A Tale of Two Mice

A Tale of Two Mice

Posted: July 1, 2008

CHAPTER 1: THE AGOUTI SISTERS

DANA DOLINOY: Hi, I'm Dr. Dana Dolinoy, a post-doctoral research fellow in the laboratory of Randy Jirtle at Duke University. In our laboratory we study epigenetic gene regulation, or how environmental exposures interact with the epigenome to affect long-term health and disease.

So today I'd like to introduce you to two Agouti mice. And as you can see, the yellow mouse is quite obese, and she is also prone to diabetes and cancer. But on the other hand, the brown mouse remains slender and lean and also has a lower risk of developing disease. But what's really amazing about these two mice are that they are genetically identical — they are two identical twin sisters from the same mother. So what makes them look so different?

CHAPTER 2: THE EPIGENOME

DANA DOLINOY: Well, it turns out that there's a second genome called the epigenome. Epigenome literally means, in addition to, or above, the genome, and while the recently completed human genome project identified approximately 25,000 genes, these genes still need instructions for what to do and when to do it and where to do it, and that's where the epigenome comes into play.

A useful analogy is to think of the epigenome as the software that directs the genomic hardware of a computer. All of our cells contain the same DNA and genes, but it is the epigenome that decides how these genes are expressed and determines how a cell becomes a heart cell, a liver cell or even a hair cell.

Epigenetics consists of molecular switches and markers, such as DNA methylation, that help control gene regulation in which a quartet of atoms called a methyl group attaches to DNA and shuts down genes. And as you can see the red balls here are attaching to the DNA and turning off the gene.

CHAPTER 3: THE ELUSIVE AGOUTI

DANA DOLINOY: So back to the Agouti sisters. In the yellow obese mouse, the Agouti gene is unmethylated and turned on all the time, while in the brown mouse, the gene is completely methylated and shut down. There are also other mice that appear mottled in which half of the cells are methylated and shut down, and the other half are unmethylated and turned on, and these mice appear to be yellow and brown. So the coat colors of these Agouti mice acts like a sensor for the amount of DNA methylation present.

We used the Agouti mice to study how maternal nutrients and environmental factors affect the epigenome. Specifically, we wanted to know whether a mom's exposure to a contaminant found everywhere in the environment can alter the fetal epigenome, and eventually the long-term fate of her offspring.

In the study, pregnant mothers were exposed to a common chemical found in certain plastics. This chemical is called bisphenol-A, or BPA for short, and it's present in many commonly used products, including food and beverage containers, baby bottles, dental sealants and the lining of food cans.

About four years ago, the CDC studied approximately 400 people, and in 95 percent of these 400 people, they measured detectable levels of bisphenol-A.

And when we fed the pregnant mothers, the mice, BPA, we noticed that the number of offspring with the yellow obese coat color increased dramatically, and we also saw that maternal exposure to this chemical decreased DNA methylation in the offspring and turned this Agouti gene on when it is supposed to be off.

CHAPTER 4: BREEDING HEALTHY PUPS

DANA DOLINOY: So we started a second study in which pregnant mothers were exposed to BPA plus nutritional supplementation such as methyl donors like folic acid or genistein, which is a common ingredient found in soy products. The level of soy that we provided is similar to what a person who eats a high soy diet or an individual living in Asia might eat.

And once we did this, we observed that the offspring were no longer predominantly yellow and more obese, and that there were more offspring with the slender brown coat color phenotype. This indicates that maternal nutrient supplementation can counteract the negative effects of exposure to that chemical.

CHAPTER 5: CONCLUSIONS

DANA DOLINOY: The traditional thinking about human health and disease is that it is affected by genetics and the environment, and whenever identical twins have different disease status, this was often attributed to the environment or different behavioral choices such as smoking status.

But with epigenetic gene regulation, we can see that we can no longer say whether genetics or the environment have a bigger impact, because it may be not only what you were exposed to, but what your mother and potentially grandparents were exposed to as well. And maybe even your father.

These studies with the agouti mice show us that we can no longer say whether genetics or the environment have a greater impact on our health, because the two are inextricably linked through the epigenome. This work suggests in the future that we may be able to protect individuals from negative epigenetic profiles, either by modifying the diet or developing drugs that can affect epigenomic profiles, although we're several years away from doing this.

Audio

Produced by

Rima Chaddha

Edited by

David Levin

Interview by

Rima Chaddha

Images

Chapter 1

(all images)

Courtesy Dana Dolinoy/Jirtle Lab, Duke University

Chapter 2

(all DNA methylation animation stills)

© NOVA/WGBH Educational Foundation

(DNA analysis)

© istockphoto.com/Andrei Tchernov

(heart cells)

Courtesy Kip D. Hauch/University of Washington

(liver cells)

Courtesy Dr. Maria Tretiakova/Human Tissue Resource Center, University of Chicago

Chapter 3

(twin mice portrait, mice coat comparison)

Courtesy Dana Dolinoy/Jirtle Lab, Duke University

(all other mice images)

© NOVA/WGBH Educational Foundation

(DNA strand)

image adapted from © Dalibor Popadic/istockphoto.com

(girl with alphabet toys)

© istockphoto.com/Kathye Killer

(beverage containers)

© istockphoto.com/Brandon Laufenberg

(baby with bottle)

©istockphoto.com/Damir Cudic

(crowd from above)

© istockphoto.com/Oleg Prikhodko

Chapter 4

(researcher in lab)

Courtesy Dana Dolinoy/Jirtle Lab, Duke University

(feeding mice, all mice images)

© NOVA/WGBH Educational Foundation

(grain products)

Courtesy United States Department of Agriculture/wikipedia.org

(soy products)

© istockphoto.com/Jennifer Borton

Chapter 5

(all twin images)

© NOVA/WGBH Educational Foundation

(girl at doctor's office)

© istockphoto.com/marmion