What are the mechanisms that keep the stem cells of an embryo capable of generating every cell type in our organism? A team of researchers in Pisa, Rome, Florence and Cambridge (UK) coordinated by Dr. Federico Cremisi, has just given an answer to this question. Dr. Cremisi is a developmental biologist working at the Bio@SNS laboratory of the “Scuola Normale Superiore”, directed by Prof. Antonino Cattaneo.

It has been long known that some of the most important genes driving cellular differentiation are already active in embryonal stem cells, a very surprising fact, given that these cells are not differentiated at all. The team of Dr. Cremisi has used an integrated approach, investigating this issue on many fronts, and elucidated the mechanism that allows stem cells to remain in a naïve state even though their differentiation machinery is already switched on.

In an article published on the journal “Genome Biology”, Dr. Luca Pandolfini (a Ph.D. student in Neurosciences at the Scuola Normale Superiore) et al. identified a group of small RNAs (microRNAs) that have the function of blocking the production of several key proteins responsible for cellular differentiation, even though their RNA is already present in the stem cells.

These microRNAs, explains Dr. Cremisi, act like the clutch of a manual transmission car, preventing the vehicle from starting even though the gear is already engaged. In the same way, the cells in the early embryo are “ready to go”, but begin to produce the cell types forming the animal only when the inhibition on the differentiation genes is relieved.

Luca Pandolfini and his collaborators have sequenced more than 300 Giga-bases of DNA, and performed a global and integrated analysis of 27,000 genes, mRNAs, microRNAs and proteins in both embryonic stem cells and differentiated cells. This allowed the identification of a set of genes, responsible for the start of differentiation, which are transcribed into RNA, but not translated into proteins. These genes were found to code preferentially for chromatin regulator proteins, enzymes capable of modifying specific regions on chromosomes, switching them from an inactive to an active status and vice versa.

This process, defined “epigenetic remodeling”, plays a fundamental role in cellular differentiation.
The discovery of Pandolfini et al, which uncovered a basic fundamental mechanism of cell development, could now be very useful to increase our knowledge regarding de-differentiation, a reverse process of differentiation, which is a relevant step in the generation of tumours from healthy cells.

 (picture: mouse embryonic stem cells)