By Karen Kreeger

Exhibit 1: Shelley Berger, Ph.D., the Daniel S. Och Univer­sity Professor with an appointment in Penn’s Department of Cell and Developmental Biology, is working in her office in the Smilow Center for Translational Research. If she turns slightly from the computer screen toward the wall within arm’s reach on her left, she sees a large framed photograph (about 15 inches high by 18 inches long) of a leaf-cutter ant. Even the largest of that species would be no longer than 0.63 inches, so the magnification is startling.

Exhibit 2: Shelley Berger is approaching her office in the Smilow Center. As she draws nearer, she sees another framed photo just to the right of the door. This one shows – in more detail than some squeamish viewers might like – two ants. Its dimensions are about 21 inches high by 16 inches long.

It’s probably safe to conclude that Berger has a strong inter­est in ants and possibly some affection for them as well. But what role do these creatures play in her scientific research?

About ten years ago, before joining Penn Medicine, Berger made a trip with her family to Costa Rica. While there, she became fascinated by the fungus-eating leaf-cutter ants. Like all ants, they are social creatures and – despite having decid­edly different castes – carry identical genes. What distin­guished one ant from the other, if it was not their genes? Ants, Berger realized, would be an ideal group for studying how epigenetics affects behavior and the overall development of individual ants. Epigenetics is the field that investigates in­herited changes in gene activity, in which genes are turned on or off via molecular “tags.” The DNA sequence itself, however, does not change. In the case of ants, each colony comprises thousands of individual sisters – notably, the queen and all workers are female – with nearly identical genetic makeup, much like human twins. At the same time, these sisters pos­sess stereotypically distinct physical traits and behaviors based on caste.

Back in the United States, Berger discussed her idea with Danny Reinberg, Ph.D., a professor of biochemistry at New York University and, like Berger, a pioneer in epigenetics. He, too, saw the possibilities in such an approach. When Berger left the Wistar Institute and joined Penn Medicine – also be­coming director of the Penn Epigenetics Program – she con­tinued her study of ants. Then, in 2008, with Juergen Liebig, Ph.D., a behavioral ecologist at Arizona State University who had studied the social behavior of ants, Berger and Reinberg received a Collaborative Innovation Award from the Howard Hughes Medical Institute. The interdisciplinary team’s initial goal was to sequence the genomes of two ant species: Jerdon’s jumping ant, which is found in India, and the Florida carpen­ter ant. Two years later, they published their results in Science. The next step: to probe more deeply into the social behavior of the carpenter ants. 

“Brawny” and “Brainy” Divide the Roles 

In carpenter ant colonies in Florida, distinct worker castes called “minors” and “majors” exhibit pronounced differences in social behavior throughout their lives. But in a study pub­lished in January 2016 in Science, the multi-institutional team anchored at the University of Pennsylvania found that these caste-specific behaviors are not set in stone. Instead, the social behavior of these ants can be reprogrammed. The findings indicate that an individual’s epigenetic – not genetic – makeup determines behavior in ant colonies.

Epigenetic regulation influences a variety of distinct traits in animals, including body size, aging, and behavior. However, there is an enormous gap in knowledge about the epigenetic mechanisms that regulate social behavior.

In their 2010 study, Berger and her colleagues showed that epigenetic regulation is crucial to distinguishing two distinct castes of Florida carpenter ants. The majors are the “brawny” soldiers of carpenter ant colonies; the minors are their smaller, “brainier” sisters. Majors have large heads and powerful man­dibles that help to defeat enemies and process and transport large food items. Minors are much smaller, outnumber majors two to one, and assume the important responsibility of searching for food and recruiting other ants to help with the harvest. Compared to majors, these foraging minors have genes involved in brain development and neurotransmission that are over-expressed. 

