The “Icing” on the DNA

XUEHUA ZHONG, an assistant professor of genetics, studies epigenetics, a growing area of research focused on how chemical tags on DNA can change the expression of genes. She and her team at the Zhong Lab of Epigenetic Regulation, located at the Wisconsin Institute for Discovery, are especially interested in the modification of genes involved in growth and development, and how epigenetics can be affected by the changing environment.

As evidence for a link between environmental factors and epigenetics grows, so does public interest in the topic as people consider the impact of their lifestyles and diets not only on themselves but also on the next generation. Zhong and her team hold talks for the public about their work and conduct a number of hands-on programs about epigenetics for undergraduate and K-12 students, including a summer science camp for local high school students, a field trip for middle-schoolers, a youth apprenticeship program in her lab and a “tabletop exploration station” about how lifestyle choices can affect gene expression. Zhong hopes opportunities such as these will raise interest in and encourage the next generation to study this rapidly growing field.

What is epigenetics?

It’s a very interesting question, I would say. The definition of epigenetics has been really challenging over the years because there are different concepts of epigenetics. Most people accept the definition that epigenetics is modifications on the genetic material, the DNA, that changes expression of the underlying genes. I like to say that epigenetics is like a Christmas decoration. You decorate the DNA in a different way, and then the expression of genes is different.

I would also use another comparison: If you think about a cake, the base of the cake is the DNA, the genes. Then the epigenetics is the frosting, the decoration on the cake. And the nice thing about that is if you don’t like the frosting, you can remove it. You can redecorate it differently, and it looks like a different cake.

Can epigenetics be passed on from one generation to the next?

This is another reason why epigenetics is so debatable—the question of inheritance. The modification on top of DNA has been well accepted, but whether it’s heritable is still being debated. Some modifications are very transient and unstable. But some of the modification, for example, methylation—the process of adding methyl groups to the DNA molecule—is fairly stable and can be inherited by the next generation. That is called transgenerational inheritance.

We talk a lot about how your diet, your exercise and your environment have a huge impact on you, obviously, but can also impact your children and even grandchildren through transgenerational inheritance. There are cases from World War II of women who lived through famine, and even 20 years later when they were leading a healthier life, those women tended to have children with more diseases and stress through- out life.

How is this inheritance being studied?

It’s very challenging to study transgenerational inheritance in humans. We’re talking about 60, 70 or 80 years for each generation. But in plants, it’s been very clear that certain epigenetic patterns can be transgenerationally inherited. For example, the Wisconsin cold can induce modifications of genes that can then be inherited. This is an area we are very interested in—environmentally induced epigenetic modifications and to what extent these modifications are transmitted to the next generation.

What plant do you use to study inherited epigenetics?

Currently we are primarily utilizing a flowering plant called Arabidopsis thaliana, or thale cress. It’s a model system that is widely used. We use it because it has a small genome, and because most of our studies are done at the whole genome scale, it’s cheaper than other model systems. Also, the generations are very short, only eight weeks. You can look at six generations in just a year. We’ve also started to extend our work to rice and maize through other collaborations on campus.

Can you explain what you’ve learned about plant aging in your work?

We have been finding that one epigenetic complex in particular is very important to make sure that a plant senesces, or ages, at the right time. Early senescence can reduce yields, so if we can find a way to delay senescence we can hopefully increase productivity. And that’s exactly what we see. If we get rid of the complex we’ve found, senescence is significantly delayed.

While we often talk about how delaying aging is good, the opposite can be true, too. Here in Wisconsin, we have relatively short windows for growing plants. If we can promote senescence, we can maybe shorten the plants’ growing season to better fit our weather patterns.

Now we are trying to understand the mechanism behind these changes because only when we know the mechanism can we really manipulate the system. Ideally, we will be able to manipulate things both ways by fine-tuning the epigenetics to different levels. It’s not all or nothing—it’s kind of an art.

How can your work help address concerns about climate change?

Heat and drought will make the areas that can grow plants limited and challenging in the future. This is a big motivation for us. We want to know what kind of epigenetic modifications happen in response to heat and drought—how strongly, uniformly, stably and rapidly do these modifications happen? Also, is this inheritable? If we treat a plant with heat and collect its seeds, will the next generation “remember” that past experience? Can that memory help the plant?

Why is it difficult to study the influence of environmental factors on epigenetics?

In the lab, it’s simple because we can control each factor and use one kind of stress. But in the real world, you are going to have multiple factors, and how they crosstalk is very complicated. Heat is associated with drought, and there may be long, dark nights and short days as well. I am interested in finding the epigenetic complexes responding to all of these factors. Ideally I want to combine all this information to establish an environmental epigenetic regulatory network. And if there is one key complex responding to all kinds of factors, that can be our target.

Is there a way to do very targeted epigenetic work?

One area we are getting into is epigenome editing (also named epigenome engineering) using a modified CRISPR–dCas9 system that others are using for genomic editing. This lets us target the genes involved in aging, let’s say, and then change only those few genes we have identified to be important. We can put a modification only in that place or on those genes. It’s more efficient.

Using CRISPR–dCas9, the epigenetic changes hopefully will be stable. That’s a question right now because we haven’t gotten to that step yet, but I hope that’s true. Ideally once we have the modification on there, it should stay and do its job.

How are epigenetic studies being used beyond the lab?

I am most interested in how epigenetics can be applied to horticulture and agriculture, but many people are interested in epigenetics for drug discovery. In human medicine, there is already a drug used clinically called azacitidine, which is used to treat a bone marrow disorder called myelodysplastic syndrome and works by blocking the methylation of DNA. This is still a huge, growing area, and whether lab findings can be used in the field or in practice is a million-dollar question. We need efforts to take the discovery from the lab into the field. Making that connection is important and challenging work in all areas of research.

Xuehua Zhong uses plants to study epigenetics, an exciting new field that is broadening our understanding of how some traits might be passed down from one generation to the next. Photo credit: Sevie Kenyon BS’80 MS’06