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Stowers research shows that DNA sequences at the beginning of genes contain more information than previously thought.
When egg and sperm combine, the new embryo bustles with activity. Cells multiply so rapidly, they largely ignore their DNA, other than to copy and read just a few essential genes. Embryonic cells mainly rely on molecular instructions placed in the egg from the mother in the form of RNA.
The cells translate these RNA molecules into proteins that manage almost everything in the first minutes or hours of the embryo's life. Then, during the "midblastula transition," cells start transcribing (reading) massive amounts of their own DNA. How embryonic cells flag a small set of genes for transcription before the midblastula transition, holds important information about normal development and disease in animals and in humans.
A new study by researchers at the Stowers Institute for Medical Research, led by associate investigator Julia Zeitlinger, Ph.D., sheds light on these questions. It appears in the Aug. 13 issue of eLife Sciences.
Researchers have long thought that once an RNA polymerase appears at the worksite it quickly finishes the job of trascription. "Our most important result is that promoters are different," Zeitlinger says. "The general paradigm for a long time has been a promoter is a promoter. But really, what we see is that they have different functions."
"We wondered whether pausing was prepartion for global gene activation during the midblastula transition," says Kai Chen, PhD, a former graduate student in Zeitlinger's lab and the study's first author. "We expected to see widespread pausing before that transition."
The fruit fly Drosophila melanogaster is a perfect test subject for this experiment as the fly embryo takes two hours to reach the midblastula transition. This provides scientists plenty of time to analyze this early embryonic phase. Chen used a method called ChIP-seq to locate RNA polymerase II molecules on a gene.
These results took the Stowers team by surprise. Before the midblastula transition, RNA Polymerase II appeared to rarely pause as it transcribed roughly 100 early genes. No construction crews sat idle on inactive genes in preparation for the midblastula transition. Pausing only became widespread during the midblastula transition.
"What we found was not what we expected at all," Zeitlinger says. Before the midblastula transition, instead of preparing for a huge workload the construction crews were busy completing rush jobs. "The polymerase has to come to the promoter and immediately transcribe because there's so little time to do the job. That's one way of making transcription faster. "
When Chen and colleagues computationally compared the DNA sequences of promoters—where pausing occurred compared with where it didn't—a pattern emerged. They found that three different types of promoters correlated with the construction crew's pausing behavior.
The genes that RNA Polymerase II reads before the midblastula transition were often preceded by a promoter that seemed to yell, "Urgent! Don't even think about pausing."
Zeitlinger hopes learning more about promoters will give clues to the functions of unknown genes, as promoter sequences are not specific to flies. Differences among promoter types may be conserved in other animals as well.
Zeitlinger adds: "My lab is interested in understanding how development or even diseases are encoded in the genome. If we understand transcription, then we can predict a lot of what genomes encode, in terms of disease or differences between individuals. Promoters had been seen by some scientists as sort of boring, but now, they are starting to get really interesting."
Other contributors include Jeff Johnston, Wanqing Shao, Samuel Meier and Cynthia Staber, all from the Stowers Institute.
The study was funded by the Stowers Institute for Medical Research, the Pew Charitable Trust and an NIH New Innovator Award.
About the Stowers Institute for Medical Research
The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife Virginia opened the Institute in 2000. Since then, the Institute has spent over 900 million dollars in pursuit of its mission.
Currently the Institute is home to nearly 550 researchers and support personnel; over 20 independent research programs; and more than a dozen technology development and core facilities. Learn more about the Institute at http://www.stowers.org.
Original press release: http://www.eurekalert.org/pub_releases/2013-08/sifm-uhg081313.php