核小体组蛋白H4的乙酰化是一个被广泛研究的重要的表观遗传调控机制。它主要由NuA4／Tip60类蛋白质复合物催化完成。NuA4的催化中心是Esa1。单独的Esa1对核小体没有活性。只有形成一个NuA4的核心复合物picNuA4，它才能选择性地乙酰化核小体组蛋白H4。目前，已有大量的关于picNuA4的生物化学研究，以及单独的Esa1晶体结构和一个低分辨的picNuA4－核小体复合物的冷冻电镜结构。但是，这些研究并不能揭示picNuA4识别并乙酰化核小体H4的机理。在这个项目中，我们将联合使用x-射线晶体学和电子显微镜学的方法研究酵母picNuA4复合物的结构及其用对核小体的识别。我们将并根据酵母picNuA4的结构信息，进一步考察人源Tip60的工作机理。

Acetylation of nucleosome at histone H4 is a well-established epigenetic control in many nuclear processes, which is catalyzed by the NuA4 and Tip60 complexes in Saccharomyces cerevisiae and animal cells, respectively. While the free catalytic subunit Esa1 is inactive, formation of the picNuA4 core complex with Epl1 and Yng2 greatly enhances its activity and specificity toward the nucleosomal H4. Currently, there are substantial biochemical studies on picNuA4. The crystal structure of the Esa1 alone, and a low-resolution cryo-electron microscopic structure of the picNuA4-nucleosome complex are known. Yet, these studies still can not reveal the mechanism of how picNuA4 selectively acetylates the nucleosomal H4. In this proposal, we will study the structures of picNuA4 complex using X-ray crystallography, and the mechanism of nucleosome recognition using electron microscopy (EM). We will further investigate the mechanism of the human Tip60 complex based on the structural information of the yeast picNuA4.