Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage

干细胞谱系生殖细胞分化的表观遗传调控

• 批准号: 10373066
• 负责人: XIN CHEN
• 金额: $ 33.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373066
• 关键词: Address; Area; Biochemical; Biological; Biological Models; Biology; Biophysics; Cancer Biology; Cell Culture System; Cell Cycle; Cell Cycle Progression; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cells; Cellular biology; ChIP-seq; Chromatin; Chromatin Fiber; Complex; DNA; DNA Sequence; DNA biosynthesis; DNA replication fork; Data; Diabetes Mellitus; Disease; Drosophila genus; Epigenetic Process; Event; Fiber; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Genomic DNA; Genomic Segment; Genomics; Germ Cells; Histones; In Vitro; Infertility; Label; Light; Malignant Neoplasms; Mammals; Maps; Methods; Molecular; Molecular Biology; Molecular Genetics; Movement; Muscular Dystrophies; Nerve Degeneration; Okazaki fragments; Phase; Play; Polycomb; Proliferating Cell Nuclear Antigen; Proteins; RNA; Regenerative Medicine; Regulation; Replication Initiation; Replication Origin; Reproductive Biology; Research; Research Personnel; Role; S phase; Series; Somatic Cell; Spermatocytes; Structure; System; Techniques; Testing; Therapeutic; Work; adult stem cell; base; dimer; epigenetic regulation; experimental study; genomic locus; germline stem cells; histone modification; human disease; in vivo; male; novel; origin recognition complex; programs; public health relevance; self-renewal; stem cell biology; stem cell function; stem cell population; stem cell proliferation; stem cells; stem-like cell; tissue degeneration; transcriptome; transcriptome sequencing

Title: Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage Project Summary: Many human diseases are caused by imbalances between self-renewal/proliferation versus differentiation of adult stem cells. Therefore, it is critical to characterize the molecular and cellular mechanisms that regulate stem cell function to understand the diseases such as cancers and tissue degeneration. Additionally, to utilize stem cells in therapeutic applications, it is critical to understand the mechanisms that maintain stem cells, regulate proper proliferation of progenitor cells and program cellular differentiation in stem cell lineages. Stem cell-based regenerative medicine also holds promise for diseases such as cancers, neurodegeneration, muscle dystrophy, diabetes, and infertility. A broad definition of epigenetic mechanisms refers to DNA-associated factors that change gene expression without altering the primary DNA sequences. Epigenetic mechanisms play crucial roles in defining stem cell identity and regulating stem cell activity. Among known epigenetic regulators, the Polycomb group (PcG) transcriptional repressive proteins have critical functions in multiple stem cell lineages across different species from Drosophila to mammals. In addition to their well-characterized functions in silencing gene expression, studies from many labs have shown other roles of PcG in areas such as DNA replication and cell cycle progression. My lab uses the Drosophila male germline stem cell (GSC) lineage as a model system to investigate how epigenetic mechanisms regulate stem cell maintenance, proliferation, differentiation, and dedifferentiation. Our previous studies have shed light on epigenetic mechanisms in regulating multiple events in GSC lineage including GSC maintenance and germ cell differentiation. Our recent work reveals under-appreciated functions of DNA replication and potentially new roles of epigenetic regulators such as Polycomb (Pc). We propose to use well-established and newly developed methods in molecular genetics, cell biology, biophysics and genomics to provide an in-depth and systematic understanding of how key epigenetic players regulate stem cells in vivo. Successful completion of the proposed studies will have a broad impact on stem cell biology, germ cell biology, DNA replication, chromatin biology, cancer biology, reproductive biology, and regenerative medicine.

标题：干细胞谱系生殖细胞分化的表观遗传调控 项目概要： 许多人类疾病是由自我更新/增殖与 成体干细胞的分化因此，关键在于表征分子和细胞机制 调节干细胞的功能，以了解癌症和组织退化等疾病。此外，本发明还 为了在治疗应用中利用干细胞，理解维持干细胞的机制是至关重要的。 细胞，调节祖细胞的适当增殖并在干细胞谱系中编程细胞分化。 基于干细胞的再生医学也有望治疗癌症、神经变性、 肌肉萎缩症糖尿病和不育症 表观遗传机制的广义定义是指改变基因表达的DNA相关因子。 表达而不改变一级DNA序列。表观遗传机制在定义 干细胞身份和调节干细胞活性。在已知的表观遗传调节因子中，Polycomb组 (PcG)转录抑制蛋白在多种干细胞谱系中具有关键功能， 从果蝇到哺乳动物。除了它们在沉默基因中的功能外， 许多实验室的研究已经显示了PcG在DNA复制和细胞增殖等领域的其他作用。 循环进展 我的实验室使用果蝇雄性生殖系干细胞（GSC）谱系作为模型系统来研究 表观遗传机制如何调节干细胞的维持、增殖、分化和去分化。 我们以前的研究已经阐明了表观遗传机制在调控多个事件的GSC谱系 包括GSC维持和生殖细胞分化。我们最近的研究揭示了 的DNA复制和潜在的新作用的表观遗传调控，如Polycomb（Pc）。我们建议 使用成熟和新开发的方法在分子遗传学，细胞生物学，生物物理学和 基因组学提供了一个深入和系统的了解如何关键表观遗传球员调节干细胞 in vivo.成功完成拟议的研究将对干细胞生物学、生殖细胞生物学和生殖细胞生物学产生广泛的影响。 生物学、DNA复制、染色质生物学、癌症生物学、生殖生物学和再生医学。