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而动态的3维结构中，可提供重要的调节控制基因表达程序对于维持细胞身份必不可少的信息。基因组结构对于在细胞核中包装基因组并保留基因组稳定性也至关重要。基因组结构主要取决于其与组蛋白蛋白的关联以形成染色质。职位 - 对组蛋白的翻译修饰在确定基因组结构时起着关键作用非内酮蛋白与基因组DNA的关联。真核生物的一个重要挑战是在DNA之后控制基因组结构的组蛋白修饰模式的表观遗传遗传复制和细胞分裂。该建议旨在确定规范的基本机制组蛋白修饰模式的表观遗传遗传。通过复制叉通过后，将新复制的DNA包装到染色质中，其中包含1：1 亲本组蛋白和新合成的组蛋白的混合物。保留修改模式父母组蛋白为特定染色质状态的复制提供了空间记忆。关键步骤表观遗传遗传是父母修饰模式向相邻新组蛋白的转移。我们的工作基于以下假设：新组蛋白在表观遗传学中起关键的调节作用染色质状态的继承。当前的建议基于我实验室对以前未知的识别新合成组蛋白的动态乙酰化与特定的表观遗传之间的联系 DNA复制后的染色质状态和3维基因组结构的恢复。这这里提出的实验将表征新的组蛋白乙酰化对结构和染色质的组成，并识别与新组蛋白乙酰化起作用的因素和途径调节染色质状态的表观遗传。另外，我们将表征以前的新组蛋白乙酰化在三维基因组表观遗传遗传中的意外作用通过调节染色质与核薄片之间的相互作用来结构。