Mechanisms of De Novo Methylation in Cancer

癌症中从头甲基化的机制

基本信息

  • 批准号:
    7792376
  • 负责人:
  • 金额:
    $ 45.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-09-17 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The objectives of this grant, which has been funded for almost 30 years, have been to understand the mechanisms for the establishment and inheritance of DNA methylation patterns and to develop drugs which can interfere with cytosine methylation and reactivate silenced genes. This research has led to the recent approval by the FDA of two DNA demethylating agents (5-aza-CR and 5-aza-CdR) for the treatment of myeloid dysplastic syndrome. In the next five year period of the project, we hope to take advantage of epigenomic analysis to understand how DNA methylation patterns are established and maintained by an interaction between DNA methyltransferases and specific chromatin components. To do this, we have developed a custom NimbleGen array allowing for the analyses of nucleosomes, histone modifications and DNA methylation in an integrated way at 1,800 transcription start sites (TSS) in normal and transformed cells. In Specific Aim 1, we will utilize the tiling array to map nucleosomes in both normal (PrECs) and transformed prostate cancer cells (PC3). We shall then determine how interfering with DNA methylation pharmacologically in PC3 cells or genetically in HCT116 colon cancer cells alters the distribution of histone marks focusing on the histone H3-K27me3 mark applied by the polycomb repressive complex 2 (PRC2). In Specific Aim 2, we shall determine how the epigenome is reorganized during the restoration of DNA methylation to HCT116 derivatives (DKO) in which two of the three DNA methyltransferases (DNMT1 and DNMT3B) have been genetically knocked down. In Specific Aim 3, we will follow-up on our new results which show the strong anchoring of the de novo methyltransferases DNMT3A and 3B to nucleosomes. We wish to determine how the enzymes interact with nucleosomes so that we can understand how specific patterns are established. In Specific Aim 4, we will continue our quest to develop DNA demethylating drugs which are more stable than those currently approved by the FDA for cancer treatment and which are able to reverse aberrant DNA methylation, histone modifications and nucleosome positioning. Achievement of these aims should have major impact in our understanding of the epigenetics of cancer and have direct relevance to new strategies to treat and prevent cancer. PUBLIC HEALTH RELEVANCE: It has become clear over the last few years that the abnormal silencing of genes by somatically heritable epigenetic processes, can contribute directly to the formation of human cancers. Although we know that altered patterns of DNA methylation play a fundamental role in the silencing of tumor suppressor genes, we do not know how these altered patterns are set up or how normal patterns are established and inherited during human development. Recent excitement in the field has focused on the potential role of gene silencing mechanisms involving the polycomb repressive complexes (PRCs), which are essential for normal development and have recently been found also to play a role in inactivating tumor suppressor genes. These PRCs can directly silence genes by themselves and also somehow set up genes for more permanent silencing induced by DNA methylation. Recently, the FDA has approved two DNA demethylating agents and one histone deacetylase inhibitor for the treatment of particular kinds of cancer.
描述(由申请者提供):这项资助已有近30年的历史,其目的是了解DNA甲基化模式的建立和遗传机制,并开发能够干扰胞嘧啶甲基化并重新激活沉默基因的药物。这项研究导致FDA最近批准了两种DNA去甲基化药物(5-aza-CR和5-aza-cdr)用于治疗骨髓增生异常综合征。在该项目的下一个五年期间,我们希望利用表观基因组分析来了解DNA甲基化模式是如何通过DNA甲基转移酶和特定染色质成分之间的相互作用来建立和维持的。为此,我们开发了一个定制的NimbleGen阵列,允许以集成的方式分析正常细胞和转化细胞中1,800个转录起始点(TS)的核小体、组蛋白修饰和DNA甲基化。在特定的目标1中,我们将利用平铺阵列来定位正常(PrECs)和转化的前列腺癌细胞(PC3)中的核小体。然后,我们将确定在PC3细胞中或在HCT116结肠癌细胞中从药物上或基因上干扰DNA甲基化如何改变组蛋白标记的分布,重点是多梳抑制复合体2(PRC2)应用的组蛋白H3-K27me3标记。在特定的目标2中,我们将确定在DNA甲基化恢复到HCT116衍生物(DKO)的过程中表观基因组是如何重组的,其中三个DNA甲基转移酶中的两个(DNMT1和Dnmt3b)已经被基因敲除。在具体目标3中,我们将跟进我们的新结果,这些结果表明从头开始的甲基转移酶DNMT3A和3B强烈地锚定在核小体上。我们希望确定酶是如何与核小体相互作用的,这样我们就可以了解特定的模式是如何建立的。在具体目标4中,我们将继续寻求开发比FDA目前批准用于癌症治疗的药物更稳定的DNA去甲基化药物,并能够逆转异常的DNA甲基化、组蛋白修饰和核小体定位。这些目标的实现将对我们理解癌症的表观遗传学产生重大影响,并与治疗和预防癌症的新战略直接相关。与公共卫生相关:在过去的几年里,通过体细胞可遗传的表观遗传过程导致的基因异常沉默已经变得明显,这可能直接导致人类癌症的形成。虽然我们知道DNA甲基化的改变模式在肿瘤抑制基因的沉默中起着基本的作用,但我们不知道这些改变的模式是如何建立的,也不知道正常模式是如何在人类发育过程中建立和遗传的。最近该领域的兴奋集中在涉及多梳抑制复合体的基因沉默机制的潜在作用上,多梳抑制复合体是正常发育所必需的,最近发现它也在失活肿瘤抑制基因方面发挥作用。这些原癌基因可以直接自己沉默基因,也可以以某种方式建立基因,使DNA甲基化导致更永久的沉默。最近,FDA批准了两种DNA去甲基化药物和一种组蛋白去乙酰酶抑制剂用于治疗特定类型的癌症。

