming systems have been described that could be used to revert somatic cell phenotype and to regenerate pluripotency: somatic cell nuclear transfer (SCNT), generation of induced pluripotent cells (iPS), cell fusion or permeabilisation of cells followed by incubation with protein extracts - amongst others. However, these in vitro reprogramming systems are very inefficient, show high degree of variability, and often generate cells with intermediate phenotypes. In order to gain deep mechanistic insights into the molecular processes underlying epigenetic reprogramming we decided to focus on the naturally occurring reprogramming that operates efficiently in the course of embryonic development. |Our laboratory uses mouse zygotes and developing germ line (primordial germ cells, PGCs) as models where epigenetic reprogramming occurs naturally in vivo. In order to decipher molecular mechanisms underlying these reprogramming processes we concentrate on 2 main areas:1) Mechanisms underlying DNA demethylation and erasure of genomic imprints. |2) Interplay between DNA demethylation and chromatin dynamics Detailed understanding of the naturally occurring reprogramming processes will add to our ability to efficiently reprogram cells in vitro.