OCT 11, 2018 1:30 PM PDT

Exploiting Cis-Regulatory Enhancers as Therapeutic Targets in Cancer

Speaker
  • Associate Professor, Associate Director, University of British Columbia
    Biography
      Dr. Hirst is an Associate Professor in the Department of Microbiology and Immunology, Associate Director of the Michael Smith Laboratories at the University of British Columbia (UBC) and Head of Epigenomics at Canada's Michael Smith Genome Sciences Centre. Dr. Hirst was one of the first in the world to successfully complete ChIP-seq, RNA-seq and miRNA-seq experiments on the nascent Solexa 1G platform and for the last 10 years he has led the development of an internationally recognized epigenomic research program at UBC and BC Cancer. As a member of the NIH Human Reference Epigenomic Mapping Consortium, he led the development of epigenomic analysis tools for comprehensive molecular profiling of human tissues and cells. He currently leads the Centre of Epigenomic Mapping Technologies (CEMT) that represents one of two Canadian epigenomic mapping centres funded as part of the CIHR signature initiative; the Canadian Epigenetics, Environment and Health Research Consortium (CEEHRC). Dr. Hirst currently chairs the Scientific Steering Committee of the International Human Epigenome Consortium (IHEC; ihec.org) and leads the Canadian Epigenetics, Environment and Health Research Consortium Network (epigenomes.ca) with a mandate to drive epigenetic research in Canada and internationally.

      Dr. Hirst's research focuses on understanding the role of epigenetic deregulation in cancer. To enable tracking and epigenomic profiling of rare subsets of normal and transformed cell types he recently developed a genomic barcoding strategy, a native ChIP-seq protocol, and a PBAT methodology for profiling DNA methylation genome wide down to a single cell level. He has applied these and other tools to explore the epigenomic states of highly-purified and functionally defined normal and transformed cell types and is currently characterizing vitamin C induced epigenomic reprograming in leukemic models.

    Abstract

    Recent work has identified epigenomic features of distal regulatory elements to be dynamic and defining indicators of cellular specification and transformation. Of particular relevance is our nascent discovery of differentially methylated cytosines in regulatory DNA elements implicated in the control of myeloid differentiation in a murine model of mutant IDH1 leukemia. Strikingly, we have also found that vitamin C, a cofactor for TET, can reverse the methylation gains characteristic of the IDH1-mutant leukemic blasts in this engineered mouse model and initiate their expression of myeloid markers. These data suggest a new/additional role of TET/IDH mutations in driving an epigenetic-mediated silencing of regulatory elements required to activate myeloid differentiation. They also show that this mechanism can be readily reversed by exposing the affected cells to a known, nontoxic molecule (vitamin C). These findings raise the exciting possibility that this type of epigenetic change may constitute a more generalized mechanism contributing to the blocked differentiation phenotype of human AML blasts and one that may be targeted by strategies that have significantly reduced side effects.

    Learning Objectives: 

    1. An introduction to epigenetic dysfunction in cancer.
    2. An understanding of the epigenetic features associated with gain of function IDH mutations in leukemia
    3. An understanding of the role of vitamin C in the maintenance of DNA methylation homeostasis


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