Chromatin maintenance in cancer progression
癌症进展中的染色质维持
基本信息
- 批准号:9150499
- 负责人:
- 金额:$ 45.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-30 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:BiochemicalBiochemical GeneticsBiological MarkersBiological ModelsC-terminalCancer Cell Growth RegulationCellsChildhood Acute Lymphocytic LeukemiaChromatinClear CellDNA DamageDNA MethylationDNA Modification MethylasesDNA RepairDNMT3aDataDefectDevelopmentDiseaseDisease ProgressionDissectionDouble Strand Break RepairEnvironmentEventFrequenciesFutureGenesGenetic TranscriptionGenomeGenomic InstabilityGenomic approachGenomicsGrowthHistone H3HistonesHumanIndividualKidney NeoplasmsLinkLysineMaintenanceMalignant NeoplasmsMalignant neoplasm of urinary bladderMediatingMediator of activation proteinMessenger RNAModelingMutateMutationNeoplasm MetastasisNucleosomesOrthologous GenePathway interactionsPatternPhenotypePositioning AttributeProcessPropertyProteinsRNA Polymerase IIRNA ProcessingRNA SplicingReaderRefractoryRegulationRegulator GenesRenal Cell CarcinomaRenal carcinomaReportingResearch PersonnelRoleSET DomainSeveritiesSignal TransductionStructure-Activity RelationshipTestingTherapeuticTherapeutic InterventionTranscriptTranscription ProcessTranscriptional RegulationTumor Cell BiologyTumor SuppressionYeastsbasecancer cellcomparative genomicsfunctional genomicsgenetic approachgenetic regulatory proteinhigh riskhistone methylationhistone methyltransferasehistone modificationhomologous recombinationkidney cellloss of functionmetaplastic cell transformationmutantneoplastic cellnovelnucleaseprogramspublic health relevancerepairedresponsetumortumor progressiontumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Mutations in chromatin regulatory proteins have recently been identified in a wide range of human cancers. Although these mutations are associated with disease progression, how they contribute to tumorigenesis remains unknown. We propose to investigate SETD2, a non-redundant histone methyltransferase that preferentially places a trimethylation mark on Histone H3 on lysine 36 in actively transcribed gene bodies. This gene is mutated in approximately 15% of renal cell carcinomas, and is being identified in a growing list of tumors. By examining chromatin organization in primary human tumors, we observed that SETD2 mutation and loss of its histone modification were associated with changes in nucleosome accessibility and widespread alteration in RNA processing. We hypothesize that histone mark dysregulation through SETD2 loss is an important component of tumorigenesis. We propose a highly collaborative project that employs biochemical, genetic and genomic approaches to comprehensively explore the effect of SETD2 mutation on chromatin and transcription, in an effort to unravel the mechanisms by which SETD2 loss leads to the promotion of cancer. To this end, we have generated a unique set of cell-based model systems which uses comparative genomic studies between human and yeast cells. We have additionally established novel domain-specific activities of SETD2, and the first demonstration of functional mutations separating di-methylating from tri-methylating activity. We propose three complementary aims: 1) to define the chromatin reprogramming and transcriptional effects of SETD2 mutation, revealing critical mechanistic features that link histone modification and nucleosome position to the transcriptional and DNA repair defects associated with SETD2 loss, 2) to utilize the separation of function revealed by high severity SETD2 mutants in the catalytic (SET) domain and the RNA polymerase II interactions domain (SRI) to reveal important determinants of the genomic phenotype, and 3) to explore discrete functions associated with SETD2 loss mediated by the altered H3K36me3 mark, by systematically examining the histone "reader" molecules that transduce signals for DNA methylation, DNA repair, and transcriptional elongation. Taken together, these studies will define the mechanistic link between SETD2 loss of function and cancer development, as well as reveal novel opportunities for biomarker or therapeutic interventions.
