Genomic plasticity and DNA transposases in childhood tumors
Half of the human genome originates from mobile DNA elements, or transposons, but their contributions to human disease and physiology remain largely unexplored.
Our studies are focused on evolutionarily conserved and developmentally regulated human DNA transposases, including their molecular biology, normal physiologic functions, and aberrant activities in human cancer. This work is predicated on the hypothesis that specific human cancers originate from the aberrant activities of endogenous DNA transposases and nucleases. We aim to define the spectrum of their enzymatic activities, cellular targeting factors, regulatory functions, and genomic targets that include essential tumor suppressor and oncogenes. In particular, we recently discovered that PGBD5 is a domesticated DNA transposase that functions as an oncogenic mutator to promote site-specific genome rearrangements in human solid tumors. This has led to a new hypothesis in which defects in developmental somatic genome remodeling cause mutations that explain many early onset cancers in children and adults.
Current projects leverage functional genomic tools for the investigation of DNA transposition and genomic plasticity, providing functional insights into the natural history of tumor origins, evolution, and therapy response. Using single-molecule real-time and single cell whole-genome sequencing, we are charting somatic genome structural variation in normal and cancer cells. Using chemical proteomics, we are defining cellular transposase complexes and their regulatory factors, with an emphasis on translating these findings into rational targeted therapies for patients.
In concert, we are investigating the mechanisms of transposase-induced tumorigenesis in vivo using inducible and conditional transgenic mouse models, with a focus on the relationship between aberrant regulation of chromatin structure and developmentally controlled somatic genomic rearrangements in human cancers and childhood tumors in particular.