Explaining the epigenome: An interview with Dr. Viviane Labrie (part two)

Dr. Viviane Labrie is an assistant professor in Van Andel Research Institute’s Center for Neurodegenerative Science. Her area of expertise is the role of epigenetics in neurodegenerative diseases, a fledging field known as neuroepigenetics. In her last post, Dr. Labrie discussed the basics of epigenetics—what it is, why it is important and how it impacts therapeutic development. In this week’s post, we’ve asked her to take us back to the beginning—why did scientists start looking at the epigenome in the brain? And how did we get to where we are?

So what’s the backstory on epigenetics? Why did the neuroscience field become interested?

When I first got into epigenetics, some people still didn’t quite believe it was a big deal. Many actually thought it was a curious fluke of the genome with no substantial consequences.

It was really the cancer field that got the ball rolling. Cancer is very different than neurodegenerative diseases—in cancer, you can see huge stretches of changes in the epigenome and you have cells that are constantly reproducing and turning over. Brain cells, however, are relatively mitotically stable, meaning that there are no new cells being added in most areas of the brain. It was hard to grasp how these relatively stable brain cells could be changing their DNA programs via the epigenome. So, when people started looking at epigenetic changes in brain cells, it was met with a bit of skepticism. It took a while for neuroscience to get on board. The field really only started gaining momentum 12 to 15 years ago, so it’s a relatively new area of research.

What were some of the challenges of studying epigenetics in the brain during the early days?

When I first started in the field, the techniques we now use to examine the epigenome were still under development. We had to ask ourselves—are we looking at the right thing? How do we best approach these problems? Again, it’s much different than cancer where you can physically remove the disease tissue as well as some neighboring healthy tissue and compare them. We can’t do this in neuroscience—you can’t simply go in and remove or biopsy part of the brain. Much of what we learned came from donated brain tissue after a patient passed away but this presented its own challenges. In science, you want to have a large and diverse sample size but access to brain tissue is limited.

It’s also not “live” tissue, that is, the tissue that we have access to is donated following a person’s death. We didn’t know what the time lag and the processing between donation and investigation would do to the epigenetic characteristics—were the epigenetic marks stable? Are we looking at postmortem effects? How do we deal with the diversity of cell types in brain, considering that each cell type hold their own epigenetic signatures? It took a while to hash out how to approach these problems. Now, thanks to a much better understanding of tissue types and the stability of epigenetic changes as well as huge advances in technology, we have some very good and very detailed approaches. The time is finally right where we can look at an individual and discover what might be happening epigenetically.

What have been some of the revelations in neuroepigenetics?

Originally, we had a more simplistic view of things and thought there were a small number of epigenetic modifications. We then came to realize that there was a huge variety of epigenetic modifications happening all over the genome, not just in the areas we originally knew about. That was a big shock. This diversity is especially abundant in the brain. And it’s not just the number and location of modifications—each of them has a unique role that adds to the complexity of the whole thing.

Traditionally, we studied genes and their promoters—the flanking regions of DNA near genes that initiate the gene expression process. But we largely ignored all this extra space that we referred to as junk DNA. This “junk” was a big question mark—no one really knew what this stuff did.

Proportionally, it was odd—why do we have so much junk DNA compared to our genes? Then projects like the National Institutes of Health’s Roadmap and ENCODE came along, and that changed everything. These projects created maps of many types of epigenetic marks across a huge array of tissue types, which was a major undertaking. They took a bird’s-eye view of what was going on and the field realized that these regions outside of the genome—the so-called junk areas— was littered with elements that are very important to the way genes work. You have this huge support system that effectively determines how these genes are going to operate. It was absolutely remarkable.