Ants first marched into Danny Reinberg’s world about four years ago as he began thinking about taking his lab in a new direction. Now, he cannot keep ants off his mind because they are the focal point of a newly funded HHMI Collaborative Innovation Award to study whether epigenetics influences the behavior and aging of ants.

Ants first marched into Danny Reinberg's world about four years ago as he began thinking about taking his lab in a new direction. Now, he cannot keep ants off his mind because they are the focal point of a newly funded HHMI Collaborative Innovation Award to study whether epigenetics influences the behavior and aging of ants.

A hard-core cellular biochemist, Reinberg had committed himself to studying something new. But it took a chance encounter with scientific colleague Shelley Berger (now one of his collaborators on the new HHMI project) to jump start his ideas. At a scientific meeting the two were attending, Berger mentioned her recent fascination with ant behavior after observing leaf cutter ants in Costa Rica. She suggested to Reinberg that ants might be a perfect organism to address the big question of an epigenetic basis underlying behavior.

I truly believe that this project has opened the door for my next 20 years of science.

Danny Reinberg

Although in many quarters of the world, ants are considered little more than a nuisance, they are remarkable in many ways. They live exceptionally long lives, they are social creatures, and they engage in stereotypical behaviors that befit their station in life, whether it be worker, soldier or queen. In short, they seemed a perfect fit for Reinberg's plans.

Epigenetics is a burgeoning research field that explores inherited changes in gene activity that do not involve alterations in the primary DNA sequence. During growth and development, genes that should not be expressed are physically tagged with chemicals, such as methyl groups. Genes can also be silenced by modification of the histone proteins that make up the “smart stuffing” of chromosomes. These chemical modifications are potentially epigenetic, Reinberg says, because they influence the expression of genes, but they are not part of the actual gene sequence. They might then play an important role in shaping the development of many types of organisms, including humans. Whether these modifications are indeed epigenetically inherited along with the gene is exactly what Reinberg and his colleagues seek to study in ants.

According to Reinberg, one of the oft-debated questions in the field is whether epigenetic mechanisms are involved, for example, in mediating long-lasting changes in the brain and behavior that occur as a consequence of living in a particular type of environment.

That question is now front and center for Reinberg, an HHMI investigator at New York University School of Medicine, and his scientific partners, Berger at the Wistar Institute, and Juergen Liebig at Arizona State University. Berger is also an expert on epigenetics and gene regulation and Liebig is a leader in the study of insect societies. Together with Reinberg, they have drawn up an ambitious project that will investigate the genetics underlying differences in longevity, social behavior and brain aging among queen and worker ants.

One of the first goals of their collaboration is to work with other researchers to deliver the first complete sequence of an ant genome. The group plans to sequence the genomes of three ant species in all.For the last 20 years, Reinberg has focused on understanding gene expression—the process that cells use to produce proteins from genes on double-stranded DNA. DNA sequences in genes are first transcribed to RNA molecules, which then become the templates for proteins. But this process must be controlled so that the correct amounts and types of proteins are made in a normal cell.

He and scientists in his HHMI lab at New York University, and before that at the University of Medicine and Dentistry of New Jersey, have made many fundamental discoveries about how the DNA inside a cell is read and transcribed. “I thought we had done a good job in understanding, for example, how chromatin affects transcription,” Reinberg says, “and, for me, the next logical step was to begin to take a closer look at epigenetics in living organisms. Epigenetics absolutely fascinates me. The more that you read about it, the more you want to know.”

Although he was by no means finished with what he calls “the bread and butter projects” in his lab, he felt very strongly that it was time to move on to something new. He threw himself into finding that something new, even though, he confesses he had no idea how the new project would be funded. He approached the search with an open mind and one firm ground rule: The project must be a “stretch” for himself and the scientists in his lab.

At this point, he struck up a conversation with his long-time friend Shelley Berger, who suggested that they collaborate on epigenetics of behavior in ants. After some months of thinking about that suggestion, Reinberg decided to commit to this project to investigate whether epigenetics influences behavior.

