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.