Epigenetics is an exciting but a weird area. It’s well recognized that messing with chromatin and chemical modifications of nucleic acids has profound consequences at the cellular and organism levels. But for me the mechanistic rationale for targeting epigenome pharmacologically was always somewhere close to throwing a monkey wrench into the clockworks and watching what will happen. It seems (not surprisingly) that in fact the effects are more predictable.
A recent paper in Science describes a collaborative work of three labs studying epigenetic manipulation of ants’ behavior. So the first thought in my head was ‘why the heck ants?’ I found the graphic answer at the home page of Reinberg lab (one of the corresponding authors).
Well, the analogy between ants in a colony and cells in a multicellular organism indeed seems quite far fetched. First of all because ants are themselves multicellular organisms, so Prof. Danny Reinberg’s explanation is somewhat recursive.
Another group of authors (Jürgen Liebig lab) started long ago from chemical signaling of ants and eventually ended up in ants’ epigenetics. The third lab (Shelley L. Berger) studies epigenetics in a broad spectrum of models, ants being one of them.
But enough prelude, let’s take a look at the actual science. The most exciting part of the paper is of course the concept: by injecting some chemicals in young ants brains (or by feeding!) authors could make them swap their social roles in adulthood. Sounds so antiutopic, doesn’t it?
The whole study is built around modulation of histone diacetylases (HDACs). It appears that 10-hydroxy-2-decenoic acid (10-HDA, a.k.a. queen bee acid), a component of royal jelly made by queen bees, is a HDAC inhibitor. The acid helps keeping subordination in bee colonies. So authors decided to check if there’s similar mechanism involved in homeostasis of ant colonies.
First, the authors observed a whole bunch of ant colonies to confirm that minor workers (with small size) are main foragers, while major (big) workers do not bother very much to bring food to the colony. Then they found correlation between the foraging activity and mRNA level of two HDACs in ant brains. Then inhibited HDAC with valproic acid (VPA) and trichostatin (TSA) and found that foraging activity of minors increased. And after that they inhibited CREB binding protein (CBP), an enzyme with opposite to HDACs acitivity, by a small molecule C646, and showed that it reversed behavioral consequences of HDAC inhibition and by itself it actually completely stopped foraging activity of minors, making them major-like.
After that authors performed the same battery of pharmacological tests with majors, adding RNAi to that, and could make them to behave minor-like (i.e. to forage).
To figure out what’s going on at the level of individual genes, the authors performed series of genomic analyses: whole-brain RNA-seq and ChIP-seq. They found out that a number of neuron-regulating genes was altered in different manner upon treatment with either TSA or C646 (along with bunch of other genes apparently, but the functions of those are not easily paralleled with behavioral plasticity).
As a result, we have a very strong case that epigenetic regulation has a very pronounced (and non-lethal) effect on the behavior of social insects. But on the molecular level it still remains a complex black box. Add to this time-dependence of the effects observed in this study and you’ll agree that it’s still difficult to predict the outcomes of external epigenetic modulation. Phenotypic screening and whole-organism studies are probably the best ways to explore it.