Advancing Epigenetics Towards Systems Biology

Striking a balance in the brain

epigenetics ainsworth 1

Photo: balance scale / winnifredxoxo
on FlickrCC License by

4 April, 2013

By Claire Ainsworth

Photo introduction: adapted from Neuron Connection
Patrick Hoesly on FlickrCC licenced by, and Biological neuron schema on wikimedia common licenced by

As recoveries go, it was simply astonishing. A month previously, biochemist Adrian Bird and his colleague Jacky Guy had been studying mice that were suffering from a raft of severe neurological problems. Many of the animals were at death's door. But then Bird, Guy and their colleagues had restored the function of the faulty gene behind the condition, hoping that it would make the mice live slightly longer or show a slight improvement in symptoms. To their surprise and delight, the results were spectacular. Instead of lying trembling in their cages, feet splayed, many of the mice improved so much that they appeared to be almost normal.

The result is all the more surprising when you consider that the gene involved, called MeCP2, is also involved in an inherited autism condition called Rett Syndrome, which affects up to 1 in 10000 girls. Babies born with the condition develop a number of neurological and intellectual problems, including severe difficulties with cognition and speech. In healthy brains, MeCP2 sticks to a particular kind of chemical mark on DNA that is known to help control the activity of genes. In children with Rett Syndrome, and in mice genetically engineered to develop an equivalent condition, the brain lacks sufficient MeCP2. As a result, its cells can't read the chemical marks properly and so cannot effectively deploy the genes needed for functions such as learning and memory.

Research into MeCP2, from Bird's lab at the Wellcome Trust Centre for Cell Biology in Edinburgh and from other labs around the world, forms part of a growing body of evidence suggesting that chemical marks on or around DNA play an important role in the normal functions of the brain, such as cognition, memory and ultimately, behaviour. These marks don't alter the genetic information spelled out in the sequence of chemical letters that make up the DNA of genes. Instead, they affect how and when the information is used in a cell, and are known as "epigenetic" marks. As well as highlighting the importance of epigenetics in brain function, Bird and Guy's discovery raises the possibility that Rett Syndrome and other inherited disorders that cause intellectual disability might not be permanent, untreatable conditions as once thought. "I think partly because of our work, but also because of other work, people are seriously entertaining the possibility that these are reversible," says Bird.

The discovery in 1999 (1) that MeCP2 was faulty in at least 95% of girls with Rett syndrome was the first link between intellectual disability and a particular kind of epigenetic mark called DNA methylation. These marks are added at certain points on the DNA itself, and usually reduce the activity of the gene concerned. The cell can add or remove DNA methylation marks, allowing it to fine-tune the activity of its genes.

Bird and his colleagues were among the first researchers to identify these marks in the human genome in the mid-1980s. The MeCP2 protein, which Bird also discovered, doesn't add or remove methylation marks to DNA, but instead sticks to them. Given that methylated DNA is found throughout the genome, "that means that every part of the genome is potentially subject to its effects," says Bird. Exactly what those effects are, however, remains something of a mystery. But it does seem as though MeCP2 somehow helps neurons with the herculean task of keeping the activity of their genes finely balanced.


1. Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., and Zoghbi, H.Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188.

epigenetics ainsworth 2

Photo: Music I was transposing / S. Parker on FlickrCC licenced by

Researchers once thought the proteins that stick to epigenetic marks fell into two camps: "repressors", which turn gene activity off, and "activators", which turn gene activity on. But a flurry of findings over the past 5 years has pointed to a far more complex picture. Rather than being simple "on" or "off" switches, epigenetic marks are more like the dynamic notations, such as piano (quiet) or fortissimo (very loud), written on a musical score to indicate how the music should be played.

If the genome is a musical score, then proteins like MeCP2 are orchestral conductors, reading the dynamics and coordinating the behaviour of the players involved in gene activity, making sure the total output is in tune, well-balanced and appropriate for the occasion. DNA methylation tends to behave most often like a piano notation, keeping the volume of gene activity dampened down. Given that MeCP2 is spread all over the genome in neurons, this suggests that turning down gene activity is important in the brain. At the moment, says Bird, no one really understands why. "That's where there's a gap."

