Uncovering a new role of nucleosomes in gene regulation

揭示核小体在基因调控中的新作用

基本信息

批准号：
9922463
负责人：
Feng Cui
金额：
$ 6.93万
依托单位：
ROCHESTER INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2023-03-31
项目状态：
已结题

项目摘要

Project Summary: Uncovering a new role of nucleosomes in gene regulation Transcriptional factors (TFs) and nucleosomes are two major determinants for gene regulation in eukaryotic cells. Traditionally, TFs and nucleosomes are considered to be mutually exclusive. Recent studies have identified a growing list of proteins including the tumor suppressor p53 that are able to bind to nucleosomal DNA without disrupting the overall nucleosome structure. At least for these TFs, nucleosomes are no longer obstacles, and in some cases, nucleosomes can facilitate or even stabilize TF-DNA interactions. However, it was not clear if such interactions (between TFs and nucleosomes) have any biological significance. Our preliminary studies have shown that the extent of accessibility of p53 target sites in nucleosomes correlates with how p53 regulates its target genes, which highlights the importance of nucleosomes in mediating TF binding and controlling gene expression. The proposed research aims to gain full understanding of this new role of nucleosomes in gene regulation. In the Aim 1, we will focus on p53, intending to establish the link between accessibility of p53 binding sites in the context of chromatin and expression patterns of nearby genes. In the Aim 2, we will discover a comprehensive set of potential nucleosomal DNA-binding proteins in humans and model organisms. Nucleosome-TF interactions of interest will be validated by in vitro assays. At the conclusion of these studies, we will have re-defined the roles of nucleosomes in TF binding and gene regulation, developed theoretical and experimental method for testing nucleosome-TF interactions, and established a computational/experimental pipeline to identify nucleosomal DNA-binding proteins.

项目摘要：揭示核小体在基因调控中的新作用转录因子（TF）和核小体是基因调控的两个主要决定因素在真核细胞中。传统上，转录因子和核小体被认为是相互排斥的。最近的研究发现了越来越多的蛋白质，包括肿瘤抑制因子 p53，能够结合核小体 DNA，而不破坏整体核小体结构。在至少对于这些TF来说，核小体不再是障碍，在某些情况下，核小体可以促进甚至稳定 TF-DNA 相互作用。然而，尚不清楚这样的情况是否相互作用（转录因子和核小体之间）具有生物学意义。我们的初步研究表明，核小体中 p53 靶位点的可及性程度与 p53 如何调节其靶基因，这凸显了核小体在介导 TF 结合并控制基因表达。拟议的研究旨在充分了解了解核小体在基因调控中的这种新作用。在目标 1 中，我们将重点关注 p53，旨在在 p53 结合位点的可及性之间建立联系染色质和附近基因的表达模式。在目标 2 中，我们会发现人类和模型中潜在的核小体 DNA 结合蛋白的综合集有机体。感兴趣的核小体-TF 相互作用将通过体外测定进行验证。在这些研究的结论，我们将重新定义核小体在 TF 结合和基因调控，开发了检测核小体-TF的理论和实验方法相互作用，并建立了计算/实验管道来识别核小体 DNA 结合蛋白。