Mcginnis

Wednesday, July 13, 2011, 12:30 pm. Leon’s Lounge, Graduate Student Centre

“Regulation of Genomic Imprinting in the Mouse Placenta”

EXAMINING COMMITTEE

Chair:
   Dr. Rosemary Jeanne Redfield (Zoology)

Supervisory Committee:
   Dr. Louis Lefebvre, Research Supervisor (Medical Genetics)
   Dr. Diana Juriloff (Medical Genetics)

University Examiners:
   Dr. Sylvie Langlois (Medical Genetics)
   Dr. Michael Underhill (Cellular & Physiological Sciences)

External Examiner:
   Dr. S. Lee Adamson
   Samuel Lunenfeld Research Institute of Mt. Sinai Hospital
   Joseph and Wolf Lebovic Health Complex
   Toronto, Ontario
   Canada

SUPERVISORY COMMITTEE:
Dr. Louis Lefebvre, Research Supervisor (Medical Genetics)
Dr. Matthew Lorincz (Medical Genetics)
Dr. Diana Juriloff (Medical Genetics)
Dr. Wendy Robinson (Medical Genetics)

ABSTRACT:
Imprinted genes are expressed either from the maternal or paternal allele during development and tend to be found in clusters throughout the mammalian genome, suggesting they may be regulated by long-range mechanisms. Many of them have important roles in placental development. The Beckwith-Wiedemann Syndrome (BWS) region on human chromosome 11p15.5 contains two imprinted subdomains each regulated by their own differentially methylated regions, known as imprinting centres (IC1 and IC2). These two imprinted subdomains are separated by an evolutionarily conserved region of about 300 kilobases. Distal mouse chromosome 7 (MMU7) shares syntenic homology with the human BWS region. Since the mechanisms by which imprinting occurs are unclear, we sought to characterize this region further using two mouse lines carrying deletions within the BWS imprinted region. The first mouse line, called DelTel7/IC2KO, allows us to dissect out the role of imprinting centre 2 in the silencing of imprinted genes. We demonstrate that all of the distal MMU7 imprinted genes implicated in placental function are silenced by IC2 and the noncoding RNA Kcnq1ot1. The second mouse line, called Del7AI, allows us to determine whether placental imprinting is perturbed when the region between IC1 and IC2 is deleted. We found that maternal inheritance of Del7AI leads to partial loss of the gene Ascl2, and we show that this affects all three layers of the mature mouse placenta. We found that paternal inheritance of Del7AI leads to partial loss of Ascl2 imprinting. Detailed investigation of the underlying mechanisms of imprinting and phenotypes in these mouse lines provides us with new fundamental insights into placental biology and the regulation of gene expression by imprinting centres in the placenta.

SELECTED PUBLICATIONS:
Rosemary Oh-McGinnis, Rita Ho, Andras Nagy and Louis Lefebvre. Partial loss of imprinting of Ascl2 and Tssc4 in paternal Del7AI heterozygotes. Manuscript in preparation.

Rosemary Oh-McGinnis, Aaron Bogutz and Louis Lefebvre. 2011. Partial loss of Ascl2 function affects all three layers of the mature placenta and causes intrauterine growth restriction. Developmental Biology, 351:277-86.

Rosemary Oh-McGinnis, Meaghan J. Jones and Louis Lefebvre. 2010. Applications of the site-specific recombinase Cre to the study of genomic imprinting.    Briefings in Functional Genomics 9:281-293.

Rosemary Oh-McGinnis, Aaron Bogutz, Kang Yun Lee, Michael Higgins and Louis Lefebvre. 2010. Rescue of placental phenotype in a mechanistic model of Beckwith-Wiedemann syndrome. BMC Developmental Biology 10:50.

Louis Lefebvre, Lynn Mar, Aaron Bogutz, Rosemary Oh-McGinnis, Mohammad Mandegar, Jana Paderova, Marina Gertsenstein, Jeremy Squire and Andras    Nagy. 2009. The IC1-IC2 interval is dispensable for imprinting centre function in the murine Beckwith-Wiedemann region. Human Molecular Genetics 18:4255-67.

Rosemary Oh, Rita Ho, Lynn Mar, Marina Gertsenstein, Jana Paderova, John Hsien, Jeremy Squire, Michael Higgins, Andras Nagy and Louis Lefebvre. 2008. Epigenetic and phenotypic consequences of a truncation engineered within the imprinted domain on distal mouse chromosome 7. Molecular and Cellular Biology 28:1092-1103.

SELECTED PRESENTATIONS:
Rosemary Oh, Aaron Bogutz and Louis Lefebvre. Regulation of imprinting and trophoblast-specific expression by the imprint control region KvDMR1 (IC2). Presented by Louis Lefebvre. EMBO World Workshop – Genomic    Imprinting. Singapore. September 2008.

Rosemary Oh, Aaron Bogutz, Michael Higgins and Louis Lefebvre. Imprinting centre 2 dictates patterns of gene expression in the placenta. Epigenetics and Chromatin Dynamics Conference held by the Canadian Society of Biochemistry, Molecular and Cellular Biology. Banff, AB. March 2008.

BIOGRAPHICAL NOTES:
Born:   December 12, 1976, Toronto, Ontario
Academic Studies:   B. Sc. University of British Columbia, 1998

GRADUATE STUDIES:
Field of Study: Epigenetics
Courses:
MEDG 520: Advanced Human Molecular Genetics. Dr. Angie Brooks-Wilson
MEDG 530: Human Genetics. Dr. Lorne Clark
MEDG 505: Genome Analysis. Dr. Steven Jones
MEDG 515: Mammalian Developmental Genetics. Dr. Diana Juriloff
MEDG 545: Current Topics in Medical Genetics. Dr. Carolyn Brown
MEDG 548: Directed Studies. Dr. Louis Lefebvre

AWARDS:
2009-2011: Four Year Doctoral Fellowship
2009: Medical Genetics Research Day Senior Poster Prize
2009: Life Sciences Institute Research Day Senior Poster Prize
2008: Poster Presentation Prize by the Canadian Society of               Biochemistry, Molecular and Cellular Biology
2007-2009: Pacific Century Graduate Scholarship
2007-2009: University Graduate Fellowship
2006: Graduate Entrance Scholarship