“There is not much known about epigenetic changes that may underlie behavior,” he says. Furthermore, although his expertise was in cellular biochemistry, he was determined to do the new work in a model organism. So, after doing his own background research, Reinberg became convinced that ants were indeed the perfect model organism for studies on behavior. As he and Berger continued to talk about how the project might evolve, they looked up Juergen Liebig at Arizona State, one of the top experts in studying how division of labor is maintained in insect societies.

For years, Liebig had been planning to expand his research to study the differential gene expression underlying ant behavior and the differences in aging in his established model ant systems. When approached by Reinberg and Berger, he was electrified at the prospect of merging their common interests in this project. He suggested that they also use their epigenetics approach to study aging in ants - an idea that was enthusiastically received by Reinberg and Berger.

After further discussion with Liebig, Reinberg learned that ants exhibit a range of interesting behaviors, including high sociability and well-defined divisions of labor within their colonies. For example, ants can assume either reproductive or non-reproductive roles. “The egg-layers, such as the queen, do not have to leave the nest, and hence, brain functions for complex tasks are unnecessary,” he notes. “In sharp contrast, non-reproductive nestmates maintain the colony, raise the brood and forage for food. All of these behaviors require complex brain function.”

The different reproductive roles also have a strong impact on the longevity of queens and workers. Released from the everyday activity of the colony and focused only on reproductive tasks, queen live up to 10 times longer than worker ants.

As a consequence of differential aging and different behaviors, some regions of the queen's brain, such as the visual system, are not as well developed as those of the workers. Even though these two types of ants begin life remarkably similar, their individual experiences and differences in aging sculpt their brains and behaviors in vastly different ways. Given the high degree of genetic relatedness among ants in colonies, Reinberg hopes that it will be easier to pinpoint the changes in gene expression that drive the changes in adaptation to specific social roles in the ant community. “If you want to understand epigenetics, then the ant is a good model organism to use. We can begin to investigate whether changes in chromatin are associated with epigenetics,” he said.

According to Reinberg, other scientists have documented that social insects can live up to 100 times longer than solitary insects. And within the ant world, the queen reigns supreme in terms of longevity when compared to the worker or soldier ants. But scientists generally have no idea about which genes confer longevity—or, of special interest to Reinberg and his colleagues, how those genes are regulated.

So far the only hint of specific genes involved in longevity come from studies of the ant species Lasius niger. Researchers have found that three genes are exclusively expressed in queen ants and those genes help maintain and repair the ants' bodies and may have a role in longevity. “However, nothing is known about possible epigenetic bases for these aging differences,” said Reinberg. “We think the ant will provide an outstanding and unique opportunity to investigate epigenetic aspects of organismal aging.”

“One reason this project is risky is that we are working with an organism whose genome has not yet been sequenced” notes Reinberg. One of the first goals of the project is to fully sequence, assemble and begin annotating the genomes of three ant species. Reinberg is currently in the final phase of selecting scientific collaborators who will do the sequencing.

After the ant genomes are finished, the scientists will look at gene expression profiles in different types of ants (worker, soldier, queen) from the same colonies and then from different colonies. They will also compare gene expression profiles of different species of ants. Questions abound for Reinberg and his colleagues: For example, how does the brain of a queen differ from that of a worker? What differences in brain function and behavior are induced when researchers apply hormonal manipulation to an immature ant to force it to follow the developmental trajectory of a worker, soldier or queen? Do the gene expression profiles in the brain change as an ant assumes its new social role as queen?

Reinberg also loves the project because he will be able to begin seriously studying neurobiology, an area of research that has fascinated him for many years. “I have been working in cells for more than 20 years. And now I have the opportunity to work on whole organisms and move into neurobiology, a field that I will enter with this project. I truly believe that this project has opened the door for my next 20 years of science.”

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