HDAC and HAT Inhibitors Reprogram Social Behavior in Carpenter Ants

Histone Deacetylase (HDAC) and Histone Acetyltransferase (HAT) Inhibitors Reprogram Social Behavior in Carpenter Worker Ants

Florida carpenter ants, or Camponotus floridanus, are social creatures that can develop into one of two distinct castes of workers – majors or minors. These two types of worker ants display specific differences in foraging and scouting behavior for their entire lives. However, a group of researchers conducted a study at the University of Pennsylvania and discovered that these castes can actually be epigenetically reprogrammed via histone acetylation with the help of epigenetic inhibitors. Surprisingly, the ant’s genetic makeup didn’t determine the caste-specific behavior, but, rather, their epigenetic makeup did.

Researchers from multiple institutions worked together to uncover fascinating insights into the social behavior of Florida carpenter ants and the underlying epigenetic control mechanisms. In a previous What is Epigenetics? article, researchers found that DNA methylation impacted continuous variation in Florida carpenter ant size. Based on the amount of DNA methylation of a growth-related gene, the ants were either larger or smaller.

These new findings, published in Science, uncovered another type of epigenetic modification, known as histone acetylation, which affects the ants’ caste-based behavioral plasticity. This histone modification is defined as the addition of an acetyl group to histone protein complexes that impacts gene expression.

Florida carpenter ants are an excellent model for social behavior because each ant colony contains thousands of females with genetic makeup that is nearly identical, similar to human twins. All the workers are actually sisters, but they display different behaviors and physical traits depending on the caste to which they belong. The major ants need big heads and strong mandibles to defeat enemies and transport heavy food items, whereas minors are more abundant in the colony, much smaller, and scout for food and recruit others to aid in the harvest.

In an earlier study, the authors composed the first genome-wide epigenetic map in ants. They found that epigenetic regulation is crucial in identifying the large, “brawny” majors and the smaller, “brainier” minors. Specifically, they found histone post-translational modifications such as the acetylation of Lys27 on histone H3 (H3K27ac), have particular genome-wide patterns in the bodies and brains of majors and minors. They hypothesized that histone acetylation might regulate which caste the workers fall into.

The team was headed by senior author Shelley Berger, PhD, from the Perelman School of Medicine at the University of Pennsylvania. Berger is a Daniel S. Och University Professor in the Cell & Developmental Biology, Biology, and Genetics Departments and is also the director of the Penn Epigenetics Program. The research team included groups of scientists from Arizona State University and New York University, which were each led by Juergen Liebig and Danny Reinberg, respectively. Together, they discovered that, through the administration of histone deacetylase (HDAC) inhibitors and histone acetyltransferase (HAT) inhibitors, they could directly change the caste-specific foraging behavior of the ants via histone acetylation. The removal or addition of acetyl groups by HDAC inhibitors and HAT inhibitors affected the expression of nearby genes related to caste behavior.

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

Nearly 10 years of collaboration among the Berger, Reinberg, and Liebig labs has unveiled caste-based differences in ants and the underlying mechanisms that control these social behaviors. Their previous studies have suggested that the gene expression of some eusocial species, or animals who are “truly social,” such as ants, termites, wasps, and certain bees, can be affected by histone acetylation. Even in animals who have an identical genetic code, histone modification could lead to distinct differences in gene expression and impact physical appearances such as body size or the ant caste’s ability to reproduce.

This study demonstrates that epigenetic changes such as histone acetylation can, indeed, regulate caste behaviors. The researchers investigated chromatin – the protein-DNA complex that contains DNA wrapped around histone proteins – and the addition or subtraction of acetyl groups. These acetyl groups can be added onto or removed from the chromatin structure and impact how compact or loose the genome becomes. Histone acetylation, for example, adds acetyl groups and loosens the structure to make it more available to transcription.

Histone modifications are known to determine the specific features of various tissues within an individual so the scientists wanted to demonstrate that this modification can also cause different traits between individuals, such as those in a eusocial community. The researchers fed the foraging, brainy minors a chemical inhibitor, or HDACi, that inhibits the removal of acetyl groups from histones, called histone deacetylation. This resulted in an increase in foraging and scouting for food, which then also led to an increase in histone acetylation near genes associated with neuronal activity. HDAC inhibitors often lead to hyperacetylation of histones. In contrast, when the researchers inhibited the addition of acetyl groups, the foraging activity decreased.

Aside from the significant boost in foraging behavior in minors, when the researchers fed the epigenetic inhibitors to mature major workers, there was only a small increase or no increase at all in foraging. But, injecting the inhibitors directly into young majors’ brains increased foraging immediately and reflected levels typically observed only in minors. Just one treatment was able to sustain the atypical foraging behavior in majors for as long as 50 days. Based off these results, there may be an “epigenetic window of vulnerability” during which young ant brains are highly susceptible to environmental factors, for instance, HDAC or HAT inhibitors, which can modify histones.

Berger also discussed the power of the ant model because all genes thought to be major epigenetic regulators in ants are also present in mammals. According to her, the ants can help provide a profound opportunity to explore the epigenetic processes in humans that may contribute to behavioral patterns at a young age. Because behavioral disorders continue to rise and many people are now realizing that diet can impact behavior, investigating this more could help progress our understanding of pervasive diseases such as Autism.

In the study, an important gene known as CBP acted as an epigenetic “writer” enzyme. CBP plays a role in histone acetylation, changing chromatin by adding acetyl groups to histones. It’s already thought to facilitate critical processes such as memory and learning in mice. It is even mutated in various human cognitive disorders like Rubinstein-Taybi syndrome. The team’s findings align with this information, suggesting that histone acetylation that is mediated by CBP could facilitate complex social interactions among vertebrate species.

The research team believes that the epigenetic writer enzyme, CBP, contributes to histone acetylation patterns that impact and improve memory pathways associated with learned behaviors, for example, foraging. The distinct neuronal functions for each ant worker caste may be controlled by varying activity of CBP, which influences gene expression and guides unique histone acetylation patterns.

“From mammalian studies, it’s clear this is an important protein involved in learning and memory,” Berger commented. “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.”

Berger and her team are now moving forward to more accurately define this epigenetic window of vulnerability and the important molecular features. She explained, “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.”


Source: D. F. Simola, R. J. Graham, C. M. Brady, B. L. Enzmann, C. Desplan, A. Ray, L. J. Zwiebel, R. Bonasio, D. Reinberg, J. Liebig, S. L. Berger. Epigenetic (re)programming of caste-specific behavior in the ant Camponotus floridanus. Science, 2015; 351 (6268): aac6633.

Reference: Penn Medicine. Penn-Led Team Reprograms Social Behavior in Carpenter Ants Using Epigenetic Drugs. University of Pennsylvania Health System. 31 Dec 2015. Web.

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About Bailey Kirkpatrick 164 Articles
Bailey Kirkpatrick is a science writer with a background in epigenetics and psychology with a passion for conveying scientific concepts to the wider community. She enjoys speculating about the implications of epigenetics and how it might impact our perception of wellbeing and the development of novel preventative strategies. When she’s not combing through research articles, she also enjoys discovering new foods, taking nighttime strolls, and discussing current events over a barrel-aged sour beer or cold-brewed coffee.


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