Re-defining the paradigm of X-chromosome inactivation

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In humans, and most mammals, the sex of an individual is determined by the presence of a pair of sex chromosomes: XX in females, XY in males. The X chromosome carries about 800 genes which contain genetic information that is essential for the body to function. The normal, healthy 'dosage' of genes is delivered through the presence of one chromosome. In males, who carry one X and one Y chromosome (XY), this genetic dosage is naturally delivered. In females, who carry two X chromosomes (XX), the correct genetic dosage is obtained through silencing of one of their X chromosomes, in a process known as 'X-Chromosome Inactivation'. Since this discovery of X chromosome inactivation in 1961, the exact mechanisms underpinning this process have been the focus of extensive study. My group recently made the surprising discovery that males also undergo X-chromosome inactivation in early embryonic development, albeit transiently. This finding has the potential to change the scientific understanding of how X-chromosome inactivation works. In the present study, we propose to use naïve pluripotent stem cells from mice and humans to study X-chromosome inactivation. Naïve pluripotent stem cells are cells that represent the very earliest stage embryonic development, and have the ability to self-replicate exactly or to change into any cell type in the body. Our research will reveal how changes in these naïve cells at key embryonic developmental stages initiates X chromosome inactivation in both males and females. Establishing these processes is central to our understanding of early developmental stem cell biology, and will shift the current accepted paradigm that X chromosome inactivation is a female-only phenomenon. In the medical context, random reactivation of X-linked genes has been reported during ageing and in cancerous cells. Understanding the process of X chromosome inactivation and reactivation in mechanistic detail may uncover pathways and processes that will enhance our understanding of pathological processes associated with ageing and cancer. Naïve pluripotent stem cells are also widely used as a platform for early developmental research, with much investment being focussed on both understanding how cells maintain their naïve state and how they commit to becoming specific cell types. The proposed research will provide insights into how we might be able to stabilise stem cells in this naïve state, providing more stable stem cell platforms for use as a research tool, in drug discovery programmes and in regenerative medicine applications. Our research group has a strong track record in stem cell biology and has the necessary expertise to successfully compete this important project. Further, working within the Cambridge Stem Cell Institute puts us in a strategically strong position, with close collaborators including Professor Austin Smith, who can provide access to new stem cell lines to facilitate pioneering research.