Grant: Project Grant

As all cells contain the same genes, the ability to shut off genes is essential if an organism is to have different cell types. Understanding how genes are shut off is challenging, but silencing of one of the X chromosomes in females is an excellent model with which to study this fundamental process. Males only have one X chromosome (and a sex-determining Y chromosome), while females have two. To avoid a double dose of the almost one thousand genes on the X chromosome, mechanisms have evolved to silence one of the female X chromosomes. The initial silencing event, which occurs very early in development, is random but once an X is silenced, that status is maintained in all progeny cells. Silencing is not always complete, about 20 percent of the genes on the 'silent' X chromosome still show expression - we call them escapees. When an escapee contributes to a medical condition, there can be differences between men and women. Because silencing takes place very early in development, much research is done using mouse embryonic stem cells. Fewer genes are expressed from the silent mouse X chromosome than the silent human X chromosome. Therefore, we examine human escapees that are integrated onto the mouse X chromosome in mouse embryonic stem cells. We have recently shown that 200 kilobase pairs of DNA around a human escapee contains the DNA elements that tell the gene to not be silenced - even on a mouse X chromosome where the equivalent mouse gene is silenced! In the work we propose here we will identify the important factors by reducing the region containing these DNA sequences. We will also examine additional escapees, including ones that differ between individuals. Overall this work will help us understand how genes are silenced, and how the X chromosome contributes to sex differences.