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.

References:

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.
http://www.ncbi.nlm.nih.gov/pubmed/10508514

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