Epigenetic Regulation by CHD7 in Colon Cancer
CHD7 在结肠癌中的表观遗传调控
基本信息
- 批准号:9296563
- 负责人:
- 金额:$ 20.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesBRAF geneBiologyBloodBreastCDH1 geneCHD1 geneCHD7 geneCancer cell lineCell LineCellsChIP-seqCharacteristicsChromatinCollectionColonColon CarcinomaColonic NeoplasmsColorectalColorectal NeoplasmsComplementary DNAComplexCpG Island Methylator PhenotypeDNADNA BindingDNA MethylationDNA-Binding ProteinsDataDatabasesDevelopmentDiseaseDown-RegulationDrosophila genusDrug TargetingEncyclopediasEnhancersEnzymesEpigenetic ProcessEpithelialEventFamilyFamily memberGene ActivationGene ExpressionGene Expression RegulationGene TargetingGenesGoalsHistonesHumanHypermethylationImmunoprecipitationLarge Intestine CarcinomaLinkLung NeoplasmsLysineMalignant NeoplasmsMapsMass Spectrum AnalysisMeasuresMediatingModelingModernizationMolecularMutateMutationOncogenesOrganOutcomeOutcomes ResearchPRC1 ProteinPathway interactionsPlasmidsPlayPolycombPost-Translational Protein ProcessingReaderRecombinant ProteinsRegulationResearchRoleSignal PathwaySignal TransductionStomach NeoplasmsSubgroupTailTestingThe Cancer Genome AtlasTherapeutic InterventionTissuesTransfectionTumor BiologyTumor Suppressor ProteinsUnited StatesUp-RegulationValidationWorkbasebisulfite sequencingcancer typechromatin remodelingcohortdrug developmentepigenetic regulationepigenomeexperimental studygene repressiongenome-wide analysishelicaseimprovedinsightinterestknock-downmembermethyl groupmethylomenoveloverexpressionpancreatic neoplasmprogramspromoterprotein complexresponsesmall hairpin RNAtherapeutic targettherapy developmenttranscription factortranscriptometranscriptome sequencingtumortumorigenesis
项目摘要
Abstract
Chromodomain helicase DNA-binding (CHD) proteins are ATP-dependent chromatin remodeler enzymes that
recognize methyl groups in lysines and participate in gene activation and repression, dependent on their
cooperation with other chromatin reader complexes. The CHD family is composed of nine members (CDH1 to
CHD9) grouped into three subfamilies based on the presence of additional functional domains. My group is
interested in this family of enzymes because we found that CHD7 and CHD8 are mutated in 50% of CIMP1
colorectal carcinomas (CRCs). Although knowingly associated to developmental diseases, new studies have
implicated these genes in other cancer types besides CRCs, including lung, gastric, and pancreatic tumors.
Other CHD members are validated tumor suppressors, as examples CHD1 and CHD5, reinforcing the
importance of the CHD family to tumor biology. In this study we will focus on the roles of CHD7 in epigenetic
regulation with the goals of identifying directly regulated target genes and protein complexes that cooperate
with this enzyme in normal and colon cancer. Colon cancer is third most deadly cancer type in the United
States, and the premise of our research is that revealing facets of its epigenetic regulation will contribute
positively to our understand of the disease and promote the development of therapies. We have collected
preliminary data supporting that depletion of CHD7 results in increase in H3K27me3 levels, and deregulated
the expression of known targets of the PRC1 and SNF2 complex. We will accomplish the goals of the project in
two aims, using as models a collection of normal-derived, non-tumorigenic cell lines and colorectal carcinoma
cell lines for which CHD7 down-regulation and up-regulation was manipulated by shRNAs and cDNA plasmids.
In aim 1 we will evaluate changes in gene expression that occur in response of altered expression of CHD7.
