24 September 2010

Stress-factors can control our genes

Cell biology

Researchers from University of Copenhagen document that external stress-factors can control our genes. The results have just been published in the renowned international journal Molecular Cell.

Stress has become one of the major disease states in the developed world. But what is stress? The causes can be plentiful and you may experience stress as something that affects your entire body and mind. But if we zoom in on the building bricks of the body, our cells, stress and its causes are defined somewhat differently. Stress can arise at the cellular level after exposure to pollution, tobacco smoke, bacterial toxins etc, where stressed cells have to react to survive and maintain their normal function. In worst case scenario, cellular stress can lead to development of disease.

Researchers from Dr. Klaus Hansen's group at BRIC, University of Copenhagen, have just shown that external factors can stress our cells through the control of our genes:

- We found that stress-activating factors can control our genes by turning on certain genes that were supposed to be silenced. It is very important that some genes are on and others are off in order to ensure normal foetal development and correct function of our cells later in life, says Dr. Klaus Hansen.

Effect during foetal development
Simmi Gehani, PhD-student in the Hansen group, found that exposing human cells to a stress-activating compound turned on silenced genes. Even brief changes in gene activation can be disastrous during foetal development as establishment of correct cellular identity can be disturbed in our cells. But altered gene activity can also have consequences in the adult body.

-For example, one could imagine that prolonged stress causes nerve cells in the brain to produce hormones and other signalling molecules they do not normally produce and this can disturb normal brain function, says Simmi Gehani.

Figure: Stress-factors signal to the enzyme MSK that attach a phosphate group to the histones. Followingly, the protective complex PRC2 falls off and the gene is turned on.
Illustration: Lise Rudkjær/Katrine Sonne-Hansen 

Gene activity can disturb normal cell development
The Hansen research group is very interested in understanding how our genes are turned on and off:

- We know that different protein complexes can associate with specific proteins (histones) to which DNA is wound around and thereby determine whether the genes are active or inactive. Small chemical groups can cause protein complexes to bind to histones and these can control gene activity, says Dr. Klaus Hansen.

The researchers have studied in detail a complex called PRC2. PRC2 can attach small chemical groups - methyl groups - to the histones. Protective complexes can bind to the histones when this marker is present and the genes are turned off. Their new results show that the protective complexes are lost and selected genes turned on when cells are exposed to external stress factors.

- The reason why the complexes are lost is that the stress factors instruct an enzyme named MSK to attach another chemical group - a phosphate group - to the histones neighbouring the methyl group. The phosphate group neutralises the effect of the methyl group and turns specific genes on. The consequence is that genes that should be turned off are now active and this may disturb cellular development, identity and growth, says Simmi Gehani.

This means that without damaging our genetic code external stress factors can control the activity of our genes. The results are published September 24th 2010 in Molecular Cell:  Gehani et al., Molecular Cell, Volume 39, Issue 6, 886-900, 24 September 2010 

How are our genes controlled?
Knowledge of how our genes are regulated is important in order to understand how stress can lead to development of disease. Our genetic code contained in the DNA is the same in all 200 cell types found in our body. Yet, the cells can develop differently and specialise. This is possible as many genes are only active in selected periods during foetal development or in selected cell types in the adult body. Thus, turning off selected genes at defined time points is important to ensure normal development and to maintain cellular identity and function. The activity of our genes is determined by the architecture of our DNA. The DNA consists of 2 meter long double strings, curled around special proteins called histones. The machinery "reading" our genes cannot work if the DNA is tightly curled around the histones and the genes are turned off. But the genes can be turned on if the DNA structure loosens and this will eventually lead to formation of protein.