Epigenetic inheritance in germline stem cell lineage

描述（由申请人提供）：生殖系干细胞谱系中的表观遗传摘要：干细胞在自我更新和产生各种分化细胞的能力方面是独特的。许多类型的干细胞经历不对称细胞分裂以产生自我更新的干细胞和致力于分化的子细胞。干细胞不对称分裂的错误调节可能导致肿瘤发生或组织营养不良。在所有已知类型的成体干细胞中，生殖细胞是最不朽的，因为它们能够在受精后产生下一代整个生物体。果蝇雄性生殖系干细胞（GSC）是最具代表性的干细胞系统之一。雄性GSC可以通过其在果蝇睾丸中独特的解剖位置和形态特征来识别。这使得在单细胞分辨率下研究这些干细胞变得可行，这允许直接比较GSC和它们的子细胞（成角细胞）。了解GSC不对称细胞分裂的分子机制对癌症生物学、生殖生物学以及再生医学具有广泛的意义。 我假设姐妹染色单体之间的表观遗传差异有助于干细胞不对称分裂。表观遗传改变是可遗传的，这一点早已为人们所知。然而，除了DNA甲基化之外，对表观遗传的分子机制知之甚少。我建议使用分子，遗传和细胞生物学工具，在真实的时间调查是否果蝇雄性GSC保留一个特定的染色质结构，通过继承一套独特的“表观遗传密码”;的监管途径，导致这样的遗传;和潜在的异常，从表观遗传的误调节所产生的。 公共卫生相关性：干细胞对生物医学研究和再生医学都具有重要价值。为了有效地利用干细胞在治疗应用中治愈许多人类疾病，我们必须彻底了解干细胞自我更新能力的分子机制。这项拟议中的工作将探索干细胞是否通过遗传一组特定的蛋白质来维持自身;以及干细胞是否通过这样做来保持一组特定的基因活跃，而其余的基因则保持沉默。我们建议使用最先进的细胞生物学工具来可视化这种过程在真实的时间和分子遗传学策略，以探索如何错误调节它可能导致疾病。

DESCRIPTION (provided by applicant): Epigenetic inheritance in germline stem cell lineage Abstract: Stem cells are unique in their abilities to self-renew and give rise to various differentiated cells. Many types of stem cells undergo asymmetric cell division to generate a self-renewed stem cell and a daughter cell committing for differentiation. Mis-regulation of stem cell asymmetric division may lead to tumorigenesis or tissue dystrophy. Of all known types of adult stem cells, germ cells are the most immortal, due to their abilities to produce the next generation of an entire organism upon fertilization. The Drosophila male germline stem cells (GSCs) are among the best characterized stem cell systems. Male GSCs can be identified by their distinct anatomical positions and morphological features within the fly testis. This makes it feasible to study these stem cells at single cell resolution, which allows direct comparisons between GSCs and their daughter cells, the gonialblasts. Understanding the molecular mechanisms underlying GSC asymmetric cell division is of broad interest to cancer biology, reproductive biology, as well as regenerative medicine. I hypothesized that epigenetic difference between sister chromatids contributes to stem cell asymmetric division. It has been known for long time that epigenetic changes are heritable. However, except for DNA methylation, little is known about the molecular mechanisms of epigenetic inheritance. I propose to use molecular, genetic and cell biology tools to investigate in real time whether Drosophila male GSCs preserve a particular chromatin structure by inheriting a unique set of "epigenetic codes"; the regulatory pathways that lead to such an inheritance; and the potential abnormalities that arise from the mis-regulation of epigenetic inheritance. PUBLIC HEALTH RELEVANCE: Stem cells are of great value for both biomedical research and regenerative medicine. To effectively utilize stem cells in therapeutic applications to cure many human diseases, we have to thoroughly understand the molecular mechanisms underlying stem cell self-renewal abilities. The proposed work will explore whether stem cells maintain themselves by inheriting a particular set of proteins; and whether by doing so, stem cells keep a specific group of genes active while the rest to be silent. We propose to use both state-of-the-art cell biology tools to visualize such process in real time and molecular genetic strategies to explore how mis-regulation of it may lead to diseases.