Interrogating the roles of canonical versus variant histone H3 in genome function during aging

探讨经典组蛋白 H3 与变异组蛋白 H3 在衰老过程中基因组功能中的作用

• 批准号: 10677916
• 负责人: Jeanne-Marie McPherson
• 金额: $ 3.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677916
• 关键词: ATAC-seq; Affect; Age; Aging; Amino Acid Sequence; Amino Acids; Binding; Cell Aging; Cell Cycle; Cells; Chromatin; Chromatin Structure; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Packaging; DNA biosynthesis; Defect; Deposition; Development; Dose; Drosophila genus; Ensure; Eukaryota; Gene Dosage; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Screening; Genetic Transcription; Genome; Genomics; Global Change; Heterochromatin; Histone H3; Histone H3.3; Histones; Homeostasis; Interphase Cell; Investigation; Knowledge; Location; Longevity; Mediating; Modeling; Mutation; Pathologic; Pathologic Processes; Pathway interactions; Pattern; Process; Proteins; Regulation; Role; S phase; Source; Testing; Variant; Work; aging brain; brain cell; defined contribution; experimental study; healthy aging; improved; insight; interest; postmitotic; protein function; screening; therapeutic development

PROJECT SUMMARY Histone proteins package and organize DNA into chromatin, which regulates every DNA-dependent process. Alterations to chromatin structure is a hallmark of aging and is characterized by global changes in gene expression, histone abundance, histone PTM landscape, and chromatin accessibility. I propose that tight control over histone abundance and histone type, which we term histone homeostasis, is essential for normal cellular aging. Cells contain two histone types: canonical histones that are expressed during S phase of the cell cycle, and variant histones that are expressed throughout the cell cycle and in non-dividing cells. Variant histones are of particular interest to aging because they are the only source of new histones in non-dividing cells and accumulate with age. Additionally, variant histone misregulation results in chromatin defects and reduced lifespan. Knowing how canonical and variant histones regulate genome function is integral to understanding normal and pathological chromatin-based aging processes. Canonical histone H3.2 and variant histone H3.3 are some of the most highly conserved proteins across eukaryotes. The high conservation of amino acid differences between canonical H3.2 and variant H3.3 suggests that they may perform unique functions in the genome, yet it is not understood if variant H3.3 function is mediated by its cell-cycle independent expression or unique protein sequence. In Drosophila, I have discovered that variant H3.3 is essential for development when canonical histone gene copy number is reduced, suggesting a previously unknown requirement for coordination between canonical H3.2 and variant H3.3 expression. However, the mechanisms underlying this coordination are unknown. The proposed project tests the hypotheses that variant H3.3 is required for normal chromatin-based aging processes and that cells possess a homeostatic mechanism to maintain the correct relative expression of canonical H3.2 and variant H3.3 throughout development. The aims of this project are to (1) determine the contributions of H3.3 expression versus protein sequence to chromatin-based aging processes and, (2) elucidate the mechanisms that achieve proper H3 abundance through the coordination of canonical and variant histone expression. This work will expand the fundamental understanding of how canonical and variant histones cooperate to regulate genome function during aging.

项目摘要 组蛋白将DNA包装并组织成染色质，染色质调节每一个依赖DNA的过程。 染色质结构的改变是衰老的标志，其特征是基因的整体变化。 表达、组蛋白丰度、组蛋白PTM景观和染色质可及性。我建议严格控制 我们称之为组蛋白稳态的组蛋白丰度和组蛋白类型对正常细胞的生长至关重要。 衰老细胞含有两种类型的组蛋白：在细胞周期的S期表达的典型组蛋白， 以及在整个细胞周期和非分裂细胞中表达的变体组蛋白。变异组蛋白是 对衰老特别感兴趣，因为它们是非分裂细胞中新组蛋白的唯一来源， 随着年龄的积累。此外，变体组蛋白失调导致染色质缺陷和减少的细胞凋亡。 寿命了解典型组蛋白和变异组蛋白如何调节基因组功能对于理解 正常和病理性的基于染色质的衰老过程。典型组蛋白H3.2和变异组蛋白H3.3是 真核生物中最保守的蛋白质。氨基酸差异高度保守 典型H3.2和变体H3.3之间的差异表明它们可能在基因组中执行独特的功能， 还不清楚变体H3.3的功能是否是由其细胞周期非依赖性表达或独特的蛋白质介导， 顺序在果蝇中，我已经发现，当典型的H3.3变异是发育所必需的， 组蛋白基因拷贝数减少，这表明以前未知的协调要求， 典型H3.2和变体H3.3表达。然而，这种协调的基本机制是 未知拟议的项目测试的假设，变异H3.3是需要正常的染色质为基础的 衰老过程中，细胞具有自我平衡机制，以维持正确的相对表达， 规范H3.2和变体H3.3贯穿整个开发过程。本项目的目的是（1）确定 H3.3表达与蛋白质序列对基于染色质的衰老过程的贡献，（2）阐明 通过典型组蛋白和变异组蛋白的协调实现适当H3丰度的机制 表情这项工作将扩大基本的理解，如何规范和变异组蛋白 在衰老过程中协同调节基因组功能。