Arefeh Rouhi
AREFEH ROUHI- PhD DEFENSE PROGRAMME
BSc (Hon), UBC, 2002
Friday, April 4, 2008, 9:00 am Room 200, Graduate Student
Centre
“A Role for Epigenetic Modifications in the Maintenance of
Mouse Ly49 Receptor Expression”
EXAMINING
COMMITTEE
Chair: Dr.
Michael Whitlock (Zoology)
Supervisory
Committee: Dr. Dixie Mager, Research Supervisor (Medical Genetics), Dr.
Fumio Takei (Pathology and Laboratory Sciences) & Dr. Carolyn Brown
(Medical Genetics)
University
Examiners: Dr. Wendy Robinson (Medical Genetics) Dr. Tom Grigliatti
(Zoology)
External Examiner: Dr. Charles Lutz. Department of Pathology and Laboratory Medicine University of Kentucky Lexington, Kentucky USA
ABSTRACT
Although structurally unrelated, the human killer cell immunoglobulin-like (KIR) and the rodent lectin-like Ly49 receptors serve similar functional roles in natural killer (NK) cells. Moreover, both gene families display variegated and mostly mono- allelic expression patterns established at the transcriptional level. DNA methylation, but not histone modifications, has recently been shown to play an important role in maintenance of the expression patterns of KIR genes but the potential role of DNA methylation in the expression of Ly49 genes was unknown. My thesis focuses on the role of epigenetic modifications, especially DNA methylation, in the maintenance of mouse Ly49 gene expression. I show that hypomethylation of the region encompassing the main promoter of Ly49a and Ly49c in primary C57BL/6 (B6) mouse NK cells correlates with expression of these genes. Using B6 x BALB/c F1 hybrid mice, I demonstrate that the expressed allele of Ly49a is hypomethylated while the non-expressed allele is heavily methylated, indicating a role for epigenetics in maintaining mono-allelic Ly49 gene expression. Furthermore, the Ly49a promoter region is heavily methylated in fetal NK cells but variably methylated in non-lymphoid tissues. In apparent contrast to the KIR genes, I show that histone acetylation state of the promoter region strictly correlate with Ly49A and Ly49G expression status. Also, the instability of Ly49G expression on some lymphoid cell lines is at least in part due to changes in the level of histone acetylation of the promoter region. As for the activating Ly49 receptors, it seems that although DNA methylation levels of the promoter regions do correlate with the state of expression of these receptors, the pattern of DNA methylation is different from that of the inhibitory Ly49a and c genes. In conclusion, my results support a role for epigenetic mechanisms in the maintenance of Ly49 expression. Moreover, these epigenetic mechanisms appear to vary among the Ly49 genes and also differ from those governing KIR expression.
PUBLICATIONS
Rouhi, A., Brooks,
C.G., Takei, F., Mager, D.L. (2007) Plasticity of Ly49g expression
Rogers, S.L., Rouhi,
A., Takei F., Mager, D.L. (2006) A role for DNA hypomethylation and histone
acetylation in maintaining allele-specific expression of mouse NKG2A in
developing and mature NK cells. J. Immunol. 177(1): 414-21. PMID: 16785537
Rouhi, A., Gagnier
L., Takei, F., Mager D.L. (2006) Evidence for epigenetic maintenance of Ly49a
mono-allelic gene expression. J. Immunol. 176(5): 2991-9. PMID: 16493057
Landry, J.R., Rouhi, A., Medstrand, P., Mager, D. L. (2002) The Opitz Syndrome Gene Mid1 is transcribed from a human endogenous retroviral promoter. Mol. Biol. Evol. 19 (11): 1934-42. PMID: 12411602 (BSc work)
SELECTED
PRESENTATIONS
Arefeh
Rouhi, Fumio Takei and Dixie Mager: Prediction of mono- or
bi-allelic expression of Ly49 genes from DNA methylation patterns. 10th Meeting
of the Society for Natural Immunity, Cambridge, UK. April 11-14, 2007. (Poster)
Arefeh
Rouhi, Sally L. Rogers, Fumio Takei and Dixie L. Mager: Role of
epigenetics in regulation of mouse lectin-like NK receptor gene expression.
Canadian Society for Immunology 19th Annual Meeting, Halifax, NS. June 9-12,
2006. (Oral presentation)
Arefeh
Rouhi, Liane Gagnier, Fumio Takei and Dixie L. Mager: DNA
methylation pattern of Ly49a correlates with mono-allelic gene expression. 9th
meeting of the Society for Natural Immunity. Kauai, Hawaii. November 4-8, 2005.
(Oral presentation)
Sally Rogers, Arefeh Rouhi, Fumio Takei and Dixie L. Mager:
A role for epigenetics in mouse NKG2A expression. 9th meeting of the Society
for Natural Immunity. Kauai, Hawaii. November 4-8, 2005. (Poster)
Arefeh
Rouhi and Dixie L Mager: Transcriptional Regulation of Murine
Natural Killer Cell Receptor Genes: Role of DNA Methylation. 12th International
Congress of Immunology and 4th Annual Conference of FOCIS. Montreal, Canada.
July 18-23, 2004. (Poster) Abstract published as supplement in Clinical and
Investigative Medicine, Vol. 27 No. 4, August 2004
Arefeh Rouhi and Dixie L Mager: Role of methylation in the expression of Ly49 NK receptor genes. 8th Annual Meeting of the Society for Natural Immunity and 20th International Natural Killer Cell Workshop. Noordwijkerhout, The Netherlands. April 24-28 2004. (Poster)
GRADUATE STUDIES
Field of Study: Gene regulation
Courses
MEDG419: Human Cytogenetics, Drs. F Dill, C. Brown & W.
Robinson
MEDG520: Adv. Human Molecular Genetics, Dr. E. Simpson
MEDG530: Adv. Human Genetics, Dr. J. Friedman
MEDG540: Medical Genetics Seminar, Drs F. Dill & C. Brown
MEDG 545: Current topics in Medical Genetics, Drs. R. Kay & P.
Hoodless
MEDG548: Directed Studies, Dr. D. Mager
AWARDS
2007 James Miler Memorial Prize
2006-2008 Natural Sciences and Engineering Research Council of
Canada Post-Graduate Scholarship-B
2006-2008 Michael Smith Foundation for Health Research Junior
Trainee Award
2005 9th meeting of the Society for Natural Immunity Travel award
2005-2006 University of British Columbia Graduate Fellowship
2004 Medical Genetics poster award, Department of Medical
Genetics, Faculty of Medicine
2003-2005 Natural Sciences and Engineering Research Council of
Canada Post-Graduate Scholarship-A
2003-2005 Michael Smith Foundation for Health Research Junior
Trainee Award
2002 Graduate Entrance Scholarship
SUPERVISORY
COMMITTEE
Dr. Dixie Mager (Research Supervisor)
Dr. Fumio Takei
Dr. Carolyn Brown
Arefeh Rouhi- PhD Defense Programme (pdf)