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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要组蛋白将 DNA 包装并组织成染色质，从而调节每个 DNA 依赖性过程。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。我建议严格控制组蛋白丰度和组蛋白类型（我们称之为组蛋白稳态）对于正常细胞至关重要老化。细胞含有两种组蛋白类型：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异组蛋白。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增长。此外，变异组蛋白失调会导致染色质缺陷并减少寿命。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基因组功能至关重要基于染色质的正常和病理性衰老过程。典型组蛋白 H3.2 和变异组蛋白 H3.3 是真核生物中一些最高度保守的蛋白质。氨基酸差异的高度保守性规范 H3.2 和变体 H3.3 之间的比较表明它们可能在基因组中发挥独特的功能，但目前尚不清楚变体 H3.3 功能是否由其细胞周期独立表达或独特蛋白质介导顺序。在果蝇中，我发现变体 H3.3 对于规范化时的发育至关重要组蛋白基因拷贝数减少，表明以前未知的协调需求规范的 H3.2 和变体 H3.3 表达。然而，这种协调背后的机制是未知。拟议的项目测试了基于正常染色质需要变体 H3.3 的假设衰老过程以及细胞拥有稳态机制来维持正确的相对表达规范 H3.2 和变体 H3.3 在整个开发过程中。该项目的目标是 (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，以及 (2) 阐明通过协调典型组蛋白和变异组蛋白实现适当 H3 丰度的机制表达。这项工作将扩展对规范组蛋白和变异组蛋白如何合作调节衰老过程中的基因组功能。