Comprehensive analysis of epigenetic regulators in their native chromatin context

表观遗传调节因子在其天然染色质环境中的综合分析

基本信息

批准号：
9037141
负责人：
Mitzi I Kuroda
金额：
$ 36.92万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-13 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037141
关键词：
Address Affinity Chromatography Binding Biological Models Biology Chemicals Chromatin Complex DNA Development Developmental Gene Disease Drosophila genus Embryonic Development Ensure Epigenetic Process Event Excision Funding Future Gene Activation Gene Expression Gene Expression Regulation Gene Silencing Genes Genome Genomics Grant Histone Code Human In Vitro Life Cycle Stages Link Location Mammalian Cell Mammals Mass Spectrum Analysis Mediating Modeling Molecular Organism PRC1 Protein Play Polycomb Proteins RNA RNA Interference Regulatory Element Reproducibility Role SAM Domain Series Sex Combs on Midleg Specificity Supporting Cell System Testing Tissues Transcription Coactivator Transcriptional Activation Variant Work base cell type chromatin protein epigenetic regulation fly histone modification improved in vivo inhibitor/antagonist insight knock-down novel novel strategies programs research study success transcriptome sequencing

项目摘要

PROJECT SUMMARY The genomes of higher organisms are highly annotated by specific chromosomal proteins and histone modifications along active genes, regulatory elements, or silent regions. An ongoing challenge is to decipher the rules that establish and maintain chromatin organization. In the upcoming funding period, we propose to focus on analysis of the Polycomb group (PcG) proteins, based on their central importance in development and disease, the intriguing hypotheses raised by our current results, and our ability to use new approaches to probe chromatin protein interactions with precision. Our studies will focus on the versatile Drosophila model, but due to the high conservation of this key regulatory system we can move between fly and human systems with ease. Our experiments will address two central problems in chromatin biology: understanding the targeting and spreading of chromatin domains, and probing the ability of chromatin factors to mark genes as future regulators of cell type specificity. In Aim 1, we will define the series of molecular interactions that coordinate canonical and variant PcG complexes. In Aim 2, we will analyze how H3K27me3 is propagated in cis, to create heritable repressive domains. In Aim 3, we will determine whether a bivalent state primes developmental genes in Drosophila. Success in our studies will be highly relevant to understanding normal and aberrant genome organization and function in development and disease.

项目摘要较高生物体的基因组由特定的染色体蛋白和沿活动基因，调节元素或无声区域的组蛋白修饰。正在进行的挑战是破译建立和维护染色质组织的规则。在即将到来的资金期，我们建议将重点放在基于Polycomb组（PCG）蛋白的分析上它们在发展和疾病中的核心重要性，我们当前提出的有趣的假设结果以及我们使用新方法以精确探测染色质蛋白相互作用的能力。我们的研究将重点放在多功能果蝇模型上，但由于该密钥的高度保存调节系统我们可以轻松地在苍蝇和人类系统之间移动。我们的实验会解决染色质生物学中的两个核心问题：了解染色质结构域，并探测染色质因子将基因标记为未来调节因子的能力细胞类型特异性。在AIM 1中，我们将定义坐标的一系列分子相互作用规范和变体PCG复合物。在AIM 2中，我们将分析H3K27me3如何传播顺式，创建可遗传的压抑域。在AIM 3中，我们将确定是否二价状态果蝇中的素发育基因。我们的研究成功将与了解正常和异常的基因组组织以及发育和疾病的功能。