’Looking’ at Eyeless from two directions

When Dr. Rui Chen, assistant professor in the Baylor College of Medicine Human Genome Sequencing Center, sought to understand further the protein called Eyeless, he faced a dilemma.

Eyeless is a transcription factor, which means one of its major activities is to turn off or turn on other genes that have an effect on eye development later in the process. It is so powerful that when it is inserted into almost any tissues of the fruit fly, eyes grow – often in unexpected places.

Because Eyeless is a critical factor in the development of eyes in fruit flies or Drosophila, (a common model organism for studying how different organs grow), understanding the genes it affects could offer key clues into how the organs for sight actually develop in fruit flies and ultimately people.

One method for locating these genes is called a microarray, a tiny DNA chip used to identify specific sequences of genetic material. A microarray can provide hundreds of candidate genes – too many to be useful. Another method is to use bioinformatics and computers to predict where transcription factors bind, but this can give thousands of candidate genes. Again, that’s too much information to be valuable.

Chen, however, took a different tack. He used both methods. Then he dealt with only the genes and binding sequences that were found by both. Of the 300 genes found by microarray and 10,000 or more by the binding site technique, only 21 were found by both.

Because 11 of these were known to play a key role in eye development, he knew he was on the right track. A report of his work appears online today in the journal Genome Research.

“The reason I like this project is that it provides the possibility of doing this in almost any species,” said Chen. “It’s a combination of genomic and biologic techniques.”

“Finding specific targets of a transcription factor is the Holy Grail for many biologists,” said Dr. Graeme Mardon, senior co-author and a professor in the Program in Developmental Biology at BCM. In this case, he said, the researchers have shown that the genes they found are, in fact, targets of the Eyeless protein.

“We are now in the process of knocking out hundreds of genes predicted to be targets of this retinal network,” said Mardon. “This has opened the door to determining what are the critical targets of this gene for eye development. Others can use similar methods to do the same thing.”

Eventually, he said, the technique could be used to identify genes that are involved in similar processes that go wrong, leading to diseases. This will identify the areas where things go wrong so that researchers can target proposed therapies and drugs in the future.

In their area, the technique speeds the process of identifying those genes that are really important in identifying the genes critical to development of the eye.

“It also gives you a global picture of what the transcription factor does,” said Chen. “This is also a molecular screen” that will be valuable in studying mammals.