Profiles in Cancer Research
Dr. Gordon Hager: From Chromatin to Cancer
Chief, Laboratory of Receptor Biology and Gene Expression
NCI Center for Cancer Research
Dr. Gordon Hager likes to know how things work. As a boy growing up in Hepler, Kansas (population 160), he built radios and conducted experiments with electricity. These days, he investigates a far more complex and dynamic subject: the cell.
Since arriving at NCI as a postdoctoral fellow in 1977, Dr. Hager has focused on a fundamental aspect of cell biology: how cells regulate genes. As genetics research has grown, it has become increasingly clear that a better understanding of the process of gene regulation could lead to new approaches for studying and treating cancer.
"Cancer is largely a disease of control," said Dr. Hager, chief of NCI's Laboratory of Receptor Biology and Gene Expression. "The cell goes bananas because it's out of control, and the genetic networks working in those cells begin to fail. But we can now watch this process in real time with new technologies."
What's more, it may be possible to correct these kinds of failures, Dr. Hager noted. Unlike mutations in DNA, which cannot be fixed, some abnormalities in gene regulation may respond to epigenetic treatments. Drugs that target these kinds of epigenetic changes are available, though developments in this area are still in their infancy.
Since the 1980s, Dr. Hager's lab has played an important role in defining mechanisms that cells use to precisely control their genetic programs, particularly mechanisms related to chromatin structure and reorganization.
Chromatin is the substance of chromosomes. It consists of long strands of DNA wrapped tightly around protein particles called nucleosomes, which are composed of four different types of histone proteins.
The strength of the interaction between nucleosomes and the associated DNA plays a role in determining whether the DNA is expressed. Nucleosome–DNA interactions, and therefore gene activity, can be controlled in part by changing the structure of histones in nucleosomes. This process of altering the interaction of nucleosomes and DNA is known as chromatin remodeling, and it occurs constantly within cells.
In 1987, Dr. Hager's group proposed that chromatin remodeling contributed to gene regulation. "At the time, nobody wanted to believe that modifying chromatin structure was important in gene regulation," he said. The idea would not gain broad acceptance until the next decade.
Today, there's also increasing awareness of the role of chromatin remodeling in cancer. Last month, for instance, researchers identified recurring mutations in genes associated with chromatin remodeling in childhood brain tumors.
Given the potential to treat tumors driven by chromatin-related changes, Dr. Hager believes the field could benefit from having an "atlas" of cancer-related abnormalities in chromatin for many types of cells, similar to The Cancer Genome Atlas.
Dr. Hager's introduction to biology came in graduate school at the University of Washington, where he switched from studying chemistry to genetics. "This was 1969, and DNA was just taking off," he recalled. "I had never taken a biology course in my life, but I could see that this research was going to be a big deal for years to come."
While graduate school provided the launch pad for Dr. Hager's career, his interest in science can be traced back to his freshman year in high school. That was when his mother found an advertisement in the newspaper for a science camp at the University of Kansas, which was about 100 miles from their hometown.
Dr. Hager earned a scholarship and spent the summer after his freshman year at the camp. One of the camp "advisors" was Dr. F. Sherwood Rowland, a physical chemist who would later win the 1995 Nobel Prize in Chemistry for his work on ozone depletion. Dr. Rowland became Dr. Hager's mentor, inviting him to work in his lab during his remaining summer vacations.
Dr. Hager believes that his background in chemistry has served him well. "Biology is chemistry," he said. "And we can now investigate the fundamentals of the cancer process, including the complexities of gene regulation."
Looking to the future, Dr. Hager hopes to see more research on living cells. Many cellular processes are fundamentally altered by experimental procedures that isolate parts of the cell. As a result, the biology of dead cells differs markedly from that of live cells.
Although most experiments are done on dead cells, some researchers, including Dr. Hager, have created tools that make it possible to study processes such as chromatin remodeling in living cells in real time.
Like a Tornado
In a recent study, Dr. Hager's team used these tools to monitor the binding of proteins called transcription factors to DNA sites on chromatin in real time. These binding events regulate the activity of target genes. The researchers found that two transcription factors that bind to the same DNA site did not compete with one another, as some previous experiments with dead cells had suggested.
Instead, each transcription factor occupied the DNA binding site only briefly. What's more, the results suggest that the binding of one transcription factor to the DNA site may facilitate the binding of another factor. This process, called "assisted loading," likely involves chromatin remodeling.
"Everything in the cell is moving," said Dr. Hager, who compares the inner workings of a cell to a tornado. "Chromatin remodeling and gene regulation are dynamic processes, and to see them you have to study living cells."
Seeing these processes in cancer cells is a step toward new treatments. "Only if you understand how the cell works, can you hope to make it behave the way you want it to," said Dr. Hager.
—Edward R. Winstead
For more about Dr. Hager's work see "Don't Throw Out the Packing Materials."
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