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

表观遗传对多能性的限制确保了胚胎发生期间的发育进程，这一现象首先由康拉德·H·沃丁顿1940年的表观遗传景观模型概括出来。谱系特异性基因表达模式的可遗传组织是由染色质修饰复合体介导的，例如保守的Polycomb基因家族的复合体。它们的活动需要动态调节，以解除细胞重新编程或再生过程中的谱系限制。果蝇系统的强大优势--优越的遗传工具、复杂的细胞分析和高度的实验可操作性--可以应用于表观遗传景观如何动态调节的突出问题。这项研究的最终目的是了解果蝇Polycomb基因家族如何调节表观遗传灵活性，这可能是受损组织愈合和再生过程中细胞行为复杂变化的基础。结合遗传、细胞和分子方法，将检验Polycomb基因功能对细胞应力信号的响应，从而允许再生组织中的细胞命运可塑性的假设，同时还通过一组新的靶基因促进再生生长和动态组织重塑。这项研究将为哺乳动物组织中介导对物理损伤的再生反应的表观遗传灵活性提供新的线索，并将有助于我们理解对细胞应激的代偿反应，例如由慢性炎症或衰老引起的代偿反应。

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.