PAX6 NETWORK · Characterisation of the Genetic Network Mediated by the Transcription Factor Pax6

Final Activity Report Summary - PAX6 NETWORK (Characterisation of the Genetic Network Mediated by the Transcription Factor Pax6)

All living cells, organs and organisms are under continuous regulation. A great part of the regulatory information is encoded in the DNA molecules that also carry the instructions (genes) for generating many of the biological building blocks, such as proteins (e.g. insulin and PAX6). Some proteins have a direct role in how and when different parts of the DNA information are used: they regulate the production of these building blocks. The initial step in producing proteins from DNA data is called transcription and these proteins are called transcription factors. Changes in the DNA information content (mutations) sometimes lead to the production of molecules that do not function normally, therefore giving rise to a disease condition. Mutations can arise in the protein coding portions of DNA but they may also occur as changes in regulatory DNA elements which disrupts regulation of transcription. Thus characterisation of transcription networks will give us important insight into the causes for many of these diseases. In addition, it is very probable that some of the regulatory elements that we can identify may become targets for novel classes of drug to bind and modulate transcription. This is due to the fact that variation at the control element level is very likely to account for some common disease mechanisms. To better understand how the transcription networks are regulated and function, we have developed a combined procedure that makes use of comparative computational analysis of DNA from multiple vertebrate species, e.g. human and zebrafish. Because functionally important sequences are usually conserved by evolution, the comparisons are used to identify specific transcription factor target sites and the genes they control, for any given that may interact directly with DNA. These target predictions are then validated experimentally using zebrafish, as a vertebrate animal model. We have developed and applied this procedure to PAX6, a transcription factor that plays a key role in the development of organs such as the eyes, brain and pancreas. PAX6 protein coding mutations have been associated with human syndromes that cause visual impairment. The results of our work will allow us to better understand the development of organs such as the eye and the biological changes that occur in patients that have a PAX6 mutation.

Data: CORDIS, © European Union