Research Summary

In placental mammals, both maternal and paternal genomes are required for normal development. This non-equivalence of the parental genomes is thought to represent the main barrier against parthenogenesis in mammals. This form of asexual reproduction in which only maternal DNA contributes to the offspring is frequently observed in insects and reptiles. In mammals, the parental genomes acquired at fertilization carry different epigenetic marks which are required for normal development. Genomic imprinting refers to this differential epigenetic marking of mammalian chromosomes in the male and female germ lines. One of the consequences of these differences between paternal and maternal homologues is the mono-allelic expression of certain genes according to their parent of origin. Unlike most genes used during development, imprinted genes are therefore only expressed from one allele, the other one being silenced by epigenetic marks such as DNA methylation and histone modifications. Because of imprinting, mutations in imprinted genes can therefore behave as dominant mutations, if inherited from the expressed allele, or as recessive mutations, when present on the silent homologue. A leading evolutionary theory to explain the emergence of imprinting in mammals proposes that imprinted genes regulate the exchange of nutrients between the pregnant female and her offspring during in utero development and the early postnatal period. The finding that imprinting seems to have evolved in lineages which exhibit placentation and that several imprinted genes are implicated in the regulation of embryonic growth and placentation all support this model.

My research program on genomic imprinting using the mouse as a model system is guided by two broad questions: what is the function of imprinting in mammalian biology, and what are the mechanisms underlying the mono-allelic expression of imprinted genes? We use homologous recombination in mouse embryonic stem cells and the site-specific Cre/loxP recombination system to engineer new mutations and chromosomal rearrangements within clusters of imprinted genes in the mouse genome. Using these techniques we have developed a new approach to introduce specific chromosomal truncations in the mouse genome. This allows us to study the phenotypic consequences of deleting large clusters of imprinted genes and has lead to the analysis of novel placental phenotypes associated with abnormal dosage of imprinted genes. We have also developed a new mouse line carrying a green fluorescent protein whose expression is regulated by genomic imprinting. This line is providing a new powerful tool to study the developmental cycle of epigenetic marking at an imprinted locus in vivo, particularly the elusive erasure of imprinting marks known to occur in the developing germline. Other ongoing projects in the laboratory address the role of imprinted genes in placental abnormalities, the characterization of a new maternally expressed placental gene and the analysis of a novel mechanism regulating allelic usage based on alternative polyadenylation at an imprinted gene.

Our work aims at elucidating important properties of the fascinating phenomenon of genomic imprinting, from the molecular basis of the underlying mechanism to the biological consequences of this mode of gene regulation. Our studies provide mouse models for human syndromes associated with imprinted genes and abnormal placentation and are ideal for students looking for a broad training in mouse developmental and molecular epigenetics.

Bio

Associate Professor, Medical Genetics, UBC (2011-present)
Assistant Professor, Medical Genetics, UBC (2003-2011)
Canada Research Chair in Genomic Imprinting (2003-2013)
Research Scholar, Michael Smith Foundation for Health Research (2003-2008)
Postdoctoral Fellow, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto (Dr. Andras Nagy) (1998-2003)
Postdoctoral Fellow, Wellcome/CRC (now Gurdon) Institute, Cambridge, UK (Prof. Azim Surani) (1994-1998)
PhD, Biochemistry & Molecular Biology, University of British Columbia (Prof. Michael Smith) (1987-1994)
BSc, Biochimie, Université Laval, Québec (1984-1987)

Publications

 
Comprehensive List
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Selected Publications

  1. Sheng Liu, Julie Brind’Amour, Mohammad M Karimi, Kenjiro Shirane, Aaron Bogutz, Louis Lefebvre, Hiroyuki Sasaki, Yoichi Shinkai, and Matthew C Lorincz.
    Setdb1 is required for germ line development and silencing of H3K9me3 marked endogenous retroviruses in primordial germ cells.
Genes & Development 28: 2041-2055 (2014).
  2. Jacob, K.J., Robinson W.R., and Lefebvre, L.
Beckwith-Wiedemann and Silver-Russell syndromes: opposite developmental imbalances in imprinted regulators of placental function and embryonic growth.
 Clinical Genetics (2013).
  3. Lefebvre, L. The placental imprintome and imprinted gene function in the trophoblast glycogen cell lineage. Guest Symposium on Trophoblast Development, Reproductive BioMedicine Online 25(1):44-57 (2012).
  4. Lefebvre, L. Engineering of large deletions and duplications in vivo.
    Chapter in Genomic Imprinting: Methods and Protocols, Methods in Molecular Biology, vol. 925, Engel, Nora (Ed.), Humana Press, Springer (2012).
  5. MacIsaac, J.L., Bogutz, A.B., Morrissy, A.S., and Lefebvre, L.
    Tissue-specific alternative polyadenylation at the imprinted gene Mest regulates allelic usage at Copg2. Nuclei Acids Research 40(4):1523-1535 (2012).
  6. Jones, J.M., Bogutz, A.B., and Lefebvre, L.
    An extended domain of Kcnq1ot1 silencing revealed by an imprinted fluorescent reporter.
    Molecular and Cellular Biology 31(14):2827-2837 (2011).
  7. Oh-McGinnis, R., Bogutz, A.B., and Lefebvre, L.
    Partial loss of Ascl2 function affects all three layers of the mature placenta and causes intrauterine growth restriction. Developmental Biology 351(2):277-86 (2011).
  8. John, R. and Lefebvre, L. Developmental regulation of somatic imprints. Differentiation 81:270-280 (2011).
  9. Oh-McGinnis, R., Jones, M.J. and Lefebvre, L. Applications of the site-specific recombinase Cre to the study of genomic imprinting. Briefings in Functional Genomics 9(4):281-293 (2010).
  10. Oh-McGinnis, R., Bogutz, A.B., Lee, Y.L., Higgins, M.J., and Lefebvre, L. Rescue of placental phenotype in a mechanistic model of Beckwith-Wiedemann syndrome. BMC Developmental Biology 10:50 (2010).
  11. Jones, M. and Lefebvre, L. An imprinted GFP insertion reveals long-range epigenetic regulation in embryonic lineages. Developmental Biology 336:42-52 (2009).
  12. Lefebvre, L., Mar, L., Bogutz, A., Oh-McGinnis, R., Mandegar, M.A., Paderova, J., Gertsenstein, M., Squire, J.A., and Nagy, A.The interval between Ins2 and Ascl2 is dispensable for imprinting centre function in the murine Beckwith-Wiedemann region. Human Molecular Genetics 18(22):4255-4267 (2009).
  13. Yuen, R.K.C., Avila, L., Penaherrera, M.S., von Dadelszen, P., Lefebvre, L., Kobor, M.S., and Robinson, W.P. Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes. PLoS ONE 4(10):e7389 (2009).
  14. Oh, R., Ho, R., Mar, L., Gertsenstein, M., Paderova, J., Hsien, J., Squire, J.A., Higgins, M.J., Nagy, A., and Lefebvre, L. Epigenetic and phenotypic consequences of a truncation engineered within the imprinted domain on distal mouse chromosome 7. Molecular and Cellular Biology 28(3):1092-1103 (2008).
  15. Kaiser-Rogers, K.A. , McFadden, D.E., Livasy, C.A., Dansereau, J., Jiang, R., Knops, J.F., Lefebvre, L., Rao, K.W., Robinson, W.P. Androgenetic/biparental mosaicism causes placental mesenchymal dysplasia. J. Med. Genet. 43(2):187-92 (2006).
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