For 3 billion years, life on Earth consisted of single-celled organisms like bacteria or algae. Only 600
million years ago did evolution hit on a system for making
multicellular organisms like
animals and plants.
The key to the system is to give the cells that make up an organism a variety of different identities so that they can
perform many different roles.
So even though all the cells carry the same genome, each type of cell must be granted access to only a few of the genes in the genome, with all the others
permanently denied to it.
People, for instance, have at least 260 types of cells, each
specialized for a different tissue or organ, but presumably each type can activate only some of the 22,500 genes in the human genome.
The nature of the system that assigns cells their various identities is a central mystery of animal existence, one that takes place at the earliest moments of life when the all-purpose cells of the early embryo are directed to follow different fates. Biologists at the Broad and Whitehead Institutes in Cambridge, Massachusetts, have delved deep into this process and uncovered what seems to be a crucial
feature of how a cell's fate is
determined, even though much remains to be understood.
They have discovered a striking new feature of the chromatin, the specialized
protein molecules that protect and control the giant molecules of DNA that lie at the center of every chromosome.
The feature explains how embryonic cells are kept in a poised state so that all of the genome's many developmental programs are blocked, yet each is ready to be executed if the cell is assigned to that developmental path.
The developmental programs, directing a cell to become a neuron, say, or a liver cell, are initiated by master regulator genes. These genes have the power to reshape a cell's entire form and function because they control many lower genes.
They do so by producing
proteins known as transcription factors that bind to special sites on the DNA and control the
activity of the lower-level target genes.
A question of interest for biologists studying cell identity is what regulates the master regulator genes. The answer has long been assumed to lie in the chromatin, which determines which genes are accessible to the cell and which are excluded. The chromatin consists essentially of millions of miniature protein spools around each of which the DNA strand is looped some one and half times.
The spools, however, are not mere packaging. They can lock up the DNA they are carrying so that it is inaccessible.
Or they can unwind a little, so that the strand becomes accessible to the transcription factors seeking to copy a gene on the DNA and generate the protein it specifies.
Working backward from that knowledge, biologists have spent much effort trying to learn how the state of the spools is determined.
They have learned there are protein complexes -- essentially sophisticated cellular machines -- that travel along the
chromosome and mark the spools with chemical tags placed at
various sites on the spool.
A complex known as a polycomb -- the name comes from the anatomy of fruit flies, in which it was first discovered -- - tags spools at a site called K27.
This is a signal for another set of proteins to make the spools wrap DNA tight and keep it inaccessible.
Another complex tags spools at their K4 site, which has the opposite effect of making them loosen their hold on the DNA.
The chromosomes of the body's mature cells are known to have long stretches of K27-tagged spools, where genes are off limits, and other regions where the spools are tagged on K4, allowing the cell to activate the local genes.
The Broad Institute scientists have made use of new techniques that let them visualize which spools along a chromosome carry the K27 or K4 tags.
They decided to map the tags in embryonic cells because of the interest of seeing how the process of determining cell fate is initiated.
In the current issue of Cell, a team led by Bradley Bernstein and Eric Lander reports that they looked at the chromatin covering the regions where the master regulator genes are sited.
They found to their surprise that these stretches of chromatin carried both kinds of tags, as if the underlying genes were being simultaneously silenced and readied for action.
These bivalent domains, as the biologists called the ambiguously tagged stretches of chromatin, were puzzling at first but make sense in terms of what embryonic cells are meant to do.
Each cell must avoid being committed to any particular fate for the time being, so all its master regulator genes must be repressed by tight winding of the spools that hold their DNA. But the cell must be ready at any moment to activate one specific master regulator as soon as its fate is determined.
The Broad team then looked at the chromatin state of the master regulator genes in several kinds of mature cell.
As was now predictable, they discovered that the bivalent domains had resolved into
carrying just one type of mark, mostly the K27 tag, indicating the master genes there were perman-ently repressed.
But in each kind of mature cell one or more of the domains had switched over to carrying just the K4 tags, within which genes would be active.
"We think the bivalent state is keeping the embryonic cells poised," Bernstein said. "It's very special; we didn't see it in any other kind of cell."
Bernstein's team worked with mouse cells, but its findings have been confirmed in human embryonic stem cells by Tong Ihn Lee and Richard Young of the
Whitehead Institute.
They and their colleagues started not with the bivalent domains but with the polycomb complex that gives the spools their K27 tag.
Working with human embryonic stem cells, the Lee-Young team mapped where a component of the polycomb complex was attached to the chromatin.
They found it had sought out some 200 sites where many of the master regulator genes of human cells are located. The Whitehead team's article, also published in the current Cell, indicates that in mice and people, just as in fruit flies, the same ancient mechanism is used to make the crucial decisions that determine cell fate.
"This is a very nice piece of work and will be widely interesting because it is funda-mental," said Allan Spradling, an expert on embryonic devel-opment at the Carnegie Institution of Washington, referring to both teams' findings.
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