A focus of the lab has always been on method development. Using antibodies and techniques developed in my lab we found that the self-renewal properties of human and murine blood forming stem cells are developmentally controlled (1). We subsequently described that human blood forming stem cell loose telomeric repeats with each division in vitro and in vivo (2) and we helped establish a critical, clinically relevant role of telomerase levels in their function (3). To study genes that regulate telomere length we collaborated with Ann Rose at UBC using C.elegans as a model. We discovered a helicase gene, that we dubbed dog-1, for deletion of G-rich DNA (4). Worms lacking dog-1, better known by the less informative human name FANCJ, show deletions throughout their genome that invariably start at the 3’ end of long G-tracts. Such G-tracts are much more abundant in the C.elegans genome than predicted by chance. Encouraged by these findings we collaborated with Hao Ding and Andras Nagy in Toronto and knocked out a similar gene in murine embryonic stem cells (5). We reported that this gene is a major regulator of telomere length and named the gene Rtel (for Regulator of Telomere Length). We postulated that epigenetic differences between sister chromatids could help establish differences in daughter cell fate before cells divide (the “silent sister” hypothesis, (6). Current studies focus on understanding the role of helicase proteins DOG-1 and RTEL-1 and their in vivo substrates, guanine quadruplex (G4) DNA structures, in normal and malignant cells. An important novel tool in these studies is Strand-seq, the single cell DNA template strand sequencing method developed in our laboratory (7,8).
Examples of our work in the Lansdorp lab:
Figure: metaphase chromosomes in a human fibroblast after fluorescence in situ hybridization (FISH) with FITC labeled PNA probes specific for telomere repeats. Telomeres are shown in yellow and DNA is counterstained with DAPI in blue.
Movie below is the live cell imaging of murine embryonic stem cells co-expressing Telomere Repeat Factor 1 fused to green fluorescent protein (TRF1-GFP) and Histone 2B fused to red fluorescent protein (H2B-RFP). Dual color images were captured at a single plane using a high resolution objective (63x, oil) over a 10 minute period. Note the anaphase bridge covered by increasingly dispersed TRF1 protein. Courtesy of Kathleen Lisaingo, Mike Schertzer and Peter Lansdorp, Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, Canada.
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