Timing is everything: Julia Yue Cui investigates how the environment sets the schedule for liver genes

Timing is everything: Julia Yue Cui investigates how the environment sets the schedule for liver genes

By Sam Million-Weaver, Environmental and Occupational Health Sciences Writing Intern

Julia Yue Cui, the Sheldon D. Murphy Endowed Chair in Toxicology and Environmental Health, researches perplexing health phenomena that cannot be explained by gene mutations.Cui joined our department as an assistant professor in July 2014.

Her previous work has furthered understanding of how biological changes that alter when and how genes are turned on and off, or expressed, influence health outcomes. Gene expression may be governed by epigenetic markers, which can change how a gene functions without altering the underlying DNA sequence.

Specifically, Cui studies how environmental factors influence gene expression in the liver, the organ that detoxifies chemicals. Some compounds make permanent epigenetic marks on the liver’s DNA, forever changing how the liver expresses certain genes. Therefore, early exposures to toxicants can have long-lasting effects, even altering how individuals respond to pharmaceutical drugs later in life.  Cui’s research into how epigenetic alterations influence the liver may help contribute to understanding some medical mysteries, such as unanticipated adverse reactions to drugs.

She started to establish a track record for investigating the reasons behind unexpected results during her Ph.D. training and subsequent post-doctoral fellowship at the University of Kansas Medical Center.  

“My project started out as purely an interesting phenomenon during my first research rotation in Dr. Curtis Klaassen’s laboratory, where I quantified the expression of some genes that are important for detoxifying chemicals during liver development,” says Cui about her research.

The conventional wisdom held that the livers of newborns should produce low levels of these genes’ products because the drug-processing system is not fully mature during this period, and newborns and children presumably would not have experienced extended exposures to environmental contaminants. Cui was surprised to find, however, that some of these genes’ expression levels peaked to their highest points immediately after birth.

Undeterred by her seemingly contradictory findings, Cui investigated the cause. She found that high expression of some detoxification genes early in life may be a necessary adaptation mechanism to prevent detrimental epigenetic changes to the liver DNA as newborns are exposed to increasing amounts of environmental compounds. She emphasizes that “children and infants are not simply small adults in how they react to the effects of chemicals.” Exposures during childhood that overwhelm the liver’s early enhanced detoxification gene expression can set the stage for undesirable health outcomes many years in the future.

One of Cui’s recent discoveries may offer another insight into unexplained differences in liver function between individuals. She found a previously unappreciated role for the communities of bacteria living inside the gastrointestinal tract, called the microbiome, in regulating how the liver copes with drugs and other chemicals. Her research revealed that mice lacking microbiomes display dramatic changes in gene expression for crucial detoxification pathways. While numerous studies have investigated how the bacteria living inside the intestinal tract themselves process environmental compounds in adults, Cui says it’s relatively less understood how the gut microbiome communicates with the liver during development.

She is now investigating how the microbiome and environmental chemicals affect the liver during childhood development and whether these factors’ influence on the liver plays a role in causing children to respond to pharmaceuticals differently than adults. This research is supported by the National Institutes of Health National Institute of General Medical Sciences, the UW Center for Ecogenetics and Environmental Health, as well as the department.  Cui hopes her findings will one day help develop new therapeutic options; for example, clinicians may be able to modify gene expression in the liver by changing the composition of the microbiome through the use of antibiotics or probiotics.

To study subtle differences in gene expression, Julia has made use of advanced next-generation sequencing technologies, proteomics, and transgenic animal models. Even though she is quick to adopt the latest methods, Cui is pragmatic and open to using multiple approaches to answer her research questions.

“There will always be a new technology that makes the current technologies antique,” said Cui, “But a great idea will never be out of date. That is why I really like to be part of our department and the Center for Ecogenetics and Environmental Health.  You can implement whatever tools are appropriate to address fundamental questions that are related to human health.”