New advances in molecular biology are allowing scientists to paint a much more detailed picture of the epigenetic changes that happen over time in the brain. For many years, scientists thought that DNA methylation was a very stable epigenetic change. But recent work has called this in to question, suggesting instead that DNA methylation in the brain is highly dynamic. In 2011, a team led by Peng Jin at Emory University in Atlanta in the US, for example, announced results (2) from a new method that allows them to track methylation marks that are in the process of being removed from DNA. By tracking these marks in the brains of mice of varying ages, they found marked shifts in the DNA methylation of different kinds of genes. In newborn mice, for example, many of these genes were involved in neuron development, while in adult mice, the genes were associated with the function of neurons and the cells that support them.

But why is DNA methylation so extensive and dynamic in the brain? One important clue comes from Bird and Guy's observation that restoring MeCP2 activity in the brains of mice lacking the protein could almost completely reverse the physical and cognitive problems those mice experienced. Until the researchers reported their finding in 2007 (3), scientists had assumed that genetic conditions that result in intellectual disabilities or problems with social interactions, such as Rett Syndrome, permanently damaged the development of the brain.

If this were true, then simply adding MeCP2 back in adult mice engineered to lack MeCP2 in their brains should have had little effect. The fact that so many of the mice had their symptoms reversed suggests that the underlying brain development was intact, but that the problem lay with the day-to-day maintenance of the neurons. "You can grow up without MeCP2 and absolutely nothing is wrong provided you put it back," says Bird. "So whatever it does is an ongoing housekeeping function." The reverse is also true: adding too much MeCP2 to the brains of mice also results in cognitive and neurological problems (4). So it seems that getting the balance just right is key.


2. Szulwach. K.E. et al. (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci Oct 30;14(12):1607-1616.

3. Guy, J.G, et al. (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science. Feb 23;315(5815):1143-7

4. Collins, A.L., Levenson, J.M., Vilaythong, A.P., Richman, R., Armstrong, D.L., Noebels, J.L., David Sweatt, J., and Zoghbi, H.Y. (2004). Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet. 2004 Nov 1;13(21):2679-89.

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.

Mon, May 29th 2017- Wed, May 31st 2017

After last year's successful kick-off meeting, the EpiGeneSwiss meeting will take place again in Weggis, Switzerland. This year we have added one day in addition to accommodate more topics and more t...

Mon, Jun 19th 2017- Wed, Jun 21st 2017

The focus of the 2017 IMB Conference is on “Gene Regulation by the Numbers: Quantitative Approaches to Study Transcription”. The conference will explore the latest findings and technological developme...

Tue, Jul 11th 2017- Thu, Jul 13th 2017

The MRC Integrative Epidemiology Unit at the University of Bristol invites all professionals interested in aetiological epidemiology and Mendelian randomization to attend our conference on the subject...

Wed, Aug 30th 2017- Fri, Sep 1st 2017

The nucleosome is the fundamental building block of chromatin organisation and genome function. The 20th anniversary of the high resolution nucleosome structure marks a milestone for bringing together...


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...

Maison des océans - Paris Read more


The Non-Coding Genome ...

December 3-4 th, 2015

The last training workshop of the EpiGeneSys network

Hotel Mediterraneo - Rome, Italy Read more

Paris / TriRhena Chromatin Club

July 9th, 2015

...exciting talks and network with members of the Chromatin community!

... An EpiGeneSys TAB workshop

June 11st-12nd , 2015

... learn about current approaches to single cell epigenetics and to meet up and network with...

Montpellier, FranceRead more

Latest publications


The impact of rare and low-frequency genetic variants in common disease.

Read more

Stable Polycomb-dependent transgenerational inheritance of chromatin states in Drosophila.

Read more

Stable Polycomb-dependent transgenerational inheritance of chromatin states in Drosophila.

Read more