“The results suggest that behavioral malleability in ants – and likely other animals – may be regulated in an epigenetic manner via histone modification,” says Daniel F. Simola, Ph.D., a postdoctoral researcher in Penn’s Department of Cell and Developmental Biology. Simola is co-lead author of the 2016 Science study with Riley Graham, a doctoral student in the Berger lab.


It’s All About the Histone

The seminal 2016 study shows that caste behaviors are reg­ulated by epigenetic changes in the way chemical tags are added to or taken away from histone structural proteins in the nucleus. To reach that conclusion, the team used the fact that chromatin structure – the coiling of the DNA around histone proteins – can be altered by adding compounds that alter the epigenetic tags such as acetyl groups. That addition ultimately changes the compaction of the genome. As described in the Science paper, the team fed foraging minors a chemical inhibi­tor that prevents cells from removing acetyl groups from his­tones. This treatment enhanced foraging and scouting for food and, correspondingly, led to increased histone acetylation near genes that are involved in neuronal activity. Conversely, inhibiting the addition of acetyl groups led to decreased foraging activity.

In contrast to the dramatic boost in foraging seen in mi­nors, feeding mature major workers these epigenetic inhibi­tors caused little to no increase in foraging. However, the team found that directly injecting the inhibitors into the brains of very young majors immediately increased foraging. The treated majors reached foraging levels normally ob­served only in minors. In addition, a single treatment with these inhibitors was sufficient to induce and sustain foraging in the majors for up to 50 days. These results suggest that there is what can be described as an epigenetic window of vulnerability in young ant brains, which confers increased susceptibility to environmental manipulations, such as with histone-modifying inhibitors.

Broader Implications

Berger observes that all of the genes known to be major epigenetic regulators in mammals are also present in ants. That, she continues, makes ants “a fantastic model for study­ing principles of epigenetic modulation of behavior and even longevity, because queens have a much longer lifespan com­pared to the major and minor workers. Because of the re­markable window we have uncovered, ants also provide an extraordinary opportunity to explore and understand the epi­genetic processes that come into play to establish behavioral patterns at a young age.” Such a topic, she continues, is of in­creasing research interest in humans, “owing to the growing prevalence of behavioral disorders and diseases and the ap­preciation that diet may influence behavior.”

One important gene implicated in the ant study is CBP, which is an epigenetic “writer” enzyme that alters chromatin by adding acetyl groups to histones. “From mammalian stud­ies, it’s clear this is an important protein involved in learning and memory,” Berger notes. “The finding that CBP plays a key role in establishing distinct social behaviors in ants strongly suggests that the discoveries made in ants may have broad im­plications for understanding social organization.”

The Berger team is now focused on precisely defining the epigenetic window of vulnerability and its crucial molecular features. She explains that “understanding the mechanisms of when and how this window is opened and how changes are sustained – and why the window closes as the major ant ages – may have profound implications for explaining human vulner­ability to early life exposures.”  

After the second study appeared in Science, Berger demon­strated a valuable talent: being able to communicate what she does not only to non-scientists but to young children as well. She appeared on “Science Knocks,” a three-minute science podcast hosted by Sindya N. Bhanoo, the “Observatory” col­umnist for The New York Times. Bhanoo, who described the carpenter ant study in the Times, gave a simplified version to Naina, her four-year-old daughter. As Bhanoo explained offscreen and her daughter echoed her or asked questions, quickly drawn sketches appeared on the screen. The queen of the carpenter ants was distinguished by a tiny crown. One of the foragers gathering food apparently decided to bring back a slice of pizza. Naina wondered why there weren’t any “boy ants.” Berger’s voice: “All of them are girls. . . . There are very, very few boys.” 

When Naina learned that the soldier ants began to act like forager ants, she asked, “Like, how did they make them act like that?” Berger replied: “There are special chemicals that change the way the brains work,” and the scientists injected these chemicals into the newborn ant brains. Naina grasped the concept: “because people give them a special chemical medicine!” Then, as the three minutes came to an end, the little girl added: “Thanks for your time, Dr. Berger.”

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