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: 10619644
• 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/10619644
• 关键词: Age; Aging; Behavior; Binding; Biology; Cell Cycle; Cells; Chromatin Modeling; Chromatin Structure; Collaborations; Complex; Development; Dissociation; Drosophila genus; Embryo; Epigenetic Process; Evolution; Genetic; Genome; Genomics; Heterochromatin; In Vitro; Intervention; Learning; 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; Specific qualifier value; Supervision; Therapeutic; Time; 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.

项目摘要/摘要 我们将讨论果蝇生物学的两个基本方面。第一个问题涉及机制。 调节幼稚胚胎基因组分化的开始。发育时间决定了渐进性 介绍染色质结构的特殊结构域的步骤。我们发现，病毒的分子特征 异染色质出现较晚，在标记被认为是特定的异染色质行为之后。我们会 探索建立异染色质结构域早期专门化的机制。群集化阵列 在组蛋白甲基化之前的第14个细胞周期，重复序列(卫星)的复制变得较晚 (H3K9me)与异染色质蛋白1(HP1)结合。我们发现，受监管的Rif1，a 复制抑制因子，解释了晚期复制的发育开始，以及其时间时间表 解离指导了卫星的顺序复制的时间程序。我们将在体内使用强大的 理解时间是如何编排的工具。但是，是什么将Rif1定位于卫星序列呢？我们发现， 卫星序列被压缩得甚至更早，在Rif1招募之前，但然后是什么基础 压实？重复性是卫星序列的普遍特征。最近，我们的 邻居Sy Redding和Rosen实验室表明，在体外，染色质与核小体组装在一起 周期性地定位在重复序列上，自主凝聚成类液体相。在……里面 与Sy Redding合作，我们将讲述简单的物理观测和卫星的活体行为 重复着。这里所采用的方法将定义进化选择来指导的交互的进程 许多复杂的后生动物生物学基础上的不同基因组亚群的初始形成。 第二个项目研究线粒体(Mt)基因组的遗传独立性。尽管它的 细菌的起源，mt基因组被认为适应良好；然而，一个独立传播的基因 元素总是有一个叛离选项。只有在有利的情况下，它才是合作的。独一无二的 多拷贝母体传播的mt基因组的遗传学通常被认为是简单的，但这是 疾病突变传播的复杂性和表型的年龄相关性。 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 新工具。我们证明了突变的mt基因组与细胞中其他基因组池竞争的能力 决定了它的命运。核基因组操纵这种mt间的基因组竞争，以提供有益的 结果，但核管理中的脆弱点允许一些突变的成功传播 并导致与年龄相关的mt基因组完整性下降。我们提出的实验将 剖析了mt基因组核管理的基础。确定调节核活动将 提高对mt疾病严重程度的可预测性，并为其治疗管理引入新的途径。