[EMAIL PROTECTED] Fascinating, complicated biological science stuff. --------------------------------------------------------------------------------
September 13, 2005 Analyzing the Circuitry of Stem Cells By NICHOLAS WADE How are the 25,000 genes of a human cell controlled and orchestrated? How does a stem cell in the embryo develop into a mature cell of the brain or heart or liver? A possibly deep insight into all these questions has been gained by mapping the top-level circuitry that controls the human embryonic stem cell. Scientists at the Whitehead Institute in Cambridge, Mass., have developed a technique for uncovering the interactions of transcription factors. These are the agents that switch genes on or off in the cell. By figuring out these interactions on a genomewide scale, they have reconstructed the top level of the controls that govern a human embryonic stem cell. The discovery is a starting point for addressing the next question, that of how an embryonic stem cell commits itself to a specific fate, like becoming a cell of the brain or liver or pancreas gland. Biologists have long understood the lowest level of gene control. In front of most genes is a sequence of DNA known as a promoter region. When the right transcription factor, a protein, lands on the promoter, the DNA of the gene is transcribed into RNA. This is the first step in generating whatever protein the gene specifies. But that has left wide open the question of the higher levels of control. The cell has not one but 25,000 genes to deal with. In each type of cell, a majority of these genes must be kept permanently switched off since their products would interfere with the cell's specific role. Other genes must respond instantly to signals arriving from the outside environment. This requires a higher level of control. But given that the cell has no central management or computer, where does this higher level of control reside? Richard Young, a Whitehead Institute biologist, investigated this question. Starting with yeast, he found three years ago that many of the yeast cell's transcription factors act on the promoters that control other transcription factor genes. This interaction between transcription factors seemed to serve as the cell's higher level control system. He has now applied the technique to human cells, starting with embryonic stem cells. The cells, he and colleagues say in the current issue of Cell, are controlled by a triumvirate of three transcription factors, known as oct4, sox2 and nanog. The three factors interact with one another to maintain joint activity. They also control a large set of promoter sites that govern genes involved in the cell's major developmental pathways. The control is exerted jointly to a surprising extent, since two or sometimes three members of the triumvirate are required at the promoter sites. They do not turn genes on, however; they keep them inactive. They inhibit genes that lead to the embryo's first developmental steps, the formation of the endoderm, mesoderm and ectoderm layers of tissue, as well as other major pathways. Geneticists have established that oct4, a characteristic ingredient of embryonic cells, disappears completely from cells that have started to develop. Dr. Young says he believes that the repressive controls exerted by the oct4 troika must somehow remain in place, even after the troika has been retired, on all but one of the main developmental paths, depending on which cues a cell is receiving from its environment. It is not clear how oct4 is activated in the first place. On its promoter site the Whitehead team could see only the fingerprints of sox2 and nanog, the other members of the triumvirate. Perhaps the egg produces some factor that jumpstarts oct4 production, Dr. Young said. Discovery of such a factor would be of great interest because it could provide an easy way of reprogramming a mature human cell back to the embryonic state. Dr. Young said he planned to study the new circuitry that may be invoked as an embryonic stem cell makes the transition to a nerve cell. "Presumably oct4 and partners will be eliminated from the cell, and other regulators will come along to create a new gene expression program," he said. Michael Snyder, a biologist at Yale, said the new report provided the first glimpse of the regulatory circuit of an embryonic stem cell. "Nobody has done global mapping on an embryonic stem cell so this is fairly groundbreaking in that sense," he said. "It's a great first start but the results need to be confirmed." Genes and control sites used to be studied one by one. Since 2003, the decoding of the human genome has made it possible to study all such elements at the same time. This requires vast scaling up by laboratories. But systems biologists, as many in this new field call themselves, believe that analysis on a genomewide basis is the only way to understand the operation of human cells in their full intricacy. a.. Copyright 2005 The New York Times Company [Non-text portions of this message have been removed] ------------------------ Yahoo! Groups Sponsor --------------------~--> Get fast access to your favorite Yahoo! Groups. Make Yahoo! your home page http://us.click.yahoo.com/dpRU5A/wUILAA/yQLSAA/LRMolB/TM --------------------------------------------------------------------~-> Yahoo! Groups Links <*> To visit your group on the web, go to: http://groups.yahoo.com/group/scifinoir2/ <*> To unsubscribe from this group, send an email to: [EMAIL PROTECTED] <*> Your use of Yahoo! Groups is subject to: http://docs.yahoo.com/info/terms/
