Advancing Epigenetics Towards Systems Biology

Striking a balance in the brain

epigenetics ainsworth 3

Photo: Neuron Connection
Patrick Hoesly on FlickrCC licenced by

Why should neurons be so sensitive to levels of gene activity? One possible answer is that they are extremely large, long-lived cells that have to constantly grow or prune connections in a hugely complex network with other neurons in response to a changing environment. Indeed, the adaptability, or "plasticity" of these connections is thought to underlie the brain's ability to process information and to form and retain memories. But it's a delicate balance to strike: too little plasticity and the connections between neurons don't form; too much and the connections don't persist. Consistent with this idea, mice lacking MeCP2 in their brains have lower levels of plasticity in their neurons and have problems generating memories (5). "My interpretation of what is going on in Rett Syndrome is that the neurons are inefficient in some way that we haven't fully described," says Bird. "If you put MeCP2 back, you restore the efficiency at which they operate."

This all fits in with findings emerging from other areas of epigenetics. One of these concerns histones, the bobbin-like proteins around which the DNA in your cells is wound. As well as packaging and protecting DNA, histones help to control the activity of the genes contained within that DNA. The cell can decorate histones with many different kinds of chemical marks. An army of enzymes adds or removes these marks, which in turn, dictate how active the surrounding genes are.

Interfering with these enzymes can have profound effects on gene activity and brain function. Increasing the activity of certain histone-altering enzymes, for example, hampers the ability of neurons to form new connections and impairs memory formation (6). In contrast, blocking the activity of certain enzymes with drugs can improve memory formation, even in aged mice (7). These drugs are now being explored as a means of treating neurodegenerative conditions such as Alzheimer's disease.

Could epigenetic drugs ever be used to treat people with inherited intellectual disabilities like Rett Syndrome? Unlikely as it sounds, it wouldn't be too surprising if the work on such drugs and the research into epigenetics and brain function did eventually converge, says Bird. Given the complexity of the brain, it's unlikely to be a simple fix: having too much MeCP2 is as bad as having too little, so getting the balance right is key. But it seems that such conditions might not be as permanent or untreatable as we might think. "It is not impossible that therapeutically one would be able to do something about brain disorders in a way that now seems inconceivable," says Bird.


5. Asaka, Y., Jugloff, D.G., Zhang, L., Eubanks, J.H., and Fitzsimonds, R.M. (2006). Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol. Dis. Jan;21(1):217-27.

6. Guan, J.S., Haggarty, S.J., Giacometti, E., Dannenberg, J.H., Joseph, N., Gao, J., Nieland, T.J., Zhou, Y., Wang, X., Mazitschek, R., et al. (2009). HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. May 7;459(7243):55-60.

7. Peleg, S., Sananbenesi, F., Zovoilis, A., Burkhardt, S., Bahari-Javan, S., Agis-Balboa, R.C., Cota, P., Wittnam, J.L., Gogol-Doering, A., Opitz, L., et al. (2010). Altered histone acetylation is associated with age-dependent memory impairment in mice. Science. May 7;328(5979):753-6.

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EpiGeneSys Final
Meeting in Paris

Thur. 11 February 2016 - Sat. 13 February 2016

More than 280 scientists attended the fifth Annual Meeting of EpiGeneSys. The conference kicked off with a talk by coordinator Geneviève Almouzni, Director of the Research Center at the Institut Curie, highlighting the achievements of the network over more than five years...

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