Study epigenetic inheritance during development and across generations using multiple model

使用多种模型研究发育过程中和跨代的表观遗传

• 批准号: 10400162
• 负责人: XIN CHEN
• 金额: $ 32.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400162
• 关键词: Adult; Animal Model; Biological Models; Biology; Caenorhabditis elegans; Cell Differentiation process; Cell division; Cells; Cellular biology; Chromatin; Complex; DNA Sequence; Development; Developmental Biology; Diabetes Mellitus; Disease; Drosophila genus; Epigenetic Process; Failure; Gene Expression; Generations; Genetic Materials; Genomic approach; Histones; Infertility; Inherited; Malignant Neoplasms; Meiosis; Mitosis; Modeling; Molecular; Molecular Genetics; Mus; Muscular Dystrophies; Neurodegenerative Disorders; Organism; Play; Positioning Attribute; Regenerative Medicine; Reproductive Biology; Research; Role; System; Work; biophysical techniques; cell behavior; cell type; daughter cell; embryonic stem cell; epigenetic memory; epigenetic regulation; gene function; germline stem cells; in vivo; intergenerational; male; self-renewal; stem cell biology; stem cells; transgenerational epigenetic inheritance; zygote

Title: Study epigenetic inheritance during development and across generations using multiple model organisms Project Summary/Abstract: Epigenetics refers to effects on gene expression or function that are inheritable through mitosis or meiosis without altering the primary DNA sequences. Epigenetic mechanisms play important roles in regulating cell identity and activity. Failure in appropriate epigenetic regulation leads to abnormal behaviors of cells, which underlies many diseases such as diabetes, muscular dystrophy, neurodegenerative disease, infertility, and many forms of cancer. Many types of stem cells undergo asymmetric cell divisions to give rise to two daughter cells with distinct cell fates: a self-renewed stem cell and to another daughter cell that differentiates. We found that during the asymmetric division of Drosophila male germline stem cell (GSC), the preexisting histone 3 (H3) are selectively segregated to the GSC whereas newly synthesized H3 are enriched in the differentiating daughter cell. Our studies provide the first direct evidence that stem cells retain preexisting histones during asymmetric cell divisions in vivo, which may contribute to maintain their unique epigenetic memory. These unprecedented discoveries have placed us at a unique position to solve a long-standing question regarding whether and how cells maintain their epigenetic memories through many cell divisions and across generations, which have become our major research focuses. Our current work has three main directions: (1) to understand the molecular mechanisms and cellular basis of asymmetric histone inheritance using Drosophila male GSC as a model system; (2) to investigate the generality of asymmetric epigenetic inheritance in other cell types of Drosophila and in other organisms/systems, such as C.elegans and mouse embryonic stem cells; (3) to study intergenerational and transgenerational epigenetic inheritance in C.elegans and Drosophila. We propose to use molecular genetics, cell biology, genomic, and biophysical approaches in our research, which will have far-reaching impact on a broad range of fields, including stem cell biology, chromatin biology, developmental biology, and reproductive biology.

标题：使用多基因技术研究发育期间和跨代的表观遗传 模式生物 项目概要/摘要： 表观遗传学是指通过有丝分裂遗传的基因表达或功能的影响 或减数分裂而不改变初级DNA序列。表观遗传机制发挥重要作用 在调节细胞特性和活性中的作用。适当的表观遗传调控失败导致 细胞的异常行为，这是许多疾病的基础，如糖尿病，肌肉 营养不良、神经变性疾病、不育症和多种形式的癌症。 许多类型的干细胞经历不对称的细胞分裂以产生两个子细胞 具有不同的细胞命运：一个自我更新的干细胞和另一个分化的子细胞。 我们发现，在果蝇雄性生殖干细胞（GSC）的不对称分裂过程中， 预先存在的组蛋白3（H3）被选择性地分离到GSC，而新合成的H3 在分化的子细胞中富集。我们的研究提供了第一个直接证据， 干细胞在体内不对称细胞分裂过程中保留了预先存在的组蛋白，这可能 有助于维持他们独特的表观遗传记忆。 这些前所未有的发现使我们处于一个独特的位置，以解决一个长期存在的问题。 关于细胞是否以及如何通过许多细胞维持其表观遗传记忆的问题 部门和跨代，这已成为我们的主要研究重点。我们目前 工作主要有三个方向：（1）了解分子机制和细胞基础 使用果蝇雄性GSC作为模型系统的不对称组蛋白遗传;（2） 研究果蝇其他细胞类型中不对称表观遗传的普遍性 以及其他生物/系统，例如秀丽隐杆线虫和小鼠胚胎干细胞;（3） 研究线虫的代际和跨代表观遗传遗传， 果蝇我们建议利用分子遗传学、细胞生物学、基因组学和生物物理学 我们的研究方法，这将对广泛的领域产生深远的影响， 包括干细胞生物学、染色质生物学、发育生物学和生殖生物学。