Identifying epigenetic targets of c-myc oncogene

识别 c-myc 癌基因的表观遗传靶点

基本信息

  • 批准号:
    9187207
  • 负责人:
  • 金额:
    $ 21.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-08-18 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY: The overarching goal of this proposal is to uncover a previously uncharacterized molecular function of c-Myc (hereafter referred to as Myc), a proto-oncoprotein that is frequently amplified in breast cancer and many other types of human cancer. Recently, we found that Myc overexpression leads to elevated expression of glutamate-ammonia ligase (GLUL) and interestingly, this Myc-induced GLUL is not through the direct transactivation by Myc, rather it involves promoter demethylation of the GLUL gene. We further found that the demethylation is dependent on increased expression of thymine DNA glycosylase (TDG), which is a direct Myc transcriptional target. These results suggest an unexpected role of Myc in promoting glutamine synthesis, and intriguingly, suggest a previously unidentified molecular function of Myc in activating gene expression by regulating DNA methylation. This prompts us to form the hypothesis that Myc can regulate gene expression via the modulation of DNA methylation. We propose two Specific Aims to study this hypothesis. In Aim 1, we plan to identify Myc-induced DNA methylation and gene expression profiles by whole genome bisulfite sequencing (WGBS) and RNA-Seq using various breast cancer cell lines with stable or inducible expression or knock-down of Myc. We will first prepare cell cultures with different treatments and extract genomic DNA and total cellular RNA for the next-generation sequencing (NGS). After NGS sequence reads are obtained, we will perform the bioinformatics analysis to (1) identify and annotate differentially methylated regions (DMR) in WGBS, with focus on gene promoters; (2) identify differentially expressed genes (DEG) in RNA-seq, using the same samples for DMR; and (3) rank Myc “epigenetic targets” using integrated bioinformatics analysis of DMR and DEG, and identify potential biological pathways preferentially affected by Myc through epigenetic regulation. We expect to discover specific “epigenetic targets” of Myc in various breast cancer cell lines. In Aim 2, we plan to validate the identified methylation profiles using traditional molecular techniques and examine their biological relevance. We will first use the quantitative PCR and focal bisulfate sequencing on specific gene promoters to validate the “epigenetic targets” targets of Myc to be found in Aim 1. We will also examine the expression of TDG and the Myc epigenetic targets in various breast cancer cell lines. Furthermore, we will examine the expression patterns of TDG and validated epigenetic Myc targets by IHC using de-identified breast cancer clinical tissue samples, and correlate them with histopathological characteristics and clinical outcomes. If successful, this project will uncover DNA demethylation as a novel mechanism for Myc regulated gene expression and oncogenesis. In the long run, the knowledge gained from this study will help with the understanding of cancer etiology and shed light on the development of novel therapeutics.
项目概要:本提案的总体目标是揭示一个以前没有特征的 c-Myc(以下简称Myc)的分子功能,是一种经常在肿瘤细胞中扩增的原癌蛋白, 乳腺癌和许多其他类型的人类癌症。最近,我们发现Myc的过度表达会导致 谷氨酸-氨连接酶(GLUL)的表达升高,有趣的是,Myc诱导的GLUL不是 通过Myc的直接反式激活,而是涉及GLUL基因的启动子去甲基化。我们 进一步发现去甲基化依赖于胸腺嘧啶DNA糖基化酶(TDG)表达的增加, 其是直接的Myc转录靶标。这些结果表明,Myc在促进细胞增殖中具有意想不到的作用。 谷氨酰胺合成,有趣的是,这表明Myc在激活 基因表达调控DNA甲基化。这促使我们形成Myc可以调节 通过调节DNA甲基化来调节基因表达。我们提出了两个具体的研究目标 假说.在目标1中,我们计划通过以下方法鉴定Myc诱导的DNA甲基化和基因表达谱: 使用具有稳定或稳定表达的各种乳腺癌细胞系进行全基因组亚硫酸氢盐测序(WGBS)和RNA测序 诱导表达或敲低Myc。我们将首先用不同的处理方法制备细胞培养物, 提取基因组DNA和总细胞RNA用于下一代测序(NGS)。NGS序列后 获得读段后,我们将进行生物信息学分析,以(1)识别和注释差异 WGBS中的甲基化区域(DMR),重点是基因启动子;(2)鉴定差异表达基因 (DEG)在RNA-seq中,使用相同的样品进行DMR;和(3)使用整合的Myc“表观遗传靶标” DMR和DEG的生物信息学分析,并确定优先受 Myc通过表观遗传调控。我们希望在不同的乳腺癌组织中发现Myc的特异性“表观遗传靶点”, 癌细胞系。在目标2中,我们计划使用传统的分子生物学方法来验证所鉴定的甲基化谱, 技术,并检查其生物相关性。我们将首先使用定量PCR和焦点硫酸氢盐 对特定基因启动子进行测序,以验证Aim 1中发现的Myc的“表观遗传靶标”靶标。 我们还将研究TDG和Myc表观遗传靶点在各种乳腺癌细胞系中的表达。 此外,我们还将通过IHC检测TDG的表达模式和经验证的表观遗传Myc靶点。 使用去识别的乳腺癌临床组织样本,并将其与组织病理学 特征和临床结果。如果成功,该项目将揭开DNA去甲基化的新篇章 Myc调控基因表达和肿瘤发生的机制。从长远来看, 这项研究将有助于了解癌症的病因,并为开发新的治疗方法提供线索。 治疗学

项目成果

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Song Wu其他文献

Song Wu的其他文献

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{{ truncateString('Song Wu', 18)}}的其他基金

Identifying epigenetic targets of c-myc oncogene
识别 c-myc 癌基因的表观遗传靶标
  • 批准号:
    9334805
  • 财政年份:
    2016
  • 资助金额:
    $ 21.41万
  • 项目类别:

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