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Brown Lab Research

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. As model systems for the study of human X chromosome inactivation, we utilize somatic cell hybrids that allow us to distinguish features resulting from XIST expression from those due to inactivation.  We have also recently established a model of XIST function using an inducible XIST transgene in somatic cells.  We are using in vitro and in vivo methods to identify proteins that interact with the RNA.

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 are collaborating 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. We are also examining the role of X-linked gene expression in the development of lymphoma in collaboration with Drs. Doug Horsman and Randy Gascoyne at the BC Cancer Agency (BCCA).

Publications

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Molecular Epigenetics
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