Dissecting epigenetic signatures and cellular plasticity of Drosophila blood cells

生理和病理刺激可诱导细胞改变其身份，这一过程称为转分化。我们将使用果蝇血细胞作为模型来剖析转分化的分子机制。幼虫对诸如黄蜂感染之类的伤害的反应是将浆细胞转变为层状细胞。值得注意的是，薄片细胞仅在8小时后出现。这种快速的转分化涉及细胞形态和功能的巨大变化：浆细胞是小的、多用途的巨噬细胞样细胞，而层状细胞是高度特化的巨细胞，它们寻找黄蜂卵并有助于破坏它们。我们的初步结果表明，在板层细胞形成的调控中有三个新的参与者：转录调节因子u形（Ush）、核小体重塑和去乙酰化（NuRD）复合物和酪蛋白激酶2 （CK2）。在这个项目中，我们将验证ck2介导的NuRD磷酸化促进表观基因组和转录组的快速改变的假设，从而允许蛋白质的快速表达，从而驱动细胞形态、运动和吞噬活性的急剧变化。为此，我们将结合我们在全基因组研究、蛋白质组学方法、遗传学和高分辨率显微镜方面的互补专业知识。果蝇和人类之间形成先天细胞免疫系统的因素和机制的强大进化守恒使我们的研究具有广泛的生物医学意义。

Physiological and pathological stimuli can induce cells to change their identity, a process referred to as transdifferentiation. We will use Drosophila blood cells as a model to dissect the molecular mechanisms underlying transdifferentiation. Larvae respond to insults such as wasp infection by a change of plasmatocyte into lamellocyte identity. Remarkably, lamellocytes appear after only eight hours. This rapid transdifferentiation involves dramatic changes to cell morphology and function: whereas plasmatocytes are small, multi-purpose macrophage-like cells, lamellocytes are highly specialized, giant cells that seek out wasp eggs and contribute to their destruction. Our preliminary results implicate three novel players in the regulation of lamellocyte formation: the transcriptional regulator U-shaped (Ush), the Nucleosome Remodeling and Deacetylation (NuRD) complex and Casein Kinase 2 (CK2). In this project we will test the hypothesis that CK2-mediated phosphorylation of NuRD facilitates swift alterations of the epigenome and transcriptome allowing the rapid expression of proteins that drive dramatic changes of cell morphology, motility and phagocytotic activity. Towards this end, we will combine our complementary expertise in genome-wide studies, proteomic approaches, genetics and high-resolution microscopy. The strong evolutionary conservation of factors and mechanisms between Drosophila and man shaping the innate cellular immune system gives our study a broad biomedical relevance.