Dr. Angela Cheung, the first Carlos PSC Research Program fellow, explains a new area of research – epigenomics – and what it means for PSC research.
Q: First off, what is a basic definition of epigenomics?
A: Epigenomics is the study of changes that happen on top of the genetic material (i.e., DNA) in a cell or an entire organism over time. These epigenomic changes occur across the genome (i.e., the epigenome) and can mark the DNA in two major ways (methylation and histone modification) both of which play a role in turning genes off or on. Epigenomic alterations are a natural process that allows our different cells to be programmed for a specific function, despite the fact that each of us have the same DNA sequence throughout our different cells. Epigenomic changes can also occur due to lifestyle changes and environmental exposures. It’s been shown that epigenomics plays an important role in diabetes, autoimmune disease, and cancer. If we understand how the epigenome is affected in PSC, we might be able to discover new treatments or cures. Also, we may be able to better address certain complications of PSC, such as bile duct cancer. For example, we could be in a position to diagnose this cancer earlier or determine who might be at greater risk.
Q: What are you doing right now with epigenomics in your study of PSC?
A: We are the first group to look at epigenetics in PSC. Specifically, we are looking at the cells that are most affected by PSC, which are in the liver. Our study includes patients with PSC, patients with other liver diseases and people who are healthy. We are interested in comparing the different epigenetic signatures between those three different groups to discover pathogenetic mechanisms of PSC. Such knowledge has the potential to help design novel avenues of treatment strategies for PSC. Currently, there are drugs that target epigenetic mechanisms; while most of these are used in patients with cancer, we are hoping if we understand the epigenomic landscape of PSC that these drugs might be one day useful in the treatment of PSC.
Q: Are you currently looking at signs of epigenomic changes in a particular stage of PSC?
A: We chose to first evaluate the epigenomics of PSC in liver tissue. As a result of this decision, late-stage disease represents an opportunity for accessing liver tissue because of the process of liver transplantation. Patients with PSC do undergo liver biopsy, an alternative way to obtain liver tissue for epigenomic studies, but they are usually few and far between, as only a small and specific set of these patients get this invasive test. However, our ultimate goal is to identify a signature that could more globally explain what is going on in patients with PSC, and so our eventual aim is to examine the epigenomics of both early- and late-stage PSC. This approach will allow us to begin addressing what drives disease progression from an epigenomic standpoint. The challenge here is the limited availability of liver tissue from patients with early-stage disease. Nevertheless, we are working to overcome this barrier.
Q: Is Dr. LaRusso’s cellular senescence research in any way related to your studies?
A: The complicated, but interesting, aspect about medical research is that often specific concepts we study are interrelated. I’ve had the opportunity to work with Dr. LaRusso and his research team, and they are looking into the epigenetics of senescence. This isn’t something they were looking for initially, but in their study of senescence they found it was connected to epigenetic changes. So that is another potential role for epigenetics – because it can influence the fate of cells, it may also lead to senescence. It could also influence whether cells become cancerous, or whether they contribute to disease. If we can understand that “switch,” then we can target it and potentially stop that cell from becoming senescent, or cancerous.
Q: Is there anything else you would like to add to this discussion of epigenomics and PSC?
A: It has been very exciting to study the epigenomics of PSC. During the past decade, there has been a lot of interest in the genomics of PSC; there has been a tremendous amount of research effort in that direction, and it has been a very informative endeavor. As thought leaders in the space of PSC, we are trying to take it to the next level by asking the question: how does epigenomics advance our understanding of PSC and simultaneously leverage existing knowledge of genomics? Dr. Lazaridis’ group and others have done extensive research in the genomics of PSC, discovering more than 20 genomic regions that contribute to this disease. Thus, we have better insight into the genetic underpinnings of PSC, but this information is not adequate to explain why people develop this rare disease. Using epigenomics, we can delve deeper and explore whether these marks on DNA sequences can predispose some people to develop PSC, or to develop specific complications of the disease. We hope our work can begin to answer some of these key questions and help improve the outcomes of patients with PSC.
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