Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage

描述(由申请人提供)：干细胞自我更新与分化之间的失衡，以及干细胞衍生品的故障是许多人类疾病的常见原因，包括不孕不育和癌症。Polycomb group(PcG)转录抑制蛋白是胚胎干细胞和成体干细胞的关键调节蛋白。严格控制PcG活性对于维持干细胞自我更新/增殖和分化之间的平衡至关重要。PcG的下调是干细胞停止自我更新/增殖并转向分化的先决条件。因此，干细胞/前体细胞中PcG活性增强会导致癌症，如白血病。然而，关于PcG基因的正常表达和活性是如何调控的，以及调控不当是如何导致疾病的，人们知之甚少。我们的长期目标是将我们的研究成果应用于治疗设计，以预防不孕不育、癌症和许多其他人类疾病。果蝇雄性生殖系干细胞(GSC)为研究干细胞的特性和活性提供了一个很好的体内模型系统。利用这一干细胞谱系，我们先前已经证明，PcG蛋白抑制了未分化细胞中末端分化基因的表达。一个精心安排的发育程序逆转了PcG沉默，并启动了分化基因。这项工作揭示了GSC谱系和哺乳动物干细胞谱系之间有趣的相似之处。这项建议的目的是利用这个成熟的干细胞系统来研究PcG活性在生殖细胞分化过程中是如何受到严格控制的，以及PcG蛋白是如何调控GSC的维持、增殖和分化的。我们的研究结果将对生殖生物学、干细胞生物学和再生医学产生广泛的影响。 公共卫生相关性：干细胞或其直接衍生物扩增不足将导致组织营养不良、因损伤或老化而无法组织再生，以及不孕不育。另一方面，以分化为代价的不受控制的扩增将导致癌症。我们建议的研究是以果蝇雄性生殖系干细胞谱系作为模型系统，解决干细胞扩增与分化的中心问题。

DESCRIPTION (provided by applicant): Imbalances between stem cell self-renewal versus differentiation, as well as malfunctioning of stem cell derivatives are common causes of many human diseases, including infertility and cancer. The Polycomb group (PcG) transcription repressive proteins are key regulators of both embryonic stem cells and adult stem cells. Tight control of PcG activity is critical for maintaining the balance between stem cell self-renewal/proliferation and differentiation. Down-regulation of PcG is a prerequisite for stem cells to stop self-renewal/proliferation and switch to differentiation. Consequently, enhanced PcG activities in stem/precursor cells result in cancers, such as leukemia. However, little is known about how normal expression and activity of PcG genes are regulated and how misregulation leads to disease. It is our long-term goal to apply our research results for therapeutic design to prevent infertility, cancer, and many other human diseases. The Drosophila male germline stem cell (GSC) provides an excellent in vivo model system to study stem cell identity and activity. Using this stem cell lineage, we have previously shown that the PcG proteins repress expression of terminal differentiation genes in undifferentiated cells. An orchestrated developmental program reverses the PcG silencing and turns on differentiation genes. This work uncovered an intriguing parallel between the GSC lineage and mammalian stem cell lineages. The goal of this proposal is to use this well-established stem cell system to investigate how PcG activities are tightly controlled during germ cell differentiation and how PcG proteins regulate GSC maintenance, proliferation, and differentiation. Results from our studies will have a broad impact on reproductive biology, stem cell biology, and regenerative medicine. PUBLIC HEALTH RELEVANCE: Insufficient amplification of stem cells or their immediate derivatives will lead to tissue dystrophy, incapability of tissue regeneration in response to injury or aging, as well as infertility. On the other hand, uncontrolled amplification at the expense of differentiation will result in cancers. Our proposed research is addressing the central question of stem cell amplification vs. differentiation using the Drosophila male germline stem cell lineage as a model system.