Dynamic modulation of Polycomb-mediated epigenetic states in Drosophila development and regeneration

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Epigenetic restriction of multipotency ensures developmental progression during embryogenesis, a phenomenon first epitomized by Conrad H. Waddington’s 1940 epigenetic landscape model. The heritable organization of lineage-specific gene expression patterns is mediated by chromatin-modifying complexes, such as those of the conserved Polycomb gene family. Their activity needs to be dynamically modulated to relieve lineage restrictions in contexts of cellular reprogramming or regenerative processes. The powerful advantages of the Drosophila system – superior genetic tools, sophisticated cellular analysis and high experimental tractability – can be applied to the outstanding problems of how epigenetic landscapes are dynamically modulated. The ultimate goal of the research proposed here is to understand how the Drosophila Polycomb gene family regulates epigenetic flexibility, which may underlie complex changes in cell behavior during healing and regeneration of damaged tissues. Combined genetic, cellular and molecular approaches will be used to examine the hypothesis that Polycomb gene function is responsive to cellular stress signals and consequently allows for cell fate plasticity in regenerating tissues, while also promoting regenerative growth and dynamic tissue remodeling via a set of novel target genes. This study will shed new light on epigenetic flexibility mediating regenerative responses to physical wounding in mammalian tissues and will contribute to our understanding of compensatory responses to cellular stress, such as those elicited by chronic inflammation or ageing.