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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：
8458997
负责人：
PETER A JONES
金额：
$ 41.12万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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

来源：
https://reporter.nih.gov/project-details/8458997
关键词：
Aberrant DNA Methylation Achievement Address Azacitidine Biochemical Cells Chromatin Colon Carcinoma Complex CpG Islands Custom Cytosine DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Deamination Deoxycytidine Development Drug Design Drug Targeting Enzymes Epigenetic Process FDA approved Funding Gene Silencing Genes Goals Grant HCT116 Cells Histone Deacetylase Inhibitor Histone H3 Histones Human Human Development Hydrolysis Inherited Maintenance Malignant Neoplasms Maps Methylation Methyltransferase Myelogenous Normal Cell Nucleosomes PC3 cell line Patients Pattern Pharmaceutical Preparations Play Polycomb Positioning Attribute Process Relative (related person)Research Role Somatic Cell Syndrome Testing Transcription Initiation Site Tumor Suppressor Genes Universities abstracting cancer cell cancer therapy cell transformation chromatin protein density design epigenome epigenomics follow-up histone modification inhibitor/antagonist knock-down malignant phenotype prevent prostate cancer cell research study restoration

项目摘要

Project Summary/Abstract 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.

项目总结/摘要这项赠款已资助了近30年，其目的是了解 DNA甲基化模式的建立和遗传机制，并开发可以干扰胞嘧啶甲基化并重新激活沉默的基因。这项研究导致了最近 FDA批准了两种DNA去甲基化剂（5-aza-CR和5-aza-CdR）用于治疗髓系白血病发育不良综合征在未来五年的项目中，我们希望利用表观基因组的优势，分析以了解DNA甲基化模式是如何通过相互作用建立和维持的 DNA甲基转移酶和特定的染色质成分之间的关系。为此，我们开发了一个定制的NimbleGen阵列允许分析核小体、组蛋白修饰和DNA 在正常和转化细胞中，在1，800个转录起始位点（TSS）处以整合方式进行甲基化。在具体目标1，我们将利用平铺阵列映射正常（PrEC）和转化的核小体前列腺癌细胞（PC 3）。然后，我们将确定如何干扰DNA甲基化，在PC 3细胞中或在HCT 116结肠癌细胞中遗传地改变了组蛋白标记的分布，组蛋白H3-K27 me 3标记由多梳抑制复合物2（PRC 2）施加。在具体目标2中，我们确定在DNA甲基化恢复为HCT 116衍生物期间表观基因组如何重组 (DKO)其中三种DNA甲基转移酶中的两种（DNMT 1和DNMT 3B）在遗传上是被击倒在具体目标3中，我们将跟进我们的新结果，这些结果表明，从头甲基转移酶DNMT 3A和3B到核小体。我们希望确定酶是如何与核小体相互作用，这样我们就可以了解特定模式是如何建立的。在具体目标4中，我们将继续寻求开发比目前更稳定的DNA去甲基化药物， FDA批准用于癌症治疗，能够逆转异常的DNA甲基化，组蛋白修饰和核小体定位。实现这些目标将对我们的国家产生重大影响。了解癌症的表观遗传学，并与治疗和预防癌症的新策略直接相关癌

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DNA methylation screening identifies driver epigenetic events of cancer cell survival.

DOI：
10.1016/j.ccr.2012.03.045
发表时间：
2012-05-15
期刊：
Cancer cell
影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA

SNF5 is an essential executor of epigenetic regulation during differentiation.

DOI：
10.1371/journal.pgen.1003459
发表时间：
2013-04
期刊：
PLoS genetics
影响因子：
4.5
作者：
You JS;De Carvalho DD;Dai C;Liu M;Pandiyan K;Zhou XJ;Liang G;Jones PA
通讯作者：
Jones PA

LINE-1 methylation in plasma DNA as a biomarker of activity of DNA methylation inhibitors in patients with solid tumors.

DOI：
10.4161/epi.4.3.8694
发表时间：
2009-04-01
期刊：
Epigenetics
影响因子：
3.7
作者：
Aparicio A;North B;Barske L;Wang X;Bollati V;Weisenberger D;Yoo C;Tannir N;Horne E;Groshen S;Jones P;Yang A;Issa JP
通讯作者：
Issa JP

MicroRNAs: critical mediators of differentiation, development and disease.