Studies Find Elusive Key to Cell Fate in Embryo

For three 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 different 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, Mass., have now 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 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 E. Bernstein and Eric S. 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. "Source":[http://www.nytimes.com/2006/04/25/science/25gene.html].

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