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 from MIT, the Whitehead Institute and Harvard have mapped how a key developmental ingredient controls the genome.
The map could be used to guide the fate of stem cells so that they could replace diseased or damaged cells.
The mouse results were published in the April 20 issue of Nature; the human results 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," said Richard Young, an MIT biology professor and Whitehead member.
His senior colleagues on the work are Rudolf Jaenisch, also an MIT biology professor and Whitehead member; David Gifford, an MIT professor of electrical engineering and computer science; and Harvard University's Douglas Melton.
Both papers focus on a set of proteins collectively called Polycomb group proteins. Previous studies have shown that 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.
But how could anyone 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 tools that can scan entire genomes 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," Young said. "Careful handling of embryonic stem cells, designing the microarray tools, 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, working with other molecules to silence genes and then gradually allowing them to activate during development," Jaenisch said. "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."
This work was funded by the National Institutes of Health.