CONTROL OF OLIGODENDROCYTE DEVELOPMENT BY OLIG2 AND CHROMATIN REMODELLING COMPLEXES

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Amazingly, the thousands of different cell types that make up our body - blood cells, muscle cells, nerve cells, for example - all develop from the same single cell, the fertilized egg. Hence, all cell types contain the same DNA, yet each contains a set of specialized proteins that are unique to that particular cell type, on top of a core set of "housekeeping" proteins found in all cells. The "cell-type-specific" proteins are what give a cell its particular identity - what defines it as a blood cell or nerve cell, for example. Examples are haemoglobin (present or "expressed" only in red blood cells), keratin (only in skin cells), insulin (only in pancreatic cells) and so on. How are these characteristic proteins expressed in only one or a few cell types despite the fact that all cells contain the same DNA - the same collection of genes? If we could understand the mechanisms that keep some genes shut down and others highly expressed, we might learn how to convert one cell type into another - for example, to cure diseases in which a particular type of cell is damaged or destroyed. Examples of such diseases are type-one diabetes, in which the pancreatic cells that make insulin are destroyed by the immune system, or motor neuron disease, in which spinal neurons that control muscle movement die for unknown reasons. If we could manufacture replacement cells from healthy cells in the body, or in a dish, this could be extremely helpful.There are many proteins in cells whose function is purely to activate or repress other protein-coding genes, by binding specific DNA sequences next to those genes. Such DNA-binding proteins are called "transcription factors" because they control whether a given gene is "transcribed" into the instructions for assembling the corresponding protein. For example, the transcription factor OLIG2 is present uniquely in cells in the central nervous system called "oligodendrocytes". These cells make "myelin", spiral wraps of insulating membrane around "axons", the long thin extensions of nerve cells that carry electrical impulses from one part of the brain to another. This greatly increases the speed at which information travels around the brain. Without myelin, we literally would not be able to think quickly, or at all! Moreover, when myelin is damaged, as it is during the demyelinating disease multiple sclerosis, nervous function can be seriously compromised. We therefore want to understand how OLIG2 can activate myelin-forming genes uniquely in oligodendrocytes.DNA in chromosomes ("chromatin") is normally tightly wound into a form that makes its encoded information inaccessible. Transcription factors like OLIG2 cannot by themselves unravel the DNA - they need to interact with many other proteins to form large "chromatin remodelling complexes" that can together release a gene from its tightly folded, "closed" state. These complexes are of several types (e.g. INO80 and ISWI complexes) whose individual functions are poorly understood. We recently found that OLIG2 is associated tightly with both of these complexes and others, raising the question of why different complexes are needed, and what do they individually do?Our hypothesis is that the different chromatin remodelling complexes come into play at different stages of oligodendrocyte development to activate different sets of genes that allow progression along the path from early embryonic stem cell to fully mature, myelin-forming oligodendrocyte. Our project will test this idea by identifying the genes associated with the INO80 and ISWI complexes, determining whether and how OLIG2 directs the INO80 and ISWI complexes to those genes and whether different sets of genes are engaged as oligodendrocytes develop. Our experiments will help to illuminate general mechanisms of transcriptional regulation, applicable to all cell types, as well as helping us understand the detailed workings of the mammalian brain.