Histone Acetylation Dynamics and Epigenome Duplication

组蛋白乙酰化动力学和表观基因组复制

基本信息

批准号：
10343912
负责人：
MARK R PARTHUN
金额：
$ 40.77万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-03 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343912
关键词：
3-Dimensional Acetylation Architecture Cell Maintenance Cell Nucleus Cell division Cells Chromatin Chromatin Structure Complex DNA DNA Modification Process DNA Sequence DNA Structure DNA biosynthesis DNA replication fork Data Daughter Defect Deposition Epigenetic Process Eukaryota Gene Expression Genes Genetic Transcription Genome Genome Stability Genomic DNA Goals HAT1 gene Heterochromatin Histone Acetylation Histone H3 Histone H4 Histones Knowledge Laboratories Lamins Link Location Mammalian Cell Methylation Modeling Modification Molecular Genetics Nuclear Nuclear Lamina Nucleosomes Outcome Pathway interactions Pattern Phenocopy Play Post-Translational Protein Processing Proteins Regulation Research Role S phase Solid Structure Therapeutic Work base chromatin modification density epigenome epigenomics experimental study genetic approach histone acetyltransferase histone modification human disease infancy innovation insight mammalian genome non-histone protein preservation programs restoration spatial memory three dimensional structure

项目摘要

Eukaryotic genomes exist in a complex and dynamic 3-dimensional structure that provides important regulatory information controlling gene expression programs essential for the maintenance of cell identity. Genome structure is also critical for packaging the genome in the nucleus and preserving genome stability. Genome structure is primarily dictated by its' association with the histone proteins to form chromatin. The post- translational modifications on histones play a key role in determining genome structure as they regulate the association of non-histone proteins with genomic DNA. An important challenge for eukaryotes is the epigenetic inheritance of the histone modification patterns that govern genome structure following DNA replication and cell division. This proposal seeks to identify fundamental mechanisms that regulate the epigenetic inheritance of histone modification patterns. Following passage of a replication fork, newly replicated DNA is packaged into chromatin that contains a 1:1 mixture of parental histones and newly synthesized histones. The retention of modification patterns on parental histones provides the spatial memory for the duplication of specific chromatin states. The key step in epigenetic inheritance is the transfer of the parental modification patterns to the neighboring new histones. Our work is based on the hypothesis that the new histones play a critical regulatory role in the epigenetic inheritance of chromatin states. The current proposal is based on my lab's identification of previously unknown links between the dynamic acetylation of newly synthesized histones and the epigenetic inheritance of specific chromatin states and the restoration of 3-dimensional genome architecture following DNA replication. The experiments proposed here will characterize the effect of new histone acetylation on the structure and composition of chromatin and identify factors and pathways that function with new histone acetylation to regulate the epigenetic inheritance of chromatin states. In addition, we will characterize a previously unanticipated role of new histone acetylation in the epigenetic inheritance of 3-dimensional genome architecture through regulation of the interactions between chromatin and the nuclear lamina.

真核基因组存在于复杂且动态的三维结构中，提供重要的调控控制基因表达程序的信息对于维持细胞身份至关重要。基因组结构对于将基因组包装在细胞核中并保持基因组稳定性也至关重要。基因组结构主要由其与组蛋白形成染色质的关联决定。后- 组蛋白的翻译修饰在决定基因组结构方面发挥着关键作用，因为它们调节非组蛋白与基因组 DNA 的关联。真核生物面临的一个重要挑战是 DNA 控制基因组结构的组蛋白修饰模式的表观遗传复制和细胞分裂。该提案旨在确定监管的基本机制组蛋白修饰模式的表观遗传。经过复制叉后，新复制的 DNA 被包装到含有 1:1 的染色质中亲代组蛋白和新合成的组蛋白的混合物。修改模式的保留亲本组蛋白为特定染色质状态的复制提供空间记忆。关键一步在表观遗传是将亲代修饰模式转移到邻近的新组蛋白。我们的工作基于这样的假设：新组蛋白在表观遗传中发挥关键的调节作用染色质状态的遗传。目前的提议是基于我的实验室对以前未知的物质的鉴定新合成组蛋白的动态乙酰化与特定组蛋白的表观遗传之间的联系 DNA 复制后染色质状态和 3 维基因组结构的恢复。这这里提出的实验将表征新组蛋白乙酰化对结构和染色质的组成并确定与新组蛋白乙酰化起作用的因子和途径调节染色质状态的表观遗传。此外，我们将描述以前的新组蛋白乙酰化在三维基因组表观遗传中的意想不到的作用通过调节染色质和核纤层之间的相互作用来形成结构。