Carolyn J. Brown, PhD
 |
Professor & Department Head Academic Office: |
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. 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 human 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 Randy Gascoyne and the Centre for Lymphoid Cancer at the
BC Cancer Agency (BCCA).
Selected Publications:
Cotton AM., Lam L., Affleck JJ, Wilson IM, Penaherrera MS, McFadden D, Kobor M, Lam WL, Robinson WP, Brown CJ. 2011. Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum Genet. 130(2):187-201. PMID: 21597963
Yang C, Chapman AG, Kelsey AD, Minks J, Cotton AM, Brown CJ. 2011. X-chromosome inactivation: molecular mechanisms from the human perspective (review for Human Genetics 50th anniversary of Lyon Hypothesis edition) Hum Genet. 130(2):175-85. PMID: 21553122
Chang SC, Brown CJ. 2010. Identification of regulatory elements flanking human XIST reveals species differences. BMC Molecular Biology. Mar 8; 11:20.
Thorogood
N, Brown CJ. 2010. Active chromatin marks are retained on X chromosomes
lacking gene or repeat silencing despite XIST/Xist expression in
somatic cell hybrids. PLoS One. 24; 5(5):e10787.
Cotton AM, Avila L, Penaherrera MS, Affleck JG, Robinson WP, Brown
CJ. 2009. Inactive X chromosome – specific
reduction in placental DNA methylation.
Hum Mol Genet. 18 (19); 3544-52. PMID: 19586922
Minks J, Robinson WP, Brown CJ.
2008. A skewed view of X chromosome inactivation. J Clin Invest. Jan;118(1):20-3. PMID: 18097476
Yen ZC, Meyer IM, Karalic S, Brown CJ. 2007. A cross-species comparison of X-chromosome inactivation in Eutheria. Genomics 90(4):453-63. PMID: 17728098
Chow JC,
Hall LL, Baldry SE, Thorogood NP, Lawrence JB, Brown CJ. 2007. Inducible XIST-dependent X-chromosome inactivation in human
somatic cells is reversible. Proc
Natl Acad Sci USA. 104(24):10104-9. PMID: 17537922