Research Interests: Human X Chromosome Inactivation

X chromosome inactivation occurs early during mammalian development to transcriptionally silence one of the pair of X chromosomes in females, thereby achieving dosage equivalence with males who have a single X chromosome and the sex-determining Y chromosome. Research in the lab is directed towards understanding both the mechanisms involved in the inactivation process and the clinical implications of X chromosome inactivation in females.

X chromosome inactivation is a truly remarkable example of both epigenetic determination (one of a pair of essentially identical chromosomes is chosen to be silenced) and of cell memory (the choice of chromosome inactivated is stably inherited throughout subsequent somatic divisions). Our research explores both the establishment and maintenance of inactivation through analysing gene expression from the active and inactive X chromosomes. The XIST gene is the only gene that is expressed from the inactive but not from the active X chromosome. This unique gene encodes a 17 kb alternatively spliced, processed transcript which is not translated into a protein but which remains in the nucleus where it associates with the inactive X chromosome. Lab research projects are directed to understanding all stages of the inactivation process. In addition to comparison of male and female cells, we utilize somatic cell hybrids that allow us to distinguish the active and inactive X chromosome, and have also established a model of XIST function using an inducible XIST transgene in human somatic cells.

Mutations affecting X-linked genes cause relatively common and often serious medical disorders. Insights into the underlying mechanisms of regulation unique to this chromosome is therefore of clinical interest. We have collaborated with Dr. Wendy Robinson’s research group at the B.C. Children’s Hospital to examine the sources of skewed inactivation in female embryonic and extra-embryonic tissues. Complex diseases often show different risk or outcome in males and females, and the different dosage of the X chromosome may contribute to these differences. We are exploring the nature of genes that show ongoing expression from the otherwise inactive X, and in collaboration with the Simpson and Wasserman groups at the Centre for Molecular Medicine and Therapeutics to identify the DNA elements involved in spreading (or blocking) silencing along the chromosome.