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11 December 2014

An unexpected role for Cbx8-Containing Polycomb Complex


In an embryo a small bundle of cells, each carrying the same genetic code eventually give rise to all the different cell types in the body. The resulting nerve cells or skins cells (for example) still carry the same genetic code, but an intricate system of switches has fine-tuned which genes will function to produce proteins in the cell and which are silent. During development of an embryo genes are constantly switched on and off in order to produce different cell types, but also to dictate their arrangement that will form the three-dimensional body of the fully developed animal. The same mechanisms are often hijacked in cancer cells, which start to multiply out of control. How these intricate switches work is a constant source of fascination to scientists and to doctors and patients eager for new forms of therapy.

Chromatin is the combination of the DNA, which carries the genetic code and the proteins around which it is tightly wrapped like wool on bobbins. Changes in these proteins can open the tight bundles allowing genes to start making proteins and functioning or close them again and silence the genes.

Given the fact that there are around 20,000-25,000 genes in the DNA in each of our cells (although the genes make up only about 1.5% of the total DNA) the number of combinations of switch mechanisms is daunting. However, the Chromatin and Cell Fate Group see this as an exciting challenge and they have become experts on some particular switches.

A group of proteins known as Polycomb repressive complexes (PRC) are known to be important players in the control of genes during the differentiation of cells into different types and development of the embryo. On one hand they silence certain genes in embryonic stem cells to maintain them as undifferentiated stem cells that divide rapidly to form new cells but in cells already destined to become one of the three types of tissue in the body they silence genes not required for the particular path that cell is taking.

However the polycomb complex is not a uniform structure, it is made up of many subunits and there are 180 different possible combinations of its parts. One combination substitutes a piece called CBX7 for CBX8 and the IMPPC group have found that this particular form of the polycomb complex activates genes instead of silencing them. This has especially been observed in cells developing into neurons.

This work shows that not all polycombs are the same. In some cases they activate genes instead of silencing them and this seems to have a particular relevance in the development of the nervous system. The same substitution has been seen in adult stem cells in blood, the cells that replenish the blood supply and further studies will be needed to see if this effect plays a part in leukaemia processes or indeed in other diseases.

Basic studies of this type are fundamental to finding out the mechanisms behind normal biological processes and what is going wrong in disease. They also provide clues as to what structures to target with new therapies in order to readdress the system when cell development goes wrong.
 

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