Walker, who has received many awards for her research, said she hoped she would do justice to the long line of esteemed speakers who have taken part in the NIEHS Distinguished Lecture series. (Photo courtesy of Steven McCaw)

Because the human genome contains the blueprint of life, its spiraling sequence of four nucleotides — thymine, adenine, cytosine, and guanine — is designed to be stable and unchanging. The epigenome, which is the assortment of chemical and protein tags that mark which parts of that sequence should be read, is a different story.

As NIEHS Distinguished Lecture Series speaker Cheryl Walker, Ph.D., told the audience during her Feb. 12 talk, the epigenome has built-in plasticity, particularly during critical periods of development. The epigenome of a developing individual can sense the environment to prepare for its adult life. But if life turns out to be different than anticipated, that positioning can end up being a vulnerability.

“If we disrupt the epigenetic programming during these critical periods or windows of susceptibility, we carry a disturbed epigenome with us for the rest of our lives,” Walker said. “This is thought to contribute to the root cause of many conditions, such as metabolic syndrome, diabetes, and obesity.”

Windows of susceptibility

Epigenetic marks come in two basic varieties — chemical tags that are attached to DNA and protein tags attached to histones — around which the DNA is spooled. These tags, referred to as chromatin marks, are placed, recognized, and removed by molecules that Walker calls “epigenetic readers, writers, and erasers,” respectively.

Epigenetic marks are particularly active during certain periods of development, such as when eggs and sperm are being formed, when a fetus is developing in the womb, and during childhood. During those times, the epigenome can be reprogrammed in response to environmental cues like diet, air pollution, and estrogen-disrupting chemicals.

Walker explained two ways that gene-environment interactions work: the environment reprograms the epigenome early in life, and that reprogramming changes the epigenome’s response to the environment later in life. (Photo courtesy of Steven McCaw)

A silent epidemic

Walker’s latest research, yet unpublished, is looking at how exposure to a class of chemicals called endocrine-disrupting compounds, including the estrogen-disrupting chemical bisphenol A (BPA), early in life can cause changes in the epigenome that have effects much later in life. Specifically, she is interested in the role BPA may play in the growing epidemic of nonalcoholic fatty liver disease (NAFLD), which now affects 30 percent of American adults. NAFLD can raise the risk of heart disease, diabetes, cirrhosis, and liver cancer.

Walker and her team exposed mice to BPA during development. They found that liver metabolism was not altered in these mice until they were exposed as adults to a diet high in fat, sugar, and cholesterol — sometimes called a western diet.

Using a sophisticated technique called CHiP-seq, Walker’s team found that many of the epigenetic marks normally present after birth disappeared and were replaced by a signature of epigenetic marks more typically found only in adult livers. The finding occurred only in the male mice.

“Initially, we looked at this and thought, ‘We’re losing all our reprogramming, this can’t be good’,” Walker said. “But you know what, we were dead wrong.”

An eye on prevention

“Her big picture discussion on the [NAFLD] seems like a clarion call to better understand how developmental exposures alter disease risk after later exposures,” Tyson said. (Photo courtesy of Steven McCaw)

What they saw is explained by a relatively new idea known as epigenetic aging. Just as the functioning of cells and tissues changes naturally as we age, so do the epigenetic marks on genes governing our body’s processes (see related story). Walker found that the natural aging of the epigenome was accelerated by early life exposure to BPA.

She showed that the epigenetic reprogramming caused a host of genes involved in various aspects of liver function, such as fatty acid metabolism and cholesterol metabolism, to respond inappropriately to a western diet.

“It is a surprising finding,” said NIEHS Program Director Fred Tyson, Ph.D., who has known Walker since they both worked as senior staff fellows at NIEHS in the late 1980s. “It provides critical information and, importantly, potential guidance on how limiting or eliminating developmental exposures will reap dividends in protecting public health.”

“The delayed manifestation of the effects of epigenetic reprogramming means that there may be things we can do to prevent the onset of disease,” said Walker. “In other words, epigenetic reprogramming may be a ticking time bomb, but later-life exposures are necessary to light the fuse.”

(Marla Broadfoot, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)