Research Summary

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.

Bio

Research Associate, Genetics, Case Western Reserve University (1992-1994)
Research Associate, Genetics, Stanford University (1990-1992)
PhD, Medical Genetics, University of Toronto (1983-1990)
BSc, Genetics, University of Guelph (1979-1983)

Awards

Killam Teaching Prize, UBC (2008)
Departmental Teaching Award, Medical Genetics, UBC (1999)
American Scoiety of Human Genetics Predoctoral Basic Science Award (1988)
NSERC Centennial Fellowship (1983)
Scholarship, Medical Research Council of Canada (1983-1988)
College of Biological Science Gold Medal, University of Guelph (1983)

Publications

Comprehensive List
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Selected Publications

  1. Chapman AG, Cotton AM, Kelsey AD, Brown CJ. 2014 Differentially methylated CpG island within human XIST mediates alternative P2 transcription and YY1 binding. BMC Genet. 2014 Sep 9;15(1):89. PMID: 25200388
  2. Cotton AM, Chen CY, Lam LL, Wasserman WW, Kobor MS, Brown CJ. 2014 Spread of X-chromosome inactivation into autosomal sequences: role for DNA elements, chromatin features and chromosomal domains. Hum Mol Genet. 23(5):1211-23. PMID: 24158853
  3. Minks J , Baldry SE , Yang C , Cotton AM , Brown CJ. 2013. XIST-induced silencing of flanking genes is achieved by additive action of repeat a monomers in human somatic cells. Epigenetics & chromatin, 6(1)
 PMID: 23915978
  4. Cotton AM, Ge B, Light N, Adoue V, Pastinen T, Brown CJ. 2013. Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome. Genome Biol. Nov 1;14(11):R122. PMID:24176135 (CIHR MOP-13690 and CIHR MOP-11958).
  5. Yang C, McLeod AJ, Cotton AM, de Leeuw CN, Laprise S, Banks KG, Simpson EM, Brown CJ. 2012 Targeting of Over 1.5 Mb of Human DNA into the Mouse X Chromosome Reveals Presence of cis-acting Regulators of Epigenetic Silencing. Genetics. 192: 12981-1293. PMID: 23023002 (CIHR MOP-13690)
  6. 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

Reviews

  1. Peeters S, Cotton AMC, Brown CJ. 2014. Variable escape from X-chromosome inactivation: Identifying factors that tip the scales towards expression BioEssays. Aug;36(8):746-56. doi: 10.1002/bies.201400032. Epub 2014 Jun 10. PMID: 24913292
  2. Yang C, Chapman AG, Kelsey AD, Minks J, Cotton AM, Brown CJ. 2012. 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
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