Regulation of Nuclear Functions by Drosophila Linker Histone H1

果蝇接头组蛋白 H1 对核功能的调节

• 批准号: 10170376
• 负责人: DMITRY V FYODOROV
• 金额: $ 37.91万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170376
• 关键词: ATP phosphohydrolase; Address; Affect; Architecture; Biochemical; Biological Models; Biological Process; Biology; Cell Nucleus; Cells; Chromatin; Chromatin Structure; Chromosome Structures; Chromosomes; Complex; DNA; DNA biosynthesis; Deposition; Development; Disease; Drosophila genus; Drosophila melanogaster; Embryonic and Fetal Development; Enzymes; Epigenetic Process; Exhibits; Genes; Genetic; Genome; Genomics; Goals; Heterochromatin; Histone H1; Histone H2A; Histones; In Vitro; Individual; Knowledge; Liquid substance; Maintenance; Malignant Neoplasms; Mediating; Methods; Methylation; Mitotic; Molecular; Nuclear; Pattern; Phase; Play; Post-Translational Protein Processing; Process; Proteins; RNA Interference; Regulation; Replication Initiation; Repression; Role; S Phase; Salivary Glands; Spatial Distribution; Structural Protein; Structure; System; Transcription Initiation; Work; genome-wide; human disease; in vivo; mutant; physical property; promoter; recruit

The goal of this proposal is to elucidate molecular mechanisms by which H1 linker histone regulates chromatin structure and activity. H1 and the four core histones (H2A, H2B, H3 and H4) are essential structural proteins of metazoan chromosomes. Much of our knowledge about H1's roles in chromatin is derived from in vitro studies, whereas our understanding of its functions in vivo remains very incomplete. We propose to use the fruit fly, Drosophila melanogaster, as a model system because it provides many advantages for studies of chromosome structure and genetic activity and because Drosophila H1 strongly resembles mammalian H1 linker histones. We developed an RNA interference (RNAi) approach to deplete Drosophila H1 nearly completely in vivo. Using this approach, we showed that H1 is essential for Drosophila development and for normal chromosome architecture. We also discovered that, in addition to its important structural role in chromatin, H1 plays an active role in regulating epigenetic marking and silencing of heterochromatin by directly interacting with and helping to recruit a core histone - modifying enzyme to chromatin. We also found that H1 has a role in controlling DNA replication of polytene chromsomes. To gain a deeper understanding of the molecular mechanisms by which H1 controls nuclear functions, we propose to: (1) Characterize the functional role of H1 in regulating DNA replication; (2) Understand how H1 interfaces with core histone posttranslational modifications in chromatin; (3) Determine the contributions of H1 structural domains and post-translational modifications to its biological functions. The successful completion of this project will help define the mechanisms by which this major constituent of chromosomes partners with other cellular factors to regulate the structure and activity of chromatin.

该提案的目标是阐明H1接头组蛋白调控的分子机制， 染色质结构和活性。H1和四个核心组蛋白（H2 A，H2 B，H3和H4）是必需的结构蛋白。 后生动物染色体的蛋白质。我们对H1在染色质中的作用的了解大多来自于 体外研究，而我们对它在体内的功能的理解仍然非常不完整。我们建议使用 果蝇作为模型系统，因为它为研究 由于果蝇H1与哺乳动物H1非常相似， 连接组蛋白。 我们开发了一种RNA干扰（RNAi）的方法，几乎完全耗尽果蝇H1在体内。 利用这种方法，我们发现H1是果蝇发育和正常染色体所必需的 架构我们还发现，除了在染色质中的重要结构作用外，H1还在染色质中起着重要的作用。 在调节表观遗传标记和异染色质沉默中的积极作用， 帮助招募核心组蛋白修饰酶进入染色质。我们还发现，H1在 控制多线染色体的DNA复制。为了更深入地了解 H1控制核功能的机制，我们提出：（1）表征H1的功能作用 调节DNA复制;（2）了解H1如何与核心组蛋白翻译后相互作用 （3）确定H1结构域和翻译后修饰的贡献。 改变其生物学功能。该项目的成功完成将有助于确定 染色体的这一主要成分与其他细胞因子合作调节的机制 染色质的结构和活性。