Histone Acetylation Dynamics and Epigenome Duplication

真核生物基因组存在于复杂而动态的三维结构中，为 对维持细胞特性至关重要的信息控制基因表达程序。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是至关重要的。基因组 结构主要是由它与组蛋白结合形成染色质决定的。邮报- 组蛋白的翻译修饰在决定基因组结构方面起着关键作用，因为它们调节 非组蛋白与基因组DNA的相关性。真核生物面临的一个重要挑战是 支配DNA后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。这项提案旨在确定监管 组蛋白修饰模式的表观遗传。 在复制叉子通过后，新复制的DNA被包装成含有1：1的染色质 亲代组蛋白和新合成的组蛋白的混合物。修饰性模式的保留 亲本组蛋白为特定染色质状态的复制提供空间记忆。的关键一步 表观遗传是将亲本修饰模式转移到邻近的新组蛋白上。 我们的工作是基于这样一个假设，即新的组蛋白在表观遗传学中起着关键的调节作用 染色质状态的遗传。目前的建议是基于我的实验室对以前未知的 新合成组蛋白的动态乙酰化与特异性表观遗传的联系 染色质状态和DNA复制后三维基因组结构的恢复。这个 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，并确定与新的组蛋白乙酰化作用的因素和途径 调节染色质状态的表观遗传。此外，我们还将描述以前的 新的组蛋白乙酰化在三维基因组表观遗传中的意外作用 通过调节染色质和核层之间的相互作用来构建。

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.