An epigenetic atlas for cancer therapy

Interviewed and edited by Sarah Anderson, PhD

 
In 1747, aboard the ships of the British Royal Navy, naval surgeon James Lind discovered that a strange disease afflicting sailors could be treated with citrus fruit.  

Scientists later determined that the body requires vitamin C to produce the structural building block collagen and that a lack of C while out at sea led to deterioration of the sailors’ skin, bones, and connective tissue, manifesting in scurvy. More recently, researchers uncovered that vitamin C’s power to combat scurvy may be in part linked to its ability to turn on certain genes that promote bone formation.

This finding doesn’t come as a surprise to Dr. Martin Hirst, the director of the Michael Smith Laboratories and a professor in the Department of Microbiology and Immunology at UBC. Research in his lab focuses on epigenetics, the study of how chemical modifications to DNA or the proteins that package it can ramp up or down the activity of specific genes. In fact, his work has explored vitamin C’s epigenetic function in another, more relevant disease — acute myeloid leukemia (AML). Nearly 20 percent of AML tumors feature mutations in the enzymes that control the addition of small chemical tags called methyl groups to DNA, altering the way that the cells can read and use the genetic information. Dr. Hirst’s work has shown that treatment with high doses of vitamin C can activate enzymes that remove these methyl groups and help to restore normal DNA processing.  

Dr. Hirst’s team continues to lead cutting-edge studies on epigenetic dysfunction, primarily in the context of cancer. In this conversation, Dr. Hirst discusses how we can leverage epigenetics for new approaches to treating cancer, his effort to build and share large epigenetic reference datasets, and the challenges and opportunities facing the field.

What role does epigenetics play in cancer? 

MH: Many of the mistakes that occur in a cell’s set of genetic information are actually found in the enzymes that make up the epigenetic machinery. These enzymes control chemical modifications to DNA or the histone proteins that package it, laying down a roadmap that guides the cell’s fate. Each of the 300 unique cell types in the human body contains the same genetic code (known as the genome), but these roadmaps allow them to interpret that information differently to function as a liver cell versus a retina cell, for example. But if there are mistakes in the map and it directs the cell to pave a road in the wrong place, that could promote malignant cell development. However, there are very few cancers that are purely driven by epigenetics, so it’s important to keep in mind that the onset of cancer is complex and likely involves a collusion between multiple factors. 

Why are epigenetic processes an attractive target for cancer therapy?

MH: Mutations in the underlying genetic code are considered permanent — although researchers are now developing gene editing technology, correcting those mutations remains extremely challenging. The epigenetic state, in contrast, is much more malleable. While there are certain epigenetic changes that are stable and persist throughout many cell divisions, others are very plastic — for example, some hormones trigger modifications that are reversed as we soon as we take the hormone away. We also know that the epigenetic state is responsive to environmental stimuli such as toxin exposure, diet, and stress. This tell us that the enzymes that carry out these modifications are dynamic and that we can look for specific compounds that activate or inhibit these enzymes in order to tune the epigenetic landscape in a way that may be therapeutically tractable.  

While the fact that epigenetic changes are impermanent presents opportunities, it also creates certain challenges. The cell may be able to reconfigure its roadmap to overcome the effects of inhibiting a specific enzyme, for example. So, it’s important to explore the potential of combining epigenetic-targeting drugs with more traditional cancer therapeutics. Additionally, in my lab, we are working to identify unique epigenetic states that cancer cells have become dependent on so that the cell might find it harder to pivot if we perturb those states. For example, we profiled 52 human samples of synovial sarcoma, a rare cancer that disproportionately affects children, adolescents, and young adults. When we compared this data to that obtained from healthy tissues, we observed clear differences in the arrangement of methyl groups on a key histone protein. We are currently investigating this epigenetic signature as a therapeutic vulnerability for synovial sarcoma. 

Can you discuss your work compiling and sharing this type of human epigenetic data?

MH: I have dedicated a significant portion of my career to generating resources for the scientific community on what the “normal” epigenetic state looks like in various cell types. I helped to develop the Canadian Epigenetics, Environment and Health Research Consortium, which is Canada’s contribution to the International Human Epigenome Consortium (IHEC), where I serve as Chair of the International Scientific Steering Committee. IHEC brings together researchers from 10 countries with the goal of generating epigenetic reference datasets for each of the different cell types. To build these datasets, we perform molecular analysis on populations of cells from human tissues that are obtained through surgical resection or autopsy.

We recently published a pre-print manuscript reporting the launch of IHEC’s EpiATLAS. With 2279 entries, EpiATLAS represents the largest collection of standardized human epigenomic datasets to date. We hope that this effort will accelerate progress by providing reference points that allow researchers to compare and contrast epigenetic features. The epigenomic state varies between individuals, reflecting differences in environmental exposures, lifestyle, and other factors that shape how the genome is used. By compiling data across many individuals, we aim to capture this natural heterogeneity within healthy tissues and define the normal range of epigenomic states. In this sense, the epigenome encodes a cellular roadmap, providing instructions on how the genome should function in a particular context. Establishing this baseline allows researchers to recognize when that roadmap has been altered due to disease and to understand both how and where it has gone wrong.

What do you see as the challenges and opportunities facing epigenetics moving forward? 

MH: Many of the challenges and opportunities have to do with generating, managing, and analyzing complex data. To build epigenetic reference datasets, we must work from an established map of all of the human genetic information. However, this map is being continually refined, and it’s not always feasible to stay up-to-date with the latest version. Another challenge is retaining access to the raw data. Because we are working with human data, it needs to be placed into protected repositories. But while these repositories store data in a secure way, they aren’t designed to allow researchers to pull that data back out at scale. To help overcome this obstacle while creating the EpiATLAS, we processed the data to de-identify the human subjects and made it publicly available. 

As international teams generate and distribute more and more standardized data, there is a huge opportunity for higher-level learning and pattern recognition using machine learning models. Within a particular cell type, there are 200,000 regulatory elements interacting with 20,000 genes, and then we layer in factors like three-dimensional structure and epigenetic modifications, and I would defy the human mind to be able to absorb and interpret all of that information. So, it’s only natural to utilize computational technology to help us understand the relationships between these various components, and the high-quality, harmonized data that we now have to feed into these models is going to make them all the more useful.

What keeps you motivated at this point in your career?

MH: Even now, I find it absolutely fascinating that, through epigenetic mechanisms, the same set of genetic information gives rise to hundreds of distinct cell types. I am curious by nature, and the more I learn about these mechanisms, the more I realize there is to learn. In addition to the thrill of basic scientific inquiry, I find it very rewarding to work towards making a difference, whether that comes in the form of leading a research breakthrough or making an incremental advance that another team can build upon. There is arguably no better job than this one, where I get to work alongside talented and caring individuals, pursue projects that I’m passionate about, and make discoveries that have the potential to be transformative in people’s lives. 

This interview has been edited and condensed for clarity.

 

This story was originally published by the UBC Department of Microbiology and Immunology