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RBP2 regulation through differential recruitment to genomic loci

RBP2 通过基因组位点的差异募集进行调节

基本信息

批准号：
8204442
负责人：
Elizaveta V Benevolenskaya
金额：
$ 31.6万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204442
关键词：
Affinity Binding Bioinformatics Biological Cell Cycle Progression Cells ChIP-on-chip ChIP-seq Chromatin DNA Binding Data Development Drug Design Elements Epigenetic Process Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genomics Health Histone H3 Histones Human Individual Knock-out Lead Light Link Lysine Malignant Neoplasms Mediating Mediator of activation protein Memory Methylation Modification Molecular Nature Neoplastic Cell Transformation Normal Cell PHD Finger Pathway interactions Plant Roots Prevention strategy Protein Isoforms Proteins Public Health Recruitment Activity Regulation Research Retinoblastoma Protein Risk Factors Role Screening for cancer Specificity Staging Testing Therapeutic Transcription Initiation Site Transcriptional Regulation Tumor Suppressor Proteins Work analog cancer cell cancer genomics cell type cost demethylation gene repression genome-wide improved inhibitor/antagonist innovation leukemia/lymphoma novel overexpression programs promoter research study therapeutic development transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): It is becoming clear that epigenetic changes are involved in cancer as much as in normal development. We recently identified RBP2, a protein interacting with the pRB tumor suppressor, which seems to mediate the pRB function in differentiation. RBP2 and the closely related protein PLU1 are two newly identified histone demethylases associated with malignancy. Their transcriptional regulation has been connected to the demethylation of trimethylated lysine 4 of histone H3 (H3K4me3). We recently identified differentiation- specific RBP2 targets genome-wide. We propose that RBP2 establishes, in a pRB dependent manner, a transcriptional program that regulates progression to a more differentiated state and may be a requisite component of leukemia and lymphoma development. In this application we will study how RBP2 is recruited to its genomic targets and which factors change the affinity or specificity of RBP2 binding. We suggest to use molecular, cell biological and genetic approaches to fulfill the following specific aims: (1) To determine the requirements of histone H3K4 methylation, sequence-specific DNA binding, the three PHD finger cassettes and E2F binding for RBP2 recruitment to genomic loci; (2) To dissect the RBP2 recruitment mechanisms that result in gene expression changes; (3) To determine RBP2 target gene expression in cancer cells deficient in RBP2 function compared with normal cells. This study will contribute to the development of therapeutic approaches involving this novel class of epigenetic regulators. PUBLIC HEALTH RELEVANCE: Understanding RBP2 function could lead to tremendous impact on public health in several ways: 1) improve cost-efficiency of cancer screening programs adapted to individual's risk factors; 2) identify individuals who will most benefit from a particular prevention strategy; 3) lead to rational drug design of demethylase inhibitors, for example, bisubstrate analogues, to target wide range of cancers.

描述（由申请人提供）：越来越清楚的是，表观遗传变化与癌症的正常发育一样多。我们最近鉴定了RBP 2，一种与pRB肿瘤抑制因子相互作用的蛋白质，其似乎介导pRB在分化中的功能。RBP 2和PLU 1是两种新发现的与恶性肿瘤相关的组蛋白去甲基化酶。它们的转录调控与组蛋白H3的三甲基化赖氨酸4（H3 K4 me 3）的去甲基化有关。我们最近确定了分化特异性RBP 2靶基因组范围。我们建议，RBP 2建立，在一个pRB依赖的方式，转录程序，调节进展到一个更分化的状态，可能是一个必要的组成部分白血病和淋巴瘤的发展。在本申请中，我们将研究RBP 2是如何被招募到其基因组靶点的，以及哪些因素改变了RBP 2结合的亲和力或特异性。我们建议利用分子生物学、细胞生物学和遗传学的方法来实现以下具体目标：（1）确定RBP 2募集到基因组位点所需的组蛋白H3 K4甲基化、序列特异性DNA结合、三个PHD指盒和E2 F结合：（2）剖析导致基因表达变化的RBP 2募集机制;（3）与正常细胞相比，确定RBP 2功能缺陷的癌细胞中RBP 2靶基因的表达。这项研究将有助于开发涉及这种新型表观遗传调节剂的治疗方法。公共卫生关系：了解RBP 2的功能可能会在几个方面对公共卫生产生巨大影响：1）提高癌症筛查计划的成本效益，以适应个人的风险因素; 2）确定谁将最受益于特定的预防策略; 3）导致去甲基酶抑制剂的合理药物设计，例如，双底物类似物，以靶向广泛的癌症。