Forever young: digging for the roots of stem cells.

Researchers have now shown how a trio of proteins controls whether an embryonic stem cell takes an irreversible step toward developing into specific tissues or retains its raw potential to become a blood cell, bone cell, brain cell, or any other kind of cell.

Stem cells' unique capacity to develop into any type of cell--a property known as pluripoteney--underlies their medical promise. Researchers argue that this trait could someday lead, for example, to lab-grown tissue and organs that would be useful for transplants.

The scientists set out to determine what genes define a stem cell. "We thought if we could uncover this network of genes, then we could see how pluripotency is established," says Laurie A. Boyer of the Whitehead Institute in Cambridge, Mass. And with knowledge of the mechanics behind pluripotency, she says, scientists might learn to reprogram a mature cell so that it, too, could have the pluripotency of a stem cell.

Boyer and her collaborators investigated three proteins known to play defining roles in keeping stem cells from developing into a specific cell type. The proteins, dubbed Oct4, Sox2, and Nanog, are classified as transcription factors. As such, they bind to specific genes and regulate the genes' activities. Scientists didn't know how these three transcription factors maintain stem cell pluripotency.

To fill that information gap, the researchers identified the genes to which Oct4, Sox2, and Nanog bind. In the Sept. 23 Cell, the researchers report that these three transcription factors attach to a region of the genome that contains genes that other researchers have shown to control cell development. At least one factor bound to each of 2,260 genes.

The researchers also found that 1,303 of these genes were active in the stem cell and that the protein products of some of these genes, in turn, activated more genes.

At the same time, the three factors repressed many genes essential for stem cells to differentiate into specific cell types during embryonic development.

The findings suggest that Oct4, Sox2, and Nanog are "master regulators," Boyer says. "These three shut off differentiation and allow for a pluripotent state."

Besides discovering that pivotal role for these regulators, the researchers mapped out the molecular biology behind pluripotency. Because all three regulators bind to 353 of the genes, the researchers concluded that the regulator proteins work together in keeping a stem cell undifferentiated.

The research also suggests that Oct4, Sox2, and Nanog interact in a complex way that controls how much of each of the three proteins is present in the cell.

The work by Boyer's group "identifies a cohort of genes" that are targets of these master regulators, comments Ian Chambers of the University of Edinburgh. This is a starting point to test more aspects of the stem cell regulatory network, he says.

To tease out additional molecular details, Boyer's group plans to perturb the proteins and genes underlying stem cell behavior and to observe how the cells respond. This work, Boyer predicts, will provide more insights both about pluripotency in stem cells and about the remarkable process by which a single fertilized cell becomes an entire organism.