FrankRamspott; Adobe Stock 287706710
FrankRamspott; Adobe Stock 287706710

DNA in Real-World Conditions

by Jackie Swift

Women on average live five years longer than men. This same pattern of female longevity can be found among other mammals. Female orcas, for instance, outlive males by up to 40 years. But while some have concluded that nature favors females, plenty of evidence refutes that. In species such as the European rabbit, for example, males have a longer life span than females. And the Japanese macaque essentially shows no difference in longevity between the sexes.

“All animals age, but length of life span of males and females among different species is really diverse,” says Jingyue (Ellie) Duan, Animal Science. “The question is, what is the evolutionary mechanism behind aging, and is it common for all species or unique within each species?”

Duan studies epigenetic regulation, the mechanisms at the molecular level that turn genes on and off without actually changing a cell’s DNA sequence. Epigenetic changes in gene expression are connected to aging, among other things. “The powerful thing about epigenetics is that it happens all along our life span,” Duan says. “Epigenetic processes occur during fetal cell differentiation, when the first embryonic cell divides into two cells and four cells and so differentiates into all the different cells of our bodies. It happens during development and during diseases like cancer—and it happens during aging.”

How Do Species Age?

Duan uses genomics and computational approaches to explore animal biology at the molecular level. She is a co-principal investigator of the Integration Institute on Sex, Aging, Genomics, and Evolution (IISAGE), which is currently carrying out a five-year project to investigate the mechanisms and evolution of sex-specific aging. Co-led by Cornell, the University of Alabama at Birmingham, Michigan State University, Marquette University, and Brown University—and funded by a $12.5 million grant from the National Science Foundation—IISAGE brings together researchers from eight institutions with expertise in more than 30 species, from invertebrates to fish, reptiles, and mammals.

Duan will take the lead in integrating and analyzing the hundreds of data sets generated by the project. She will also oversee the establishment of a central database for IISAGE at Cornell. Ultimately, the researchers hope to create predictive models for how genome architecture, organismal biology, and phenotypic plasticity can interact and lead to differences in aging. “No one has studied this question at such a level before, so it’s a really exciting topic,” Duan says.

Heat Stress and Milk Production

In a related line of research, Duan and her lab are examining how environmental factors affect whether a gene gets turned on or off, or gene expression. The specific goal is to better understand the effect of heat stress on dairy cow milk production.

“What is the evolutionary mechanism behind aging, and is it common for all species or unique within each species?”

Climate change has increased heat stress on dairy cows, Duan explains. The production of milk already generates increased heat within the animal’s body, and when the external environment becomes warmer, the result is a high heat load for the cow. The impact on overall milk production can be significant.

To explore the biological mechanisms behind lower milk production and ways to counteract them, Duan has joined with Joseph W. McFadden, Animal Science, in a two-pronged project. The McFadden lab is working on a nutritional approach to counteracting the effects of heat stress while the Duan lab is delving into the epigenetic mechanisms that are triggered by a hotter environment in an in vitro cell model.

Recently, Duan and her colleagues focused on liver cells from heat-stressed and non-heat-stressed dairy cows. They carried out transcriptome analysis, looking at all the RNA transcripts present in the cell models to search for epigenetic changes in gene expression between the two groups of cows. “The liver is a key organ involved in milk production,” Duan says. “It takes up nutrition and metabolizes it and transports glucose for both milk synthesis and energy requirement. It’s very important to a dairy cow’s adaptation and metabolism.”

In addition, Duan has joined with Gerlinde Van de Walle, Microbiology and Immunology, to establish a culture system for mammary epithelial cell lines known as MAC-T cells. The researchers want to understand how high temperatures turn off some genes so they are unable to activate the milk protein gene.

“We can add lactogenic media with hormones to induce these MAC-T cells to differentiate and produce milk protein in vitro,” Duan says. “Then we can do the heat-stress test right in the Petri dish. We can compare how different temperatures impact the cows and hopefully discover the key regulatory mechanism of the epithelial cell changes in milk-related genes in response to heat stress.”

Epigenetics in the Early Embryo

Duan, who came to Cornell in 2021, began her academic career in graduate school investigating two phenomena of epigenetic regulation in ruminant models: genomic imprinting (where the copy of a gene inherited by one parent is silenced while the other parent’s copy is expressed) and X chromosome inactivation (where one of two X chromosomes is silenced in females). Both of these phenomena are integral to early embryonic development, but exactly how they are biologically regulated is unknown.

Duan helped shed light on the mysterious workings of epigenetic regulation as a postdoctoral researcher at Brown University. While there, she identified the DNA binding protein CLAMP as a pioneer transcription factor with a key function of regulating the Zygotic Genome Activation (ZGA) that ensures the progression of early embryotic development in the fruit fly. She is currently collaborating with Soon Hon Cheong, Clinical Sciences, to explore and identify key proteins involved in regulating bovine ZGA.

Understanding how epigenetic regulation works in the early embryo is a major step in optimizing animal health and reproduction, Duan says. “We can use what we learn about basic molecular-level regulation to help us understand animal biology and development,” she says. “Then we can take what we know and improve the health of animals by enhancing embryonic quality and improving fertility. When we do that, we improve food security and the quality of life for humans as well.”

The Road to Cornell

Biology fascinated Duan as a child. She grew up in China during the 1990s, when the first cloning projects made big news. “When I was in middle school we learned about the concept of cloning in biology class, and I thought it was so cool and amazing that they can do that in the lab,” she says.

Duan earned her PhD at the University of Connecticut. Her adviser, Xiuchun (Cindy) Tian, and Tian’s late husband, Xiangzhong (Jerry) Yang, cloned the first calf in North America in 1999. Tian and Yang graduated from Cornell and took the research they started at Cornell with them to the University of Connecticut, Duan explains. “I was so lucky to be able to learn from them, it was just like my childhood dream came true. I have this long connection to Cornell through them,” she says, noting that the couple used to work in Morrison Hall where her office is now. At Cornell, she has even had the opportunity to meet Tian’s postdoctoral adviser, professor emeritus Joanne E. Fortune, Biomedical Sciences. “She’s like an academic grandmother to me,” Duan says.