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Function of ING PHD domains in chromatin regulation

ING PHD 结构域在染色质调控中的功能

基本信息

批准号：
7268239
负责人：
Or P. Gozani
金额：
$ 28.46万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268239
关键词：
Acute Affinity Amino Acid Motifs Binding Biochemical Biological Biological Process Biology Cell physiology Chromatin Complex Condition DNA Damage Deacetylase Disease Disruption Family Gene Expression Gene Targeting Genes Genotoxic Stress Goals Growth Hereditary Disease Histone Deacetylase Histone H3 Histones Human Immunodeficiency and Cancer Immunologic Deficiency Syndromes In Vitro Lead Link Lipids Lysine Malignant Neoplasms Mental Retardation Methylation Modeling Modification Molecular Mono-S Multienzyme Complexes Mutation Nuclear Outcome PHD Finger Pathologic Phosphatidylinositols Physiological Plants Play Post-Translational Protein Processing Process Protein Binding Proteins Proteome Proteomics Recruitment Activity Regulation Role Series Signal Transduction Specificity Syndrome Testing Transferase Tumor Suppressor Proteins V(D)J Recombination Work base gene repression homeodomain human disease insight member novel phosphatidylinositol 5-phosphate programs promoter recombinase response

项目摘要

DESCRIPTION (provided by applicant): The PHD finger is a signature chromatin-associated protein motif, mutations in which are associated with cancers, immunodeficiency syndromes, and other genetic disorders. Our long-term goal is to develop a comprehensive molecular understanding of how PHD domains impact on chromatin dynamics and the relationship of such activities to fundamental nuclear functions and human disease processes. The general hypothesis to be tested in this proposal is that PHD domains recognize specific methylated histone marks. Preliminary work indicates that several PHD domains bind with high affinity and specificity to histone H3 methylated at lysine 4 (H3K4me3). Characterization of the physiologic role of H3K4me3-recognition by model PHD domains should be instrumental for elucidating how disruption in chromatin dynamics can contribute to numerous pathologic states. Here, a series of biochemical, cellular, and proteomic analyses are proposed to investigate the molecular activities of PHD domains. (1) To determine the molecular function of the ING2 PHD domain in H3K4me recognition at chromatin. Biochemical and functional studies are proposed to investigate the hypothesis that the PHD domain of the ING2 tumor suppressor protein is a specific effector molecule of H3K4me3. We will (i) elucidate the molecular basis of ING2 PHD domain specificity for H3K4me states, (ii) determine how H3K4me impacts on ING2-associated histone deacetylase activity, and (iii) characterize regulation of the ING2-H3K4me3 interaction by phosphoinositides. (2) To elucidate the cellular functions of H3K4me recognition by the ING2 PHD domain. Based on preliminary work, we will investigate the hypothesis that the ING2 PHD domain links H3K4me3 to acute gene repression. We will characterize the physiologic interaction of the ING2 PHD domain with H3K4me at target genes, and determine how these interactions impact on gene expression programs. We will also test how select nuclear factors regulate ING2-H3K4me functions. (3) To characterize the H3K4me-recognition activity of specific PHD fingers with functions distinct from ING2. Preliminary work indicates that besides ING2, the PHD domains of the other ING proteins and that of the RAG2 recombinase bind H3K4me3, potentially linking H3K4me3 to diverse nuclear processes. Biochemical and functional approaches are proposed to study the biology of H3K4me3-recognition by these PHD fingers-containing proteins.

描述（由申请人提供）：PHD 指是一种标志性染色质相关蛋白基序，其突变与癌症、免疫缺陷综合征和其他遗传性疾病相关。我们的长期目标是对 PHD 结构域如何影响染色质动力学以及此类活动与基本核功能和人类疾病过程的关系建立全面的分子理解。本提案中要测试的一般假设是 PHD 结构域识别特定的甲基化组蛋白标记。初步研究表明，多个 PHD 结构域以高亲和力和特异性与 4 位赖氨酸甲基化的组蛋白 H3 (H3K4me3) 结合。通过模型 PHD 域表征 H3K4me3 识别的生理作用应该有助于阐明染色质动力学的破坏如何导致多种病理状态。在此，提出了一系列生化、细胞和蛋白质组学分析来研究 PHD 结构域的分子活性。 (1)确定ING2 PHD结构域在染色质H3K4me识别中的分子功能。提出生化和功能研究来调查 ING2 肿瘤抑制蛋白的 PHD 结构域是 H3K4me3 的特异性效应分子的假设。我们将（i）阐明 H3K4me 状态的 ING2 PHD 结构域特异性的分子基础，（ii）确定 H3K4me 如何影响 ING2 相关组蛋白脱乙酰酶活性，以及（iii）表征磷酸肌醇对 ING2-H3K4me3 相互作用的调节。 (2)阐明ING2 PHD结构域识别H3K4me的细胞功能。基于前期工作，我们将研究 ING2 PHD 结构域将 H3K4me3 与急性基因抑制联系起来的假设。我们将表征 ING2 PHD 结构域与 H3K4me 在靶基因上的生理相互作用，并确定这些相互作用如何影响基因表达程序。我们还将测试选定的核因子如何调节 ING2-H3K4me 功能。 (3) 表征具有与 ING2 不同功能的特定 PHD 手指的 H3K4me 识别活性。初步研究表明，除了 ING2 之外，其他 ING 蛋白的 PHD 结构域和 RAG2 重组酶的 PHD 结构域也结合 H3K4me3，可能将 H3K4me3 与不同的核过程联系起来。提出了生物化学和功能方法来研究这些包含 PHD 手指的蛋白质对 H3K4me3 识别的生物学。