| Project Detail |
This proposal aims to decipher the dynamic regulatory landscapes of chromatin modifiers during embryogenesis. In particular, I envision to unravel their mechanism of action at unprecedented resolution using single-cell based techniques, and provide novel insights on the molecular deregulation that leads to diseases such as cancer. The originality of this approach is to simultaneously address the function of hundreds of chromatin modifiers in early development by using a higher throughput, stem cells-based in vitro screen. In order to achieve this, we will take advantage of a recently established culture system that faithfully recapitulates embryonic development up to somitogenesis in the dish. The combination of various cutting-edge techniques with this model (Cas9-based screening, targeted protein degradation, low input CUT&RUN and single cell RNA-seq) and our sophisticated computational strategies will allow a precise understanding of how various chromatin regulators act on specific targets in individual cell. In particular, we will resolve gaps of how two essential, global modifiers, Polycomb repressive complex 1 and 2, cooperate to regulate distinct cell identity decisions. Ultimately, we will hope to reconstruct the hierarchal dynamics of chromatin regulators at a temporal and spatial resolution of single cells through embryogenesis. The result of this action will be shared with scientific community by open-access peer-reviewed journals, conferences, analytic codes and sequencing data; and with general public through Open Science Days. The Meissner laboratory will provide the ideal environment not only to carry out this project, but also expand my scientific expertise and train my skills to better prepare me to become an independent group leader in the future. |
