The role of nuclear phosphoinositides in epigenetic signalling - N Divecha - BBSRC

If genetics is represented by a book containing the sequence of DNA encoding humans then epigenetics can be considered as the notes written in the margins by a previous reader. They do not alter the code itself but remind and instruct the next reader how they might interpret the written code. Epigenetics provides the means for environmental signals, such as how much food has been eaten or how warm it is, to be written on top of the genetic code to help instruct how cells and organisms might respond. Like the DNA code the notes can also be inherited. In essence epigenetics provides a rational model for the nature versus nurture hypothesis. DNA is complexed with proteins to form a structure called chromatin that enables the large amount of DNA to be packed into the very small volume of the cell. Problematically this packing prevents the DNA from being used easily. The epigenetic notes which are deposited on to the components of chromatin help to pack and un-pack the chromatin. The notes are deposited, removed and interpreted by a series of enzyme complexes. Exactly how these complexes are regulated in response to environmental signals is not very well understood. We have found that one of these enzyme complexes is regulated by an enzyme called PIP5K1A. In response to environmental signals PIP5K1A produces a small molecule called PIP2. Our studies suggest that PIP2 sticks to the enzyme complex and controls how well it works. This leads to changes in the epigenetic notes that are deposited and eventually to how the cell behaves. In this way we think that PIP2 acts a messenger informing and controlling the enzyme complex in response to changes in the environment. In this proposal we intend to understand how PIP2 sticks to and changes how well the enzyme complex works. The enzyme complex is made up of many different protein components and we have found that one of these proteins can stick to PIP2. By using different molecular technologies we want to find out exactly how PIP2 sticks to this protein and if this alters how well the enzyme complex deposits the epigenetic notes. Understanding the molecular details of this process is important as it increases our basic understanding of how cells respond to their environment. Furthermore the enzyme complexes that deposit epigenetic notes often do not work properly which can change how organisms age. It can also lead to the development of different human diseases such as cancer and diabetes. Understanding how the enzyme complexes are controlled will help us to design medicines that alter how well these complexes work which could be useful in modulating how well we age and how we combat diseases.