Research
We aim to understand the molecular mechanism of X chromosome inactivation - X inactivation for short. . . . . . .
X inactivation evolved in mammals to balance the levels of gene output in females, which have two X chromosomes, relative to males which only have one. Early in the development of female embryos each cell inactivates one of the two X chromosomes. The X that becomes inactive is usually chosen at random. Thereafter the inactive state is stably inherited through all subsequent cell divisions. Consequently females are mosaics, being made up of clonal groups of cells that have either inactivated one X chromosome or the other.
A nice illustration of this is seen with tortoiseshell and calico cats which have the ‘orange’ gene, giving rise to orange pigment in the fur, on one of their two X chromosomes.
Calico and tortoishell cats are females. Their coat colour patterns are due to X inactivation acting on the orange gene.
X inactivation provides us with a powerful model to study how genes are regulated through embryonic development from a single cell to a complex multicellular organism.
In studies to date we have learned that X inactivation is regulated by a remarkable and unusual RNA, Xist (X inactive specific transcript), produced by a gene on the X chromosome. The Xist gene is activated on the future inactive X chromosome where the RNA accumulates, eventually covering the entire length of the chromosome.
Xist RNA then recruits protein partners that act by modifying the chromosome to trigger gene silencing. As a result the chromosome switches from an ‘open’ state, allowing gene activity, to a ‘closed’ state, inhibiting gene activity. You can find out more about X inactivation research here.
Image showing a ‘cloud’ of Xist RNA molecules accumulated over the inactive X chromosome in the nucleus of a single female cell. There are around 150 Xist RNA molecules in a cell.
Our current research is focused on two central questions:
What are the molecular mechanisms that control the accumulation of Xist RNA molecules over the territory of a single X chromosome?
How do 150 Xist RNA molecules and their associated protein partners bring about silencing of more than 1000 genes across the entire length of the X chromosome?