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U.VA. SCIENTISTS DISCOVER NEW LINK IN GENETIC RESEARCH

Researchers at the University of Virginia have found another key to the genetic puzzle that controls development of birth defects and diseases like cancer. In a paper published Friday, August 6 in the journal Science, U.Va. researcher C. David Allis and a team of scientists led by Paolo Sassone-Corsi at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, identified a new way that DNA in a human cell is controlled.

The DNA inside the cell is packaged inside a protein coating called chromatin, Allis said. The proteins, called histones, are coiled around the DNA in a very complex way. The question is, how do you open that package to regulate the genes inside? Scientists have usually focused on the DNA and the genes themselves, but this study is one of the first clear examples of signaling to chromatin, the outer layer that needs to be penetrated first.

Cell signaling takes place when substances in the body tell cells how to grow and what genes to activate – resulting in traits like eye color or risks for hereditary diseases. Those substances talk or signal instructions to the genes in the cell's nucleus through certain chemical reaction pathways. Learning what chemical reactions take place and how they turn various genes on and off, may enable scientists to control genes that may predispose people to disease, and turn these genes off.

In addition to the new focus on chromatin, the study found that a well-known enzyme protein called Rsk2 was causing changes in the chromatin proteins. Defective Rsk2 enzymes are active in causing the Coffin-Lowry syndrome (CLS), a rare condition that causes deformity and mental retardation in children.

In part of the study, the researchers compared cells from CLS patients and cells from their normal siblings. Stimulating the cells to divide by using a protein substance called epidermal growth factor, they found that the enzyme Rsk2 caused a chemical reaction called phosphorylation in the healthy cells' chromatin proteins, and did not in the CLS patients' cells. Finding that Rsk2 is required for phosphorylation of chromatin histones has far-reaching implications for human biology and kids with CLS, Allis said.

I think we're going to find more and more cell signaling pathways that affect DNA, which is the center of everything biological, Allis said. Understanding what turns genes on and off in their natural chromatin setting is key to solving some of the most difficult health puzzles we face, Allis said. U.Va. has established a research center that focuses exclusively on cell signaling.

August 5, 1999