Epigenetic mechanisms for regulation of p300

项目摘要 人p300是一种转录辅激活因子，也是一种主要的乙酰转移酶， 组蛋白和其他蛋白质，促进基因转录。P300适用于各种 细胞程序，包括细胞生长，分化，凋亡和DNA修复， 与人类疾病，特别是癌症和遗传疾病有关。P300及其参数 CBP是人类恶性肿瘤中最常见的突变基因之一。p300包含一个 与ZZ紧密相连的催化组蛋白乙酰转移酶（HAT）结构域的独特组装 域，其生物学作用仍不清楚。我们已经确定了p300的ZZ结构域 （ZZp300）作为识别组蛋白H3尾的新型表观遗传阅读器。我们的发现表明 这种识别介导p300的催化和染色质结合活性。分子 这些新的p300活性的机制和功能意义是未知的， 建议研究的重点。 我们假设ZZp300与H3的相互作用促进了蛋白质的选择性乙酰化。 组蛋白H3K27和H3K18位点。此外，我们建议ZZp300与 溴结构域（BDp300）在p300在染色质的募集和稳定中的作用。我们将雇用一名 体外和体内方法的有力组合，以建立分子和结构 基础，机制的见解，和生物学意义的组蛋白读者之间的串扰， p300。这项研究对我们理解生理和 p300的致病活性。这些研究也将阐明新的表观遗传的作用， 读者，ZZp300，使我们能够建立一个模型的信号通过这个主要的乙酰转移酶，并将 从而更好地了解与异常p300活性相关的人类疾病，包括 癌症和遗传疾病。

Project Summary Human p300 is a transcriptional co-activator and a major acetyltransferase that acetylates histones and other proteins, facilitating gene transcription. P300 is required for a wide array of cellular programs, including cell growth, differentiation, apoptosis, and DNA repair, and is implicated in human diseases, cancer and genetic disorders in particular. P300 and its paralog CBP are among the most frequently mutated genes in human malignancies. p300 contains a unique assembly of the catalytic histone acetyltransferase (HAT) domain closely linked to the ZZ domain, the biological role of which remains unclear. We have identified the ZZ domain of p300 (ZZp300) as a novel epigenetic reader that recognizes histone H3 tail. Our findings suggest that this recognition mediates catalytic and chromatin binding activities of p300. The molecular mechanisms and functional significance of these novel p300 activities are unknown and are the focus of the proposed studies. We hypothesize that the interaction of ZZp300 with H3 promotes selective acetylation of the histone H3K27 and H3K18 sites by p300. Furthermore, we propose that ZZp300 cooperates with bromodomain (BDp300) in the recruitment and stabilization of p300 at chromatin. We will employ a powerful combination of in vitro and in vivo approaches to establish the molecular and structural basis, mechanistic insights, and biological significance of crosstalk between histone readers in p300. This research is of fundamental importance to our understanding of the physiological and pathogenic activities of p300. These studies will also shed light on the role of the novel epigenetic reader, ZZp300, allowing us to build a model of signaling by this major acetyltransferase, and will lead to a better understanding of human diseases associated with aberrant p300 activity, including cancer and genetic disorders.