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Graduate Student Seminar Series – Richard Saint-Laurent
March 3 @ 5:55 pm - 6:10 pm EST
Graduate Student Seminar Series
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Location: HS610 – 155 College St, Room 610
Presentation Title: Designing silencing-resistant promoters for hiPSC development
Abstract: Synthetic cell & gene therapies are designed to drive therapeutic gene expression and can enhance the current field of living therapies by augmenting cell function to overcome roadblocks like poor cell engraftment and mediocre efficacy. Synthetic therapies drive the expression of genes using promoter DNA sequences which recruit and position RNA polymerase upstream of the gene of interest. In human induced pluripotent stem cells (hiPSCs), many of the available promoter sequences undergo a phenomenon known as transgene silencing, where the promoters are functionally active after transgene delivery but are epigenetically turned off, or “silenced”, by the host cell over days to weeks. Transgene silencing in hiPSCs severely limits the lifespan and potency of engineered cell & gene therapies. The current repertoire of mammalian promoters available are not immune to transgene silencing and are often large (>1 kb) and difficult to clone due to high GC% and repetitive DNA regions. Therefore, this project aims to design a library of short, silencing-resistant promoters that can be used to engineer robust hiPSCs. An assay capable of screening the silencing tendency of integrated promoters in a high-throughput manner will be developed using massively parallel reporter assays (MPRA) and iPSC landing pad cells. Using this assay, thousands of candidate promoter sequences will be assessed and scored on strength and silencing. These data will be analyzed to determine what in the DNA sequence contributes to silencing, allowing biomedical engineers to use, predict, and design a repertoire of synthetic promoters that are robust, long-lasting, and fine-tuned for the treatment of debilitating disease.
Supervisor Name: Michael Garton
Year of Study: 2
Program of Study: MASc
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