Dr. Viviane Labrie joined Van Andel Research Institute’s Center for Neurodegenerative Science as an assistant professor in March 2016. She now runs the Labrie Laboratory that studies the complex interplay between genetic and epigenetic features in both Parkinson’s and Alzheimer’s diseases in an effort to better understand disease origins and to aid in the development of new diagnostics and therapies.
Dr. Labrie was among the first to characterize the role of a novel neurotransmitter D-serine, in the brain and its role in schizophrenia. She also created a new method for mapping epigenetic marks and has contributed to the field’s understanding of a particular epigenetic mark called 5-hydroxymethylcytosine and its impact on brain function. Recently, Dr. Labrie has been investigating the contribution of the epigenome to aging phenotypes.
Watch the video below from the team at Crash Course for a brief overview of Epigenetics.
The following has been paraphrased from an interview with Dr. Viviane Labrie on March 1st, 2018.
(Click here for the full audio version)
The epigenome seems to be an abstract concept that encompasses everything that could potentially alter gene expression. Is there something we can point to and say this is the epigenome? How would you define it?
Epigenetics was first introduced in 1942 by Conrad Waddington, he was a geneticist in the UK who defined epigenetics as ‘the causal interactions between genes and their products that allow for phenotypic expression’. He drew this image of a ball rolling down a hill with different curves in the hill that affect which way the ball will roll. Similarly, epigenetics affects which way a cell will develop or how it changes as a consequence of aging.
In the 90’s this field really took off, first in cancer research and more recently in neuroscience. Over time the definition changed slightly and now the general consensus is that epigenetics refers to the collective heritable changes that affect genomic function and activity that are independent of the DNA sequence.
The epigenetic code can determine how cells are going to form in the body as well as how they will behave over time. The code is a second layer sitting over top of the DNA sequence that opens and closes the door to allow the DNA to be read. There are different types of epigenetic marks. Some are chemical marks that sit on top of the DNA, for example DNA methylation (a chemical modification that typically suppresses the functions of genes wherever it is located.) There are also proteins called histones, which DNA is wrapped around (these protein package DNA in the cell nucleus). Epigenetic marks affecting histones determine how tightly these proteins are clustered, which in turn affects how accessible DNA is to proteins coming in to read it. These marks and others alter gene activity and are part of the epigenetic code.
The basic model of biology taught in school is DNA codes for RNA which creates the proteins that allows life to do everything it does. Can you explain how our emerging understanding of epigenetics is changing this model?
Yes, normally we think of DNA sequences that form RNA that form proteins. But, what we now know is that you can have two identical DNA sequences, and if one is coded with different epigenetic marks then the outcome can be completely different. They affect what genes get expressed along with how much, where and when.
If you think of the analogy like a book, the DNA sequence is the actual letters in the book and the epigenetic code is all the footnotes and subscripts that help you understand what the meaning of the text is.
There seems to be a growing understanding in the field of neurodegeneration that these diseases are caused by some unknown combination of genetic and environmental factors. How does epigenetics play into this picture?
Well, normally when you think of health and disease you think of nature and nurture or a combination of these two elements; the epigenetic code affects both. With nurture we often think of aging, for example, there are certain epigenetic markers that are so closely correlated with age that just by looking at them you can predict a person’s chronological age within four years. Also the epigenetic code itself can change as you age due to lifestyle choices such as nutrition and exercise. It tells us that your experiences matter in determining how your cells will function.
On the other side of the equation are the inherited factors, the nature aspect. When an embryo is being made there are steps that occur in which the epigenetic code from the parents is erased, but there are some epigenetic marks that escape this erasing process. This allows you to inherit part of your epigenome from your parents. In animal studies we have seen epigenetic marks being passed down for up to four generations, meaning that the lifestyle choices of your great great grandparents could be responsible for parts of your epigenetic code.
How much difficulty have you faced in getting the field of neurodegeneration to seriously consider the role of epigenetics?