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(1)

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PETER A JONES其他文献

PETER A JONES的其他文献

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{{ truncateString('PETER A JONES', 18)}}的其他基金

Cancer Epigenetics Training (CET) Program
癌症表观遗传学培训 (CET) 计划
  • 批准号:
    10646461
  • 财政年份:
    2021
  • 资助金额:
    $ 45.75万
  • 项目类别:
Cancer Epigenetics Training (CET) Program
癌症表观遗传学培训 (CET) 计划
  • 批准号:
    10269565
  • 财政年份:
    2021
  • 资助金额:
    $ 45.75万
  • 项目类别:
Cancer Epigenetics Training (CET) Program
癌症表观遗传学培训 (CET) 计划
  • 批准号:
    10445044
  • 财政年份:
    2021
  • 资助金额:
    $ 45.75万
  • 项目类别:
Targeting DNA Methylation and the Cancer Epigenome
靶向 DNA 甲基化和癌症表观基因组
  • 批准号:
    10541829
  • 财政年份:
    2017
  • 资助金额:
    $ 45.75万
  • 项目类别:
Establishing and Interpreting Abnormal DNA Methylation in Cancer
建立并解释癌症中的异常 DNA 甲基化
  • 批准号:
    10732031
  • 财政年份:
    2017
  • 资助金额:
    $ 45.75万
  • 项目类别:
Targeting DNA Methylation and the Cancer Epigenome
靶向 DNA 甲基化和癌症表观基因组
  • 批准号:
    10320866
  • 财政年份:
    2017
  • 资助金额:
    $ 45.75万
  • 项目类别:
USC/NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORT
南加州大学/诺里斯综合癌症中心(核心)支持
  • 批准号:
    7930202
  • 财政年份:
    2009
  • 资助金额:
    $ 45.75万
  • 项目类别:
USC/NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORT
南加州大学/诺里斯综合癌症中心(核心)支持
  • 批准号:
    7931719
  • 财政年份:
    2009
  • 资助金额:
    $ 45.75万
  • 项目类别:
Senior Leadership
高层领导
  • 批准号:
    7302427
  • 财政年份:
    2006
  • 资助金额:
    $ 45.75万
  • 项目类别:
Developmental Funds
发展基金
  • 批准号:
    7302440
  • 财政年份:
    2006
  • 资助金额:
    $ 45.75万
  • 项目类别:

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