We will also measure the effects of altered expression of CHD7 on DNA methylation and selected histone tails
posttranslational modifications. Histone marks associated with enhancers and promoters are of key interest. In
aim 2, we will perform immunoprecipitation to validate and identify the interacting complexes that work along
CHD7 in colon cells. Candidate partners are selected members of the PBAF and PRC1 complexes. CHD8 has
been shown to act downstream to BRAF mutations to mediate DNA hypermethylation of CIMP genes, and we
will also evaluate whether CHD7 partners with CHD8 and DNMT3A/B in wild type and mutated BRAF CRCs.
Mass spectrometry will be used to account for unexpected interactions. The results of this project are expected
to bring novel insights into how CHD7 in particular, and epigenetic alterations in general contribute to colorectal
carcinomas, and identify novel pathways involved in CRC tumorigenesis that may represent opportunities for
therapeutic intervention. In addition, they will also provide basic information on the role of CHD7 in gene
regulation and its interacting complexes in colon cells.
抽象的
染色体构酶DNA结合(CHD)蛋白是ATP依赖性的染色质重塑酶,
识别赖氨酸中的甲基并参与基因激活和抑制作用,取决于它们
与其他染色质读取器复合物的合作。 CHD家族由九个成员组成(CDH1至
CHD9)基于其他功能域的存在分为三个亚家族。我的小组是
对这个酶家族感兴趣,因为我们发现CHD7和CHD8在50%的CIMP1中突变
结直肠癌(CRC)。尽管有意与发育疾病有关,但新研究已经
除了肺,胃和胰腺肿瘤在内的CRC之外,还暗示了这些基因。
其他CHD成员是验证的肿瘤抑制剂,例如CHD1和CHD5的例子,加强了
CHD家族对肿瘤生物学的重要性。在这项研究中,我们将重点介绍CHD7在表观遗传学中的作用
调节的目标是识别合作的直接调节靶基因和蛋白质复合物
在正常和结肠癌中使用该酶。结肠癌是联合国最致命的癌症类型
国家,我们的研究的前提是,揭示其表观遗传调节的方面将有助于
积极地了解我们对疾病的理解并促进疗法的发展。我们已经收集了
支持CHD7耗竭的初步数据导致H3K27me3水平增加,并放松管制。
PRC1和SNF2复合物的已知靶标的表达。我们将实现项目的目标
两个目标,AS AS模型是正常的非肿瘤细胞系和结直肠癌的集合
SHRNA和cDNA质粒操纵CHD7下调和上调的细胞系。
在AIM 1中,我们将评估基因表达的变化,而基因表达发生了改变CHD7表达的反应。
我们还将测量CHD7表达改变对DNA甲基化和选定组蛋白尾巴的影响
翻译后修改。与增强子和启动子相关的组蛋白标记具有关键兴趣。在
AIM 2,我们将执行免疫沉淀以验证和确定相互作用的相互作用复合物
结肠细胞中的CHD7。候选合作伙伴是PBAF和PRC1复合体的成员。 CHD8有
被证明对BRAF突变作用起来介导CIMP基因的DNA高甲基化,我们
还将评估CHD7在野生型和突变的BRAF CRC中与CHD8和DNMT3A/B的合作伙伴。
质谱法将用于解释意外的相互作用。期望该项目的结果
带来新的见解,尤其是CHD7,以及一般的表观遗传学变化有助于结直肠
癌,并确定参与CRC肿瘤发生的新型途径,这可能代表
治疗干预。此外,他们还将提供有关CHD7在基因中的作用的基本信息
调节及其相互作用的复合物在结肠细胞中。
项目成果
期刊论文数量(0)
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Marcos Estecio其他文献
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{{ truncateString('Marcos Estecio', 18)}}的其他基金
The Role of the Nuclear Lamina in Chromatin Organization and Gene Expression in N
核层在染色质组织和基因表达中的作用
- 批准号:
8233985 - 财政年份:2011
- 资助金额:
$ 20.88万 - 项目类别:
The Role of the Nuclear Lamina in Chromatin Organization and Gene Expression in N
核层在染色质组织和基因表达中的作用
- 批准号:
8099826 - 财政年份:2011
- 资助金额:
$ 20.88万 - 项目类别:
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