Developmental biologist Mary Goll investigates the mechanisms of epigenetic regulation and its role in development using zebrafish as a model system. We spoke with Dr. Goll about her work in 2012.
I was always a curious child, performing science experiments around the house. As a teenager, I wanted to go to medical school. Research had never struck me as a career because I didn’t come from a scientific family — I was actually the first in my family to go to college.
The transition from high school in northern New Jersey to Cornell University, in Ithaca, New York, was very challenging for me. I needed a job to pay for my expenses, so I applied for a part-time position in the laboratory of Robert Last, a plant molecular biologist. He was studying the production of an essential amino acid, tryptophan, in a plant called Arabidopsis.
My years in the Last lab, from 1995 to 1998, were a formative time. I found that I thoroughly enjoyed learning about the scientific process, and I wanted to be in the laboratory more than anywhere else on campus. I was drawn to the camaraderie of the lab, the logic of science, and the challenge of solving new problems.
I enjoyed research so much that I spent two summers working on biomedical projects in additional labs, one at Weill Cornell Medical College and the other at the University of Medicine and Dentistry of New Jersey. By the time I graduated with a degree in biology, I knew that I wanted to pursue a PhD. One particular classroom experience, however, drew me to my current field.
A human genetics professor exposed me to the phenomenon of genomic imprinting. We inherit two copies of every gene — one from our mother and one from our father — but one of these copies is silenced through a process called imprinting. Silencing is caused in part by a small molecule known as a methyl group, which is added to the DNA. I was completely fascinated by the idea that methylation could enable two identical copies of DNA to behave differently — one silenced, and one activated.
We know that DNA methylation is essential for normal development in vertebrates, and patterns of methylation are disrupted in almost every cancer genome, so the process is clearly relevant to human health and disease. Methylation patterns can also be passed on to other cells through cell division and potentially to subsequent generations.
This idea of epigenetics — that we could inherit changes unrelated to DNA sequence — really struck me. I wanted to further understand how this could happen.
A Crystal Clear Interest in Epigenetics
In 1998, I enrolled as a PhD candidate at Columbia University, with Tim Bestor as my advisor. His interests involve DNA methyltransferases, the enzymes that facilitate methylation of DNA. We began investigating Dnmt2, a newly identified protein resembling a DNA methyltransferase. We tried, unsuccessfully, to characterize this protein by mutating it in flies, plants, and mice.
In the meantime, scientists figured out the Dnmt2 crystal structure. We examined it and noticed a tiny residue that isn’t present in enzymes that facilitate DNA methylation, so we started to wonder if Dnmt2 might instead act on RNA. Eventually, we found that despite its similarity to DNA methyltransferases, Dnmt2 actually facilitates methylation of a specific RNA. We published our discovery in Science in 2006.
I found the process of following a specific scientific problem to its unexpected conclusion extremely rewarding. As a reminder, I have kept a model of the Dmnt2 crystal structure on my desk ever since.Back to top
Zebrafish Go Green
When I finished my PhD, I wanted to continue to investigate the genes involved in methylation and to clarify their roles in animal development. I wondered whether a new, emerging research model — zebrafish — might provide opportunities to explore these areas.
Zebrafish are useful for studying human development and genetics. Many genes are well conserved between fish and humans, and both species develop in a similar manner. In addition, zebrafish embryos are transparent, enabling scientists to view the early stages of development and perform live tissue imaging under a microscope.
Still, few labs were using fish to study epigenetics. I contacted the Department of Embryology at the Carnegie Institution for Science, in Baltimore, which has a reputation for allowing researchers to pursue new directions. I became the first Carnegie collaborative fellow under the mentorship of Marnie Halpern, an experienced zebrafish researcher, and Allan Spradling, who is interested in epigenetic regulation. This was a transformative opportunity for me, and I learned a tremendous amount through their guidance.
During my four years there, we developed a method for monitoring DNA methylation in live zebrafish larvae. We began by inserting a gene that codes for a green fluorescent protein (GFP). When expressed, this gene causes the zebrafish cells to have a green glow under a fluorescent microscope.
However, when the region of DNA that regulates this gene becomes methylated, GFP is not expressed, preventing some or all of the cells from turning green. The beauty of this scientific method is that by tracking a color change, we have a simple, live readout of methylation.Back to top
Methylation and Cancer Research — A Perfect Fit
When I was offered a position at the Sloan Kettering Institute, it seemed like a perfect fit. Understanding the fundamental biology of DNA methylation is highly relevant to cancer research, and I had always wanted to return to the New York City area. So in September 2010, I drove hundreds of zebrafish in coolers from Baltimore to New York.
Since I arrived, I have had the opportunity to interact with a great community of scientists that I respect. I also have the resources and support to continue using the method we developed at the Carnegie Institute to study methylation in zebrafish. My lab is currently investigating several questions, including: What is the purpose of methylation? What genes are required? Do different cells or developmental stages have different requirements for methylation?
When we find answers to these questions, we can better understand the diverse responses of tumors to methylation, which could lead to future cancer treatment targets. I can’t imagine a more exciting or rewarding career path.Back to top