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Conquering Chromatin

by UNC Health Care — last modified Nov 14, 2013 04:39 PM
Five questions for Greg Wang, a new Jefferson-Pilot fellow searching for better ways to shut down cancer cells.
Conquering Chromatin

Greg Wang, PhD

Ever since his days as an undergraduate in China, Greg Wang knew he’d study the molecules that make us human. Today, as a molecular biologist in the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center, Wang is unraveling the mysteries of gene regulation, which he hopes will lead to cancer therapies that target cancer cells while leaving normal cells unscathed.

For his work he earned a Jefferson-Pilot Fellowship from the UNC School of Medicine to further his research mission. We sat down with Dr. Wang to discuss the science behind gene regulation and his most recent research findings.

What was the driving force behind your majoring in biochemistry at Fudan University and then pursuing a doctorate in biomedical sciences at UC San Diego?

I liked science all the way back to when I was young, especially physics and chemistry. I love science. It’s very rigorous but logical, and I like logic. In college I realized that there’s a molecular basis for human disease, and I wanted to contribute to our understanding of that.

I entered my undergraduate study at a time when people thought molecular medicine would be the science of the next century. I majored in biochemistry, learning the molecular basis for genes and cells. My thesis project was to study p53, a tumor suppressor gene that’s commonly mutated in human cancers. Mutations are one of the driving forces of cancer. I felt like molecular biology was the field for me. So, I got admitted into the Ph.D. program in Biomedical Sciences at UC San Diego to learn how to use modern molecular biological approaches to study human disease.

I just felt that we haven’t been able to understand the molecular biology of diseases including cancer as much as we need to.

In 2012, you published a paper about a unique class of proteins that bridge the gap between a gene’s “on” and “off” stages. What role do these proteins have in cell differentiation and cancer biology?

Your cells – in your heart, muscles, blood, brain – all of them are different. How stem cells differentiate into all those kinds of cell types is due to a “switch” on our genes. We call this “on” or “off.” But what this really means is that when a gene is “off” then that gene’s function is closed down; it doesn’t transcribe a protein to do something. Or, if the gene opens up and is “on” then that means a lot of RNA is produced and proteins are translated. So, there’s a fundamental molecular biology question: how are these “on” and “off” switches being regulated when stem cells develop into differentiated cells?

In that 2013 paper, we studied the “off” mechanism related to a protein complex called PRC2. We found a protein sequence or structure that partially explains how this protein complex finds and locates the genes that are on and then work to turn them off. Then, we realized that the factor related to this mechanism is overexpressed in cancer cells – notably lymphoma and some solid carcinoma subtypes. So we’re now studying how this overexpression factors into other cellular relationships in the development of cancer cell types.

The study could lead to a target for better anti-cancer therapies.

A focus of your lab is chromatin. What is it and why is it important in the study of cancer biology?

Chromatin is a combination of nucleic acids and types of proteins called histones that package DNA inside cells. A lot of gene regulation occurs on chromatin; it controls whether DNA is available or not – whether genes are “on” or “off” in specific cells. Basically, chromatin is a platform for how genes regulate their own function.

This relates to cancer biology. There’s recently been a lot of sequencing efforts, and what people have seen is that a significant amount of the new recurrent mutations found in cancer cells are actually affecting the pathways that we know are involved in chromatin regulation. In turn, these new mutations may lead to a drastic change in gene expression and cause cancer development. This is why we study chromatin.

How might your work translate into treatments for disease, especially various cancer types?

This is a very exciting field because there are a lot of proteins – often enzymes –involved in regulating chromatin. These enzymes either add tiny chemical modifications onto chromatin, or they act as motors that slide onto chromatin to open or close down a gene’s expression.

Often, enzymes are good drug targets because you can design a compound to inhibit their activity. So many of these chromatin regulators are actually what drug-discovery scientists can target. We also know that many of these enzymes are perturbed in human disease. For example, in one cancer type we see hyperactivity of a certain chromatin-regulatory enzyme, and theoretically you could design a drug to target that enzyme. Also, we’re learning that some mutated enzymes are unique to cancer cells. That is, we don’t find them in normal cells. That’s an Achilles heel of cancer, because that it allows us to target just the cancer cells, not normal cells. The current front-line chemotherapies affect cancer cells and normal cells equally, which is one of the downsides to current cancer therapies.

There have been a couple of good examples of deregulated enzymes that specifically perturb chromatin regulation in cancer cells. I think in the next few years we’ll see more and more of such examples that may serve as excellent drug targets. We’re all very excited about that.

What is the most rewarding part of your job as a researcher?

The most rewarding part of science is to promote our understanding of human disease, which can have a contribution, eventually, to cures. Also, I feel very fortunate to be working on this very exciting and active research area, which nicely connects the basic mechanism of gene regulation to cancer and disease. There’s a lot of opportunity to translate our basic understanding of genes and cells into medicine and into clinics.

With a lot of questions to be answered, you just have to ask yourself: what is the most critical question and how can we take the best path toward understanding and treatment? Then we set up a plan, execute, and try to achieve the goal. Getting all of it done and making things happen – that’s the most exciting part. We want our research to have a benefit for patients down the road.

Greg Wang, PhD, is an assistant professor of in the Department of Biochemistry and Biophysics in the UNC School of Medicine and Lineberger Comprehensive Cancer Center. The Jefferson-Pilot Fellowship is a four-year, $20,000 award to support the research mission of junior faculty.

This article was originally published by UNC Health Care. To access the original article, click hereExternal Site 

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