Grant: Project Grant

Female cells are generally XX while male cells are XY. The sex chromosomes (X and Y) were once the same size as each other, but now while the Y has critical functions in spermatogenesis, it has lost most of the genes that it once shared with the X chromosome. Therefore, there is a big imbalance in genes on the X between XX females and XY males. The XIST RNA is expressed from one X, which it then coats and recruits proteins in order to silence this chromosome. We want to understand how XIST does this silencing, and what happens in XX cells when XIST is lost. By putting the human X chromosome into mouse cells we have shown that the DNA must match the cell in order for XIST to coat the chromosome. We will look for the essential proteins and DNA allowing this coating. Separately we will take out pieces of the RNA until we have a smaller RNA that can still function. We have observed that some regions of the mouse RNA are smaller than human, so we are combining human and mouse to make a small functional XIST. In our third part of the work, we are using our knowledge to take away important parts of the RNA to see what happens to XX cells without XIST and test if they are more sensitive to drugs or changes that happen in cancer cells. Overall, these experiments will help us understand how female cells manage the different X chromosome content from male cells and how that management can be disrupted in disease.