Transfer: DNA Methylation Canyons in Human Cancers: Methods, Target Genes and Functional Consequences
转移:人类癌症中的 DNA 甲基化峡谷:方法、靶基因和功能后果
基本信息
- 批准号:10543784
- 负责人:
- 金额:$ 55.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAlgorithmsAnimal ModelAtlasesBig DataBioinformaticsBiological AssayCell modelCellsCloud ComputingColonic NeoplasmsDNA MethylationDataDevelopmentEpigenetic ProcessEventExhibitsFollow-Up StudiesGalaxyGene ExpressionGenesGeneticGrowthHematopoietic stem cellsHomeobox GenesHumanHypermethylationIn VitroInternationalMalignant NeoplasmsMediatingMethodsMethylationModelingModificationMutationMyeloid LeukemiaNatureNormal CellOncogene ActivationOncogenesOncogenicPaperPopulationPopulation ProcessProto-OncogenesPublic DomainsRegulator GenesReportingRoleSamplingSoft Agar AssayTestingThe Cancer Genome AtlasTissuesTumor PromotionTumor Suppressor GenesUntranslated RNAValidationWorkXenograft procedurebisulfite sequencingcancer typecell typeclinically relevantcohortdata portaldesignepigenomicsexperimental studygain of functiongenome wide methylationgenome-wideimprovedin vivoinsightleukemiamalignant breast neoplasmmammalian genomemouse modelnoveloverexpressionpersonalized diagnosticspersonalized medicinepromotersoftware developmenttooltumortumor growthtumorigenesisweb interfacewhole genome
项目摘要
PROJECT SUMMARY / ABSTRACT
Activation of growth-promoting oncogenes, largely driven by genetic alterations, is a key step during
tumorigenesis. Meanwhile, tumors are not only genetically, but also epigenetically, distinct from their tissues of
origin. Yet, little is known regarding the extent to which epigenetic mechanisms can activate oncogenes. DNA
methylation is the most extensively documented epigenetic modification that can influence cell fate and gene
expression. For example, promoter hypermethylation that silences tumor suppressor genes is a key epigenetic
event in tumorigenesis. In addition, gene-body hypomethylation is positively correlated with gene expression,
although the causal relationship remains to be established. Recently, our group and that of Dr. Bing Ren
independently reported broad (e.g. >3.5-kb) under methylated regions (UMRs), termed DNA methylation
canyons (Nature Genetics 2014) or valleys (Cell 2013), which in most cases span promoters and gene bodies.
Canyons exhibit very low levels of methylation (<10%) in almost all normal cells. Canyon-associated genes
(~1,100 in each cell type) are enriched in developmental regulators and homeobox genes, many of which
exhibit low or no expression in normal cells. However, despite numerous follow-up studies (i.e., ~540 citations
for both papers), the functional role of canyons in gene expression and tumorigenesis remains poorly
understood. Nevertheless, our preliminary data indicated that canyons found in normal cells are prone to
gene-body, but not promoter, hypermethylation in tumors, with the hypermethylated canyon genes surprisingly
enriched in oncogenes. Furthermore, our dCas9-mediated DNA methylation editing experiments revealed an
unexpected causal role of gene-body canyon hypermethylation in oncogene activation. Therefore, we
hypothesize that we can use cancer DNA methylation data from public domains such as The Cancer Genome
Atlas (TCGA) and the International Human Epigenomics Consortium (IHEC), as well as powerful bioinformatics
algorithms, to identify genes with cancer-specific hypermethylated canyons in thousands of tumors. We further
hypothesize that we can test the functional roles of the hypermethylated canyons in cell and animal models
using a dCas9-mediated genome-wide methylation screen. The proposed work is expected to identify
hypermethylated canyons that can activate oncogenes and promote tumor growth in vitro and in vivo. Thus,
this work can fundamentally transform our understanding about how DNA methylation regulates gene
expression and tumorigenesis.
