What makes a neuron a neuron? An epigenetic view

Epigenetics is an emerging field that is proving to be important in an ever-increasing range of biological processes. With the “Breakthroughs in Epigenetics” workshop coming up at IMB on 19-20 March, we asked Angela Garding and Sudhir Thakurela from the Tiwari lab about one of the epigenetic questions that’s interesting them at the moment.

Blue DAPI stain of an embryonic mouse cortex (developmental stage E16.5). Inset: DAPI stain in a non-differentiated embryonic stem cell shows areas where chromatin is more densely packed (darker blue) and genes are less likely to be turned on (red traffic light), compared with lighter areas where chromatin is less densely packed and more likely to be turned on (green traffic light).
Blue DAPI stain of an embryonic mouse cortex (developmental stage E16.5). Inset: DAPI stain in a non-differentiated embryonic stem cell shows areas where chromatin is more densely packed (darker blue) and genes are less likely to be turned on (red traffic light), compared with areas where chromatin is less densely packed and more likely to be turned on (green traffic light).

Neurons play an essential role in the human body, so when they go wrong or become damaged during embryonic development the effects at birth can be severe. Part of the reason such malfunctions are so difficult to treat is that neurons do not repair themselves. If we could understand the features that make a neuron a neuron during embryonic development, and how to influence them, that would help in the development of new therapies for these conditions.

One of the things that defines whether a cell is of a particular type is the combination of genes that are “turned on”, or expressed, at a given time point during the development in that cell. A combination of the cell’s history and influences from its surroundings can affect which genes are turned on and off when, and consequently what sort of cell it will become.

The question is how are genes turned on and off, and how do the particular conditions in which a cell finds itself affect that? It has become clear that epigenetic mechanisms play a key role in this process.

The Tiwari group have seen that the way genes are packaged changes as cells become more committed towards becoming neurons. Precursor cells, which have not yet decided what to become, have a more open chromatin structure, meaning that it is relatively easy for genes to be turned on or off. By contrast, neuronal cells have a more closed chromatin structure. Genes that they will never need to turn on as a neuron tend to be more tightly packaged, leaving genes that the cell might need more accessible.

The group have started to identify specific epigenetic regulators that they think are responsible for such regulation, and are now trying to uncover the details of how they work, using a mixture of computational biology and molecular biology techniques.