Epigenetic mechanisms for regulation of p300

p300 调节的表观遗传机制

基本信息

批准号：
10077864
负责人：
TATIANA G KUTATELADZE
金额：
$ 44.44万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077864
关键词：
Acetylation Acetyltransferase Affinity Apoptosis Binding Biological Biological Assay Biological Process Bromodomain Calorimetry Cell physiology Chromatin Complex Crystallization DNA Repair Data EMSA EP300 gene Epigenetic Process Event Fluorescence Fluorescence Resonance Energy Transfer Genes Genetic Diseases Genetic Transcription Histone Acetylation Histone H3 Histones Human Impairment In Vitro Length Light Link Malignant Neoplasms Measures Mediating Modeling Molecular Molecular Conformation Molecular Structure Mutagenesis Mutate Nucleosomes Pathogenicity Peptides Physiological Play Proteins Reader Regulation Research Role Signal Pathway Signal Transduction Site Structure Tail Therapeutic Titrations Transcription Coactivator Transcriptional Activation Western Blotting cancer genetics cell growth chromatin immunoprecipitation design histone acetyltransferase human disease in vivo insight leukemia loss of function mutant novel paralogous gene prevent programs recruit screening

项目摘要

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.

项目概要人类 p300 是一种转录辅激活因子，也是一种乙酰化的主要乙酰转移酶组蛋白和其他蛋白质，促进基因转录。 P300 需要广泛的细胞程序，包括细胞生长、分化、凋亡和 DNA 修复与人类疾病，特别是癌症和遗传性疾病有关。 P300 及其旁系同源物 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) 作为一种新型表观遗传阅读器，可识别组蛋白 H3 尾部。我们的研究结果表明这种识别介导 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尚不清楚，拟议研究的重点。我们假设 ZZp300 与 H3 的相互作用促进了 p300 的组蛋白 H3K27 和 H3K18 位点。此外，我们建议ZZp300与 bromodomain (BDp300) 参与染色质 p300 的募集和稳定。我们将聘请一名体外和体内方法的有力结合，建立了分子和结构组蛋白阅读器之间串扰的基础、机制见解和生物学意义 p300。这项研究对于我们了解生理和 p300 的致病活性。这些研究还将揭示新型表观遗传的作用阅读器 ZZp300，使我们能够建立这种主要乙酰转移酶的信号传导模型，并将更好地了解与 p300 活性异常相关的人类疾病，包括癌症和遗传性疾病。