项目摘要/摘要
促生长癌基因的激活在很大程度上是由基因改变驱动的,是在
肿瘤发生学。同时,肿瘤不仅在基因上,而且在表观遗传学上,与它们的组织不同。
起源。然而,关于表观遗传机制能在多大程度上激活癌基因,人们知之甚少。脱氧核糖核酸
甲基化是最广为人知的表观遗传修饰,可影响细胞命运和基因
表情。例如,使肿瘤抑制基因沉默的启动子超甲基化是一种关键的表观遗传学
肿瘤发生中的事件。此外,基因体低甲基化与基因表达呈正相关,
虽然因果关系仍有待确定。最近,我们团队和任炳斌博士的团队
在甲基化区域(UMR)下独立报道了广泛的(例如>;3.5-kb),称为DNA甲基化
峡谷(自然遗传学2014)或山谷(细胞2013),在大多数情况下跨越启动子和基因体。
峡谷中几乎所有正常细胞的甲基化水平都很低(10%)。峡谷相关基因
(每种细胞类型约1,100)富含发育调节因子和同源框基因,其中许多
在正常细胞中低表达或不表达。然而,尽管有许多后续研究(即约540次引用
对于这两篇论文),峡谷在基因表达和肿瘤发生中的功能作用仍然很差
明白了。然而,我们的初步数据表明,在正常细胞中发现的峡谷容易发生
肿瘤中的基因体,而不是启动子,高甲基化的峡谷基因令人惊讶
富含致癌基因。此外,我们的dCas9介导的DNA甲基化编辑实验显示
基因-体峡谷高甲基化在癌基因激活中的意外因果作用。因此,我们
假设我们可以使用来自公共领域的癌症DNA甲基化数据,例如癌症基因组
Atlas(TCGA)和国际人类表观基因组学联盟(IHEC),以及强大的生物信息学
算法,在数千个肿瘤中识别癌症特异性高甲基化峡谷的基因。我们进一步
假设我们可以在细胞和动物模型中测试高甲基化峡谷的功能作用
使用dCas9介导的全基因组甲基化筛选。拟议的工作预计将确定
高甲基化的峡谷,可以激活癌基因,促进肿瘤的体外和体内生长。因此,
这项工作可以从根本上改变我们对DNA甲基化如何调控基因的理解
表达与肿瘤发生。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Separation of vitamin B6 compounds by paired-ion high-performance liquid chromatography.
通过配对离子高效液相色谱分离维生素 B6 化合物。
- DOI:10.1016/s0378-4347(00)80369-2
- 发表时间:1982
- 期刊:
- 影响因子:0
- 作者:Tryfiates,GP;Sattsangi,S
- 通讯作者:Sattsangi,S
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Wei Li其他文献
Light Harvesting and Enhanced Performance of Si Quantum Dot/Si Nanowire Heterojunction Solar Cells
硅量子点/硅纳米线异质结太阳能电池的光收集和性能增强
- DOI:
10.1002/ppsc.201500192 - 发表时间:
2016-01 - 期刊:
- 影响因子:0
- 作者:
Ling Xu;Wei Li;Linwei Yu;Kunji Chen - 通讯作者:
Kunji Chen
Wei Li的其他文献
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{{ truncateString('Wei Li', 18)}}的其他基金
Developing a novel disease-targeted anti-angiogenic therapy for CNV
开发针对 CNV 的新型疾病靶向抗血管生成疗法
- 批准号:
10726508 - 财政年份:2023
- 资助金额:
$ 55.02万 - 项目类别:
Integrative genomic and functional genomic studies to connect variant to function for CAD GWAS loci
整合基因组和功能基因组研究,将 CAD GWAS 位点的变异与功能联系起来
- 批准号:
10639274 - 财政年份:2023
- 资助金额:
$ 55.02万 - 项目类别:
IMAT-ITCR Collaboration: Develop deep learning-based methods to identify subtypes of circulating tumor cells from optical microscope images
IMAT-ITCR 合作:开发基于深度学习的方法,从光学显微镜图像中识别循环肿瘤细胞的亚型
- 批准号:
10675886 - 财政年份:2022
- 资助金额:
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小脑胶质细胞在 Rett 综合征中的病理生理学作用
- 批准号:
10183494 - 财政年份:2021
- 资助金额:
$ 55.02万 - 项目类别:
The role and mechanism of necrosis in glioblastoma
坏死在胶质母细胞瘤中的作用和机制
- 批准号:
10097263 - 财政年份:2021
- 资助金额:
$ 55.02万 - 项目类别:
The role and mechanism of necrosis in glioblastoma
坏死在胶质母细胞瘤中的作用和机制
- 批准号:
10330992 - 财政年份:2021
- 资助金额:
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The Pathophysiological Role of Cerebellar Glia in Rett Syndrome
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- 批准号:
10591567 - 财政年份:2021
- 资助金额:
$ 55.02万 - 项目类别:
The role and mechanism of necrosis in glioblastoma
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- 批准号:
10553723 - 财政年份:2021
- 资助金额:
$ 55.02万 - 项目类别:
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- 批准号:
10380144 - 财政年份:2021
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