Two studies in the April 21, 2006 Cell report new details of the "genetic program" that affords embryonic stem cells the flexibility to give rise to any cell type in the body. Both groups identified mechanisms by which the embryonic stem cells of mice or humans keep from going down any one particular developmental path--that of muscle or nervous tissue, for example--while remaining "poised for activation."
Human embryonic stem cells can be kept in an undifferentiated state and selectively induced to form many specialized cell types, which could potentially replace cells lost or damaged by disease. The new findings may therefore aid in the realization of embryonic stem cells' therapeutic potential for regenerative medicine, according to the researchers, while furthering scientists' understanding of early development.
In one of the studies, Richard Young of the Whitehead Institute, and his colleagues, found that a member of the so-called Polycomb-group proteins is distributed across a special set of more than 200 developmental genes in human embryonic stem cells. Polycomb proteins are known to silence gene activity through chemical, or "epigenetic," modifications that alter the way that DNA is packaged into chromatin.
"We saw that the Polycomb protein preferred to occupy genes for most of the human developmental regulators to repress their activity," Young said. "These genes encode transcription factors that control development downstream of the embryo."
"This makes sense because were the developmental transcription factors 'on,' they would cause the embryonic stem cells to differentiate into specific cell types. It's an exciting result because it appears that the Polycomb proteins are generally responsible for maintaining developmental genes in an 'off' state."
Developmental genes found in association with the Polycomb protein were also occupied by histone proteins chemically modified at sites known to repress gene activity, they found. Histones--the chief proteins of chromatin--act as spools around which DNA winds and play a role in gene regulation.
Furthermore, they found, the silenced developmental genes became preferentially activated in human embryonic stem cells undergoing differentiation.
The findings help to explain earlier results in mice deficient for Polycomb proteins, Young said. The embryonic stem cells of those mice were "extremely unstable" and tended to specialize or die in culture, he said.
The results also add to the team's earlier finding, reported in Cell last year, that a trio of transcription factors--Oct4, Sox2, and nanog--are key regulators of embryonic stem cells' pluripotency and self-renewal," he said. Pluripotency refers to the cell's ability to develop into multiple cell types. The three factors apparently work together to activate pathways critical for stem cell identity, while repressing those leading to differentiation.
The researchers now report that the stem cell regulators Oct4, Sox2, and nanog co-occupy "a significant subset" of the developmental genes that are repressed by the Polycomb protein, further supporting a link between repression of developmental regulators and embryonic stem cell identity.
"This paper connects the two classes of embryonic stem cell regulators and provides a foundation for understanding the basic circuitry underlying human development," Young said.