Transcriptional control of cell fate decisions by chromatin remodelling proteins

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A cell's identity is defined by its genes. A cell located in the heart, for example, will express heart genes, but not genes important for liver or brain function. Conversely, liver cells express liver genes but not heart or lung genes. During embryonic development animals are formed by different groups of stem cells, which are able to give rise to the myriad of different cell types found in an adult organism. When stem cells undergo the process of differentiating into a new cell type, it is critically important that they turn on genes appropriate for the new cell type, but also turn off the genes that define a 'stem cell' identity and also keep off any genes associated with other cell types. Failure to properly regulate expression of all these different kinds of genes can result in the wrong decisions being made, or the inability to make any decision when required. The consequences of such failure can be developmental abnormalities or cancer. Unsurprisingly, then, our cells contain many proteins whose jobs are to ensure the proper control of gene expression. This proposal focusses on two such proteins, called Chd4 and Brg1. These proteins control the way genes get packaged within the cell. Though at a mechanistic level these two proteins appear to have similar activities, a number of studies have found that they actually tend to work in opposition. We know that loss of either protein results in failed development from very early stages, and both proteins are often found to be deleted or mutated in cancer. We propose that it is precisely this balance of opposing activities between Chd4 and Brg1 that fine tunes gene expression patterns, and that this balance is crucial for cells to successfully make developmental decisions. Yet exactly how the biochemical activities of these proteins controls gene expression, and whether the two really directly control the expression of the same genes during development is not well understood. In the work proposed herein we will use cutting edge technologies to very accurately define the function of these proteins in stem cells and in early embryonic cells as they make their very first decisions. We will show how loss of one either protein impacts the function of other key regulatory proteins, and how this leads to developmental failure. We will then examine how these proteins function during the very first cell fate decision in mammalian embryogenesis. Together this project will reveal how gene expression is controlled as cells make decisions, and how the cells use these proteins to precisely control cell fate choices during normal development. This will inform the creation of new methods for controlling gene expression in mammalian cells. Such methods could be of considerable benefit in efforts to prevent the progression of cancer, and to enable more efficient and effective protocols to use stem cells in regenerative medicine.