Grant: Project Grant

Most females have two X chromosomes while males generally have one and the sex-determining Y chromosome. To minimize the impact of having double dose of the almost 1000 genes on the X chromosome, there is a process called X-chromosome inactivation (XCI) that silences most of the X chromosome. Once this silencing occurs it is maintained through cell division, so we call it 'epigenetic' - control above the genetic instructions. For 75% of the genes on the X chromosome this silencing is complete, but we seek to understand how the other 25% are skipped by this chromosome-wide silencing. From our previous grant we have found important differences in how these 'escape' genes are controlled. We can put a human transgene into the future inactive X chromosome of a mouse, or a mouse embryonic stem cell, and when the X inactivates we have defined a critical 6 kilobases of DNA sequence that keeps the gene expressed. We will now refine those elements both by manipulation of the DNA in the transgene and also by computational analysis of the regulatory elements. Overall, understanding how genes escape from XCI lets us understand the epigenetic rules and also will provide tools to keep genes active if they are put into cells as a therapy or for research.