Mapping the foundation of human development

CAMBRIDGE, Mass. (April 20, 2006) — Embryonic stem cells may one day provide a means to treat disease, but according to two new reports, they are already revealing remarkable insights into the mysteries of human biology. How humans manage to develop from a single fertilized egg into the trillions of cells that make up a mature adult remains a poorly understood process. Now, using both human and mouse embryonic stem cells, researchers in the Whitehead Institute labs of Richard Young and Rudolf Jaenisch, in collaboration with Harvard University's Douglas Melton and MIT's David Gifford, have mapped how a key developmental ingredient controls the genome.

The mouse results were published in the April 20 issue of Nature, and the human results were published in the April 21 issue of Cell.

"These papers are a major step forward in our efforts to map the regulatory circuitry of embryonic stem cells—which constitutes the founding circuitry of human beings," says Young.

Both papers focus on a set of proteins collectively called Polycomb group proteins. Previous studies showed that the Polycomb proteins are essential for early development. If the genes that code for Polycomb proteins are lost in embryonic stem cells, the cells begin to develop in an uncontrolled fashion and lose their unique properties. Knowing that Polycomb is key to an embryonic stem cell's identity, Young and Jaenisch realized that catching it in action as it interacts with all its target genes would provide an unprecedented look into how stem cells are wired.

However, such a project raises a daunting question: How do you scan all 3 billion letters of the genome to identify several hundred protein/DNA interactions? It's the biological equivalent of poring over satellite images of North America to find all the power stations that power the electrical grid.

Young's lab has developed a suite of microarray tools that can scan entire genomes in order to locate certain targeted molecules. However, this is the first time such technology has been used to scan the entire genomes of embryonic stem cells.

A group of researchers, led by postdoctoral scientists Laurie Boyer, Matthew Guenther, Richard Jenner, Tony Lee, Stuart Levine, and Kathrin Plath applied the technology to human and mouse embryonic stem cells. "It required tremendous innovation from this group," says Young. "Careful handling of embryonic stem cells, designing the microarrays, analyzing the sheer volume of data from the human genome—these experiments were technical feats carried out by an exceptionally talented team in an interdisciplinary environment."

Polycomb, it turns out, represses entire networks of genes that are essential for later development, the same genes that begin to turn on as a stem cell starts to differentiate. That explains why embryonic stem cells immediately grow into specialized cells when Polycomb proteins are lost.

"Polycomb is dynamic," says Jaenisch, "working with other molecules to silence genes and then gradually allowing them to activate during development. It is also the founding ingredient for development, so knowing how it works and which genes it interacts with will be invaluable for understanding these amazing cells."

"We're continuing to map the regulatory network that controls stem-cell state and development," says Young. "We hope to use this map to guide the fate of cells so that they can be used to replace diseased or damaged cells."

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Lee, T. et al. "Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells." Cell, 125, April 21, 2006.