Initially there was some push back in the neuroscience field from embracing epigenetic findings because neurons don’t divide like other cells do. So people didn’t think that these cells that stopped dividing would show much change in the epigenetic code. But actually we found that it does change, every time you make a memory or when your brain is exposed to chemicals, the epigenetic code changes. This is important to understanding your responses and the ways neurons age, and these epigenetic changes could be a very important contributor to neurodegenerative diseases like Parkinson’s. This understanding is becoming pretty widespread. I came into the neuroepigenetics field in the 2000’s when this field was starting to get some real traction, before then it was hard for people to see how epigenetics plays a role. Since then it has become one of the essential pillars to the study of complex diseases. The next step is to interpret how epigenetic changes interplay with genomic sequence changes or proteomic (the large-scale study of proteins) outcomes. But we are still just scratching the surface in trying to understand the epigenome and how it contributes to health and disease.
How big of a role does ‘junk DNA’ play in gene expression and is it part of the epigenome?
Originally ‘junk DNA’ was the term for all the sites along our DNA that don’t code for proteins, we termed it junk thinking it was useless. However, once we started making comprehensive epigenetic maps we realized that junk DNA was littered with areas that were actually very important for explaining how genes work. Junk DNA now is an out-of-date term and we now refer to it as the intergenic space. We have come to realize that the majority of DNA is marked off by the epigenetic code and has functions that fine-tune gene regulation. Each type of cell will have unique epigenetic codes that influences their biological functions. By this I mean that the DNA sequence and genes are pretty much the same in every single cell type in your body, yet every cell type behaves differently because of the differences in the epigenetic code, including the code within the intergenic space.
What do we know about the differences between the epigenomes of people with Parkinson’s and those without?
The epigenome does differ between people with Parkinson’s disease and healthy individuals. First, studies examining specific genes implicated in Parkinson’s disease show differences in DNA methylation (a chemical modification that typically suppresses the functions of genes wherever it is located.) For example, in the Parkinson’s disease brain (especially in the substantia nigra region involved in motor symptoms of Parkinson’s disease), you see a loss of DNA methylation at the alpha-synuclein gene. Alpha-synuclein is a key gene involved in Parkinson’s disease and is a major component of Lewy Bodies (the pathological hallmark of Parkinson’s disease). Loss of DNA methylation at this gene could explain the increased alpha-synuclein expression that has been observed in the brains of Parkinson’s disease patients. In addition, excessive epigenetically-mediated production of alpha-synuclein could contribute to the formation of Lewy Bodies.
Second, there are large studies that see more widespread epigenetic abnormalities occurring in the Parkinson’s disease brain, these are also detectable in blood. These studies show that epigenetic changes are not limited to specific genes already implicated in Parkinson’s disease, but that there could be more genes that play a role in the disease that we don’t yet fully understand.
Finally, there is evidence in Parkinson’s disease for an acceleration in epigenetic changes related to aging. Studies in blood cells show that epigenetic marks associated with aging have a pattern of more advanced in age in Parkinson’s disease. Therefore, cells of Parkinson’s disease patients have epigenetic changes that could signify that they are behaving much older than their real age.
What do you think the future of this field will look like?
Less than five years ago, sequencing the entire epigenome was something that only the richest labs in the world could do. But now we can examine the entire epigenome and are able to compare how these marks are different in various diseases.
One project going on is the creation of atlases of gene expression profiles for all the different cell types in the human body. They are looking at gene expression in single cells and can see differences even within cells of the same type (for example a dopamine neuron in the substantia nigra compared to other neurons in this brain region). Soon they will do the same thing for the epigenetic code and examine the differences between cell types within tissues and between cells of the same type. So we will learn why different types of cells behave differently and have different vulnerabilities to disease.
Another advancement will come from integrating the big data sets that are being created. We will examine DNA polymorphisms (differences in the base pair sequence), proteomic (the large scale study of proteins) and transcriptomic (the large scale study of gene expression) data, as well as epigenetic data, and start to merge all that information to give us a much more holistic understanding of the changes found in various diseases.
Right now we are still just trying to understand how changes in the epigenome impact diseases, but one day we might use it for therapeutic purposes and disease diagnosis. In the future we may detect changes in epigenetic marks in individuals and prescribe different treatment options based off of that information.
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