Embryonic Emergence of Heterochromatin and Nuclear Supervision of Mitochondrial Genetics

异染色质的胚胎出现和线粒体遗传学的核监督

• 批准号: 10406864
• 负责人: PATRICK H O'FARRELL
• 金额: $ 83.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406864
• 关键词: Address; Age; Aging; Behavior; Binding; Biology; Cell Cycle; Cells; Chromatin; Chromatin Structure; Collaborations; Complex; Development; Dissociation; Drosophila genus; Embryo; Epigenetic Process; Evolution; Genetic; Genome; Genomics; Heterochromatin; In Vitro; Intervention; Liquid substance; Malignant Neoplasms; Mitochondria; Mitochondrial Diseases; Mitochondrial Inheritance; Molecular; Mutation; Nuclear; Nucleosomes; Outcome; Pathogenicity; Phase; Phenotype; Positioning Attribute; Repetitive Sequence; Schedule; Severity of illness; Supervision; Therapeutic; Time; To specify; age related; disease transmission; experimental study; genetic element; genome integrity; heterochromatin-specific nonhistone chromosomal protein HP-1; histone methylation; in vivo; inhibitor; mitochondrial genome; mutant; programs; recruit; tool; transmission process

Project Summary/Abstract We will address two fundamental aspects of biology in Drosophila. The first involves the mechanisms regulating the onset of differentiation of a naïve embryonic genome. Developmental time resolves progressive steps that introduce the specialized domains of chromatin structure. We found that the molecular hallmarks of heterochromatin emerge late, after heterochromatic behaviors that the marks were thought to specify. We will explore the mechanisms establishing the earlier specializations of heterochromatin domains. Clustered arrays of repeated sequences (satellites) become late replicating in the 14th cell cycle prior to histone methylation (H3K9me) and heterochromatin protein 1 (HP1) binding. We found that regulated recruitment of Rif1, a replication inhibitor, explains developmental onset of late replication, and that a temporal schedule of its dissociation directs a temporal program of sequential replication of the satellites. We will use powerful in vivo tools to understand how time is programmed. But what targets Rif1 to satellite sequences? We found that the satellite sequences are compacted even earlier, prior to Rif1 recruitment, but then what is the basis of compaction? Repetitiveness is the universal distinguishing feature of satellite sequences. Recently, our neighbor Sy Redding and the Rosen lab showed that in vitro assembled chromatin with nucleosomes periodically positioned on repetitive sequences autonomously condenses into a liquid-like phase. In collaboration with Sy Redding we will relate the simple physical observations and in vivo behavior of satellite repeats. The approaches taken here will define the progression of interactions that evolution selected to guide the initial formation of distinct genomic subdivisions that underlie much of complex metazoan biology. The second project examines the genetic independence of the mitochondrial (mt) genome. Despite its bacterial origins, the mt genome is viewed as well adapted; however, an independently transmitted genetic element always has a renegade option. It is cooperative only as long as it is advantageous. The distinct genetics of the multicopied maternally transmitted mt genome is usually learned as uncomplicated, but this is belied by complexities in the transmission of disease mutations and age dependent onset of phenotypes. Inadequate genetic tools have hidden important features of mt genome behaviors that we have accessed with new tools. We show that the ability of a mutant mt genome to compete with the pool of other genomes in a cell determines its fate. The nuclear genome manipulates this inter-mt genome competition to give beneficial outcomes, but fragile points in this nuclear management allow successful transmission of some mutant genomes and underlie an age-associated decline in mt genome integrity. We propose experiments that will dissect the basis of nuclear management of the mt genome. Identifying modulating nuclear activities will enhance predictability of mt disease severity and introduce new avenues for their therapeutic management.

项目概要/摘要 我们将讨论果蝇生物学的两个基本方面，第一个涉及机制。 调节幼稚胚胎基因组分化的开始可以解决渐进问题。 引入染色质结构特殊域的步骤我们发现了染色质结构的分子特征。 异染色质出现较晚，在标记被认为指定的异染色质行为之后。 探索建立异染色质域早期特化的机制。 重复序列（卫星）在组蛋白甲基化之前的第 14 个细胞周期中复制较晚 (H3K9me) 和异染色质蛋白 1 (HP1) 的结合可调节 Rif1 的募集。 复制抑制剂，解释了晚期复制的发育开始，以及其时间安排 解离指导卫星顺序复制的时间程序，我们将使用强大的体内功能。 但我们发现 Rif1 的目标是什么？ 卫星序列的压缩甚至更早，在 Rif1 招募之前，但随后的基础是什么 压缩？重复性是卫星序列的普遍特征。 邻居 Sy Redding 和 Rosen 实验室表明，染色质与核小体在体外组装 位于重复序列上的粒子会自动凝结成液态。 与 Sy Redding 合作，我们将把简单的物理观察和卫星的体内行为联系起来 这里采取的方法将定义进化选择引导的相互作用的进展。 不同基因组细分的最初形成，是许多复杂的后生动物生物学的基础。 第二个项目研究线粒体（mt）基因组的遗传独立性。 细菌起源，mt 基因组被认为具有良好的适应能力；然而，它是一种独立传播的遗传基因； 元素总是有一个叛逆的选择，只要它是有利的。 多拷贝母体传播的 mt 基因组的遗传学通常被认为并不复杂，但这是 人们相信疾病突变传播的复杂性和年龄依赖性表型的发生。 不充分的遗传工具隐藏了我们已经获得的 mt 基因组行为的重要特征 我们展示了突变体 mt 基因组与细胞中其他基因组竞争的能力。 核基因组操纵这种 mt 基因组间的竞争来产生有益的结果。 结果，但这种核管理中的脆弱点允许某些突变体的成功传播 我们提出的实验将是与年龄相关的 mt 基因组完整性下降的基础。 剖析 mt 基因组核管理的基础将确定调节核活动。 增强MT疾病严重程度的可预测性并为其治疗管理引入新途径。