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As a fertilized egg develops into a full-grown adult, mammalian cells adopt careers as different cell types, from liver cells to neurons. One of the most fundamental mysteries in biomedicine is how cells make such different career decisions despite having exactly the same DNA.
Now a team led by scientists at the Broad Institute of MIT and Harvard and Massachusetts General Hospital has unveiled a special code--not within DNA, but rather within the so-called "chromatin" proteins surrounding it--that could unlock these mysterious choices underlying cell identity.
One of the most surprising findings of the study, published in the July 1 advance online edition of Nature, is that this chromatin-based code may reveal the developmental choices cells have already made as well as those decisions that lie ahead.
"If true, this would have enormous implications for our understanding of developmental biology and for guiding regenerative medicine," said Broad Institute Director Eric Lander, a co-senior author of the study, MIT professor of biology and member of the Whitehead Institute for Biomedical Research.
"Unraveling the mysteries of chromatin holds great promise for understanding how cells in the body...assume such different forms and functions," said co-senior author Bradley Bernstein, an associate member of the Broad Institute and an assistant professor at Massachusetts General Hospital and Harvard Medical School. "By applying a new technology for sequencing DNA, we have been able to look across the genome at chromatin, with greater resolution and efficiency than ever before."
The team has already created genome-wide chromatin maps for embryonic stem (ES) cells and two cell types derived from them.
Chromatin proteins are more than just packing material for the genome. By virtue of different chemical groups fastened to them, these proteins influence which parts of the DNA double helix are open--or not--to the cellular machinery, thus controlling which genes get turned on or off.
To decipher this code requires ways of determining precisely which chromatin proteins sit at which locations along a cell's DNA. In principle, scientists could infer the locations using specialized DNA chips. In practice, though, the technique has proven to be slow and expensive.
Empowered by a new method of massively parallel DNA sequencing, the researchers set out to study chromatin in cells with drastically different behaviors: mouse ES cells--known for their unusual ability to form nearly any tissue--as well as two other types of descendant cells that are more limited in the developmental paths they can choose.
One of the most remarkable findings involves a way of using chromatin to look into a cell's past to determine the developmental decisions it has already made, and to peer into the future to read its potential choices. The fortuneteller lies in a unique form of modified chromatin known as a "bivalent domain," which marks the control regions of important genes. Such domains merge both activating and repressive chemical tags, keeping genes quiet yet poised for later activity.
Bivalent domains had been noted for their role in ES cells, helping keep these cells' developmental options wide open. But with the new genome-wide chromatin data, the scientists discovered that these domains also function in more specialized kinds of stem cells. In neural stem cells, for example, bivalent domains sit near genes important to various types of brain cells but are notably absent from genes that would be active only in, say, skin cells or blood cells.
"Looking at a cell through a microscope often cannot tell you what kind of cell it is, or more importantly, what it has the potential to become," said first author Tarjei Mikkelsen, a Broad Institute researcher and a graduate student in the Harvard-MIT Division of Health Sciences and Technology. "But by decoding its chromatin on a genomic scale, we can now begin to systematically address such questions."
This research was supported by the National Human Genome Research Institute, the National Cancer Institute, the Burroughs Wellcome Fund, Massachusetts General Hospital and the Broad Institute of MIT and Harvard.