Epigenetic inheritance in germline stem cell lineage

摘要：干细胞具有独特的自我更新能力，可分化为多种细胞。许多类型的干细胞经历不对称的细胞分裂，以产生一个自我更新的干细胞和一个用于分化的子细胞。干细胞不对称分裂的错误调控可能导致肿瘤发生或组织营养不良。在所有已知的成体干细胞类型中，生殖细胞是最不朽的，因为它们在受精后能够产生整个生物体的下一代。果蝇雄性生殖系干细胞（GSCs）是最具特征的干细胞系统之一。雄性GSCs在蝇睾丸内具有独特的解剖位置和形态特征。这使得在单细胞分辨率下研究这些干细胞成为可能，从而可以直接比较gsc和它们的子细胞——性腺母细胞。了解GSC不对称细胞分裂的分子机制对癌症生物学、生殖生物学和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。长期以来，人们都知道表观遗传变化是可遗传的。然而，除了DNA甲基化外，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来实时研究果蝇雄性GSCs是否通过继承一组独特的“表观遗传密码”来保留特定的染色质结构；导致这种遗传的调控途径；以及由于表观遗传调控不当而产生的潜在异常。

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.