Victor Corces, Epigenetics
Faculty Distinction Fund Recipient

 


Victor Corces, Arts and Sciences Distinguished Professor and Chair of Biology, is thinking about accordions and flowers.

Corces specializes in epigenetics. While geneticists study the transmission of information within DNA, epigeneticists ask how that DNA is arranged and organized in the nucleus. While genetics examines content, epigenetics prioritizes form. And the intricate coils and loops in which these materials arrange themselves - similar in appearance to a flower and in function to an accordion - constitute sources of genetic information. These arrangements could help explain why identical twins begin life exactly the same but, by age 40 or 50, exhibit numerous differences, not all of which can be explained by changes in the sequence of their DNA. They also could help explain inherited diseases, such as progeria, that have confounded scientists for decades.

Understanding how DNA arranges itself in the nucleus is a mind-bending exercise. A cell nucleus measures approximately 6-8 microns in diameter, with one thousand microns equaling just one millimeter. The DNA thread that must fit inside this space extends around 2 meters in length. Not only must this thread "pack" itself into a much smaller space, but it also must do so in an organized manner, so that genetic information remains accessible to the cell. Epigeneticists have discovered that this organization process is facilitated by histones, which are proteins that bond in groups of eight and form spools around which the DNA thread - called chromatin fiber - can wind or coil itself. The same process also regulates gene expression, and therein allows for cell differentiation, or for a muscle cell to be a muscle cell and not a neuron. The chromatin fiber that winds itself around these histones forms an elegant series of loops that expand and contract to turn genes 'on' and 'off.' "Genetic information can be found not only within these histone proteins, but also in the way the fiber is coiled around them," Corces says. "All these different levels of organization and location deliver information that affects gene expression."

In his current research, Corces explores how phosphate modifications to these histones affect the biological organism. This is not genetic mutation. Says Corces: "The basic sequence of the DNA is not changing. What is changing is the information that affects whether or not a given part of the sequence is expressed."

A related project in the Corces laboratory poses a different kind of challenge. As they explore how condensed DNA (as chromatin fiber) is organized in a cell nucleus, Corces's team is asking if or why this formal patterning matters in the first place. "If you have two muscle cells whose DNA content is exactly the same but whose chromatin is arranged differently, does that matter?" Corces asks. "Does that arrangement confer epigenetic information? This is a very difficult problem." Working with fruit flies, he and his researchers have discovered sequences in the DNA known as insulators, which bind certain proteins and play an important role in the organization of chromatin into those flower-like accordion structures. "We have some evidence that this arrangement contains epigenetic information," he says.

What's more, Corces has discovered that one of the insulators in these fruit flies has a correlate in humans. "We found that one particular 'flavor' of insulator in their DNA interacts with human proteins," he says. "So now we are going to be able to extrapolate this knowledge to humans and move much faster in our investigations of human cells: this is our bridge."

The implications of these findings are wide-ranging. Biologists may be able to advance understanding of several diseases associated with genetic factors, including laminopathies, which are caused by particular mutations in the LMNA (lamina) gene. These include certain types of muscular dystrophy, as well as progeria, a rare and fatal disorder characterized by accelerated aging in very young children. Corces and his team have undertaken a project to manipulate the genetic organization of fruit flies so that they will mirror the genetic organization of a child with progeria. This experiment could help them understand how the arrangement or form of DNA plays a causal role in the disorder.

Corces is as committed to teaching as he is to research. In 2006 he was named a Howard Hughes Medical Institute Professor. In that capacity, he now leads a program at Emory called the Research Internship and Science Education (RISE), aimed at providing opportunities for underprivileged youth to study biology and prepare for a college education. "We have 12 students working with us from various public schools in Atlanta," Corces says. "They work on the same projects we work on. They're helping us find some of the proteins on these insulators that have not been discovered yet." Corces hopes that some RISE students will apply to Emory College in order to continue their studies in his laboratory. He sees these students as future mentors to the next cadre of high school researchers. Any RISE student who is admitted to Emory will receive a full-tuition scholarship.

Corces welcomes the opportunity to pursue this kind of mentoring at Emory. Next semester, Corces also will teach "Epigenetics and Human Disease" to undergraduates. He believes Emory offers student interns, undergraduates, and faculty alike a thriving intellectual community. "One of the things that attracted me to Emory was the collegial and collaborative spirit," he says. "Not every university is like this."