The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics

项目摘要 每个真核细胞的细胞核内都有一个基本的矛盾：遗传物质必须是 组织和压缩，但仍然可以通过转录机器读出。众多因素中的两个 保持这种平衡的是组蛋白和组蛋白结合蛋白。组蛋白最终负责 将染色体DNA压缩了近50万倍以适应细胞核。虽然基因组可及性是 部分受组蛋白乙酰转移酶（KAT）的作用调节，组蛋白伴侣直接与 组蛋白，并且可以在DNA上组装和/或分解它们。KAT共价修饰组蛋白， 因此，具有改变染色质结构的潜力。令人兴奋的新证据在结构上和功能上 KAT和组蛋白伴侣。然而，几乎没有人知道这些机制， 蛋白质协作以管理压缩和基因组可及性。我们已经证明了 组蛋白伴侣（Asf 1），识别组蛋白的乙酰化状态，并共同修饰 KAT的特异性。我们提出，这些分子伴侣的功能是保持适当的乙酰化配置文件， 通过调节赖氨酸的乙酰化和它们在染色质中的掺入，来调节染色质的结构。生化 以及如何实现特异性和选择性的分子理解目前是生物学领域的一个主要挑战。 染色质场该项目将采用并扩展研究复杂蛋白质-蛋白质的新方法 调节染色质动力学和翻译后特异性所需的网络。

Project Summary There is a fundamental paradox within the nucleus of every eukaryotic cell: The genetic material must be organized and compacted yet remain accessible for readout by transcription machinery. Two of the many factors that retain this balance are histones and histone binding proteins. Histones are ultimately responsible for compacting the chromosomal DNA almost 500,000-fold to fit into the nucleus. While genome accessibility is regulated in part by the actions of histone acetyltransferases (KATs), histone chaperones interact directly with histones and can assemble and/or disassemble them on DNA. KATs covalently modify the histones and therefore, have the potential to alter chromatin structure. Exciting new evidence structurally and functionally link KATs and histone chaperones. However, virtually nothing is known about the mechanisms by which these proteins cooperate to manage compaction and genome accessibility. We have demonstrated the ability of histone chaperones (Asf1), to recognize the acetylation state of histones and work together to modify the specificity of KATs. We are proposing that these chaperones function to maintain the proper acetyl-profiles of chromatin by regulating both which lysines get acetylated and their incorporation in to chromatin. A biochemical and molecular understanding of how specificity and selectivity is achieved is currently a major challenge in the chromatin field. This project will employ and expand on new methodologies for studying complex protein-protein networks needed to regulate chromatin dynamics and post-translational specificity.