18 March 2019

In order to survive, all organisms must be able to detect (threatening) changes in their environment and respond to them adequately and quickly. However, such stress responses (e.g., escape from a predator or immune response to an infection) are very energy-consuming. Very little is known about the way in which organisms organize and regulate this energy supply. Annette Schenck and her colleagues discovered a primary driver of this regulation process in fruit flies. Their research is now published in Plos Biology.

Annette Schenck has been working with the fruit fly Drosophila for years, to gain a better understanding of rare neurological developmental disorders. She discovered that the EHMT/G9a gene (hereafter referred to as G9a) acts like a conductor, orchestrating various other genes involved in learning and memory. This is important for flies to learn and remember (yes, normal flies can, but G9a mutant flies cannot).

Such findings are relevant, because mutations in the human G9a gene lead to a hereditary form of intellectual disability, called the Kleefstra syndrome. Recently, together with her colleague Ronald van Rij, she found indications that G9a is also important for cellular adaptations in response to infections. These adaptations can be seen as a stress response of the immune system to an intruder.

Faltering energy supply

In Plos Biology Schenck and her colleagues have now carefully dissected the role of G9a in stress responses. Schenck: ‘G9a is an epigenetic regulator. This means that it is able to respond quickly to external stimuli and activate or switch off other genes. We found that it also is a factor that can cause rapid changes in metabolism. When we switched off G9a in our mutated fruit flies and exposed them to stress, we did not only see over-activation of stress response genes, but also that the energy supply faded away very quickly. Sugars were burned at a rapid pace, while fat could not be used as an energy source. As a result, our mutant flies ran out of energy and died.’

Stress and sugar

The research makes clear how energy-consuming - literally - stress responses can be. A well-functioning energy supply is perhaps even more important to deal with stress than clearing up proteins and fats that have been damaged by it. If the mutated fruit flies were given extra sugar – that is: energy - they stayed alive.


This research in fruit flies about the response to oxidative stress is quite fundamental, but it does have interesting connections with clinical aspects, Schenck states. ‘Some other recent studies show that G9a also affects genes needed to handle lack of oxygen, that regulate the construction of new blood vessels, tumor growth and a process of self-eating (autophagy). These are all processes that play a role in cancer. It is now becoming very interesting to investigate what role this G9a gene plays in cancer. G9a could be an Achilles heel that can be used to fight cancer’

Kleefstra syndrome

And apart from cancer, further possible clinical connections emerge from this fundamental research. Mutations in the G9a also cause Kleefstra syndrome, a rare neurological developmental disorder that has been discovered in the Radboudumc by clinical geneticist Tjitske Kleefstra. The Radboudumc is a worldwide recognized expertise center for patients with this syndrome. ‘It is remarkable,’ says Schenck, ‘that, when not challenged by stress, we see very high levels of fat and sugars in our mutated fruit flies. This is similar to patients with Kleefstra syndrome, who in addition to intellectual disability, have an increased risk of obesity. The EHMT1/G9a gene appears to play a role in more and more processes and is therefore becoming increasingly fascinating.’

The histone methyl transferase G9a regulates tolerance to oxidative stress-induced energy consumption
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