Characterization of factors involved in the X inactivation counting and choice process

My research group studies different aspects of the X-chromosome inactivation process. We have initiated studies aimed to understand the mechanism involved in counting the number of X-chromosomes in a nucleus and the choice which X will be inactivated. Existing models explained X-chromosome inactivation as a mutually exclusive process, in which either one of the two X-chromosomes is inactivated. In contrast, our studies revealed that counting and choice is a stochastic process, in which each X-chromosome has an independent probability to be inactivated. The last few years we have tried to identify factors that count the number of X chromosomes in the nucleus, involved in the initiation of X-chromosome inactivation. Our studies revealed RNF12 to be an XCI-activator; two copies of this X-linked gene are sufficient for the initiation of X inactivation (Cell 2009). This is the first protein shown to be involved in the XCI counting process, and analysis of knockout female ES cell lines indicated the presence of one or more additional activators that cooperate with RNF12 in counting the number of X-chromosomes in the nucleus, and in initiation of X-chromosome inactivation (PLoS Genet.). Future research directions will involve the identification of the targets of E3 ubiquitin ligase RNF12, the role of Rnf12 in X-chromosome inactivation in vivo, and the identification of other XCI-activators.