描述(申请人提供):染色质调节蛋白的突变最近在广泛的人类癌症中被发现。尽管这些突变与疾病进展有关,但它们如何促进肿瘤发生仍不清楚。我们建议研究SETD2,一种非冗余组蛋白甲基转移酶,在活跃转录的基因体中优先在赖氨酸36上的组蛋白H3上放置一个三甲基化标记。这种基因在大约15%的肾癌中发生了突变,并在越来越多的肿瘤中被发现。通过检测人类原发肿瘤中的染色质组织,我们观察到SETD2突变及其组蛋白修饰的丢失与核小体可及性的改变和RNA加工中的广泛改变有关。我们假设,通过SETD2缺失的组蛋白标记的失调是肿瘤发生的重要组成部分。我们提出了一个高度合作的项目,利用生化、遗传学和基因组学方法来全面探索SETD2突变对染色质和转录的影响,努力揭示SETD2缺失导致癌症促进的机制。为此,我们创建了一套独特的基于细胞的模型系统,使用人类和酵母细胞之间的比较基因组研究。此外,我们还建立了SETD2的新的区域特异性活性,并首次证明了将双甲基化活性与三甲基化活性分开的功能突变。我们提出了三个互补的目标:1)定义SETD2突变的染色质重编程和转录效应,揭示组蛋白修饰和核小体位置与与SETD2丢失相关的转录和DNA修复缺陷之间的关键机制特征;2)利用高度严重的SETD2突变体在催化(SET)域和RNA聚合酶II相互作用域(SRI)中揭示的功能分离,揭示基因组表型的重要决定因素;以及3)通过系统地检测组蛋白“读取器”分子,系统地检测组蛋白“读取器”分子,以探索与改变的H3K36me3标记介导的SETD2丢失相关的离散功能。综上所述,这些研究将确定SETD2功能丧失和癌症发展之间的机制联系,并揭示生物标记物或治疗干预的新机会。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Ian J Davis其他文献
Linking germline and somatic variation in Ewing sarcoma
尤因肉瘤中种系和体细胞变异的联系
- DOI:
10.1038/ng.3387 - 发表时间:
2015-08-27 - 期刊:
- 影响因子:29.000
- 作者:
Nicholas C Gomez;Ian J Davis - 通讯作者:
Ian J Davis
Ian J Davis的其他文献
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{{ truncateString('Ian J Davis', 18)}}的其他基金
Developmental control of chromatin states in cancer
癌症中染色质状态的发育控制
- 批准号:
10567242 - 财政年份:2023
- 资助金额:
$ 45.97万 - 项目类别:
Development of a cavitation enhancement technology to access archived tissues for epigenetic-based biomedical research
开发空化增强技术以获取存档组织以进行基于表观遗传学的生物医学研究
- 批准号:
10211263 - 财政年份:2021
- 资助金额:
$ 45.97万 - 项目类别:
Development of a cavitation enhancement technology to access archived tissues for epigenetic-based biomedical research
开发空化增强技术以获取存档组织以进行基于表观遗传学的生物医学研究
- 批准号:
10580496 - 财政年份:2021
- 资助金额:
$ 45.97万 - 项目类别:
Development of a cavitation enhancement technology to access archived tissues for epigenetic-based biomedical research
开发空化增强技术以获取存档组织以进行基于表观遗传学的生物医学研究
- 批准号:
10381604 - 财政年份:2021
- 资助金额:
$ 45.97万 - 项目类别:
Development of a cavitation enhancement technology to access archived tissues for epigenetic-based biomedical research
开发空化增强技术以获取存档组织以进行基于表观遗传学的生物医学研究
- 批准号:
10576937 - 财政年份:2021
- 资助金额:
$ 45.97万 - 项目类别:
Unified Program for Therapeutics in Children (UPTiC)
儿童治疗统一计划 (UPTiC)
- 批准号:
10400848 - 财政年份:2019
- 资助金额:
$ 45.97万 - 项目类别:
Unified Program for Therapeutics in Children (UPTiC)
儿童治疗统一计划 (UPTiC)
- 批准号:
10159122 - 财政年份:2019
- 资助金额:
$ 45.97万 - 项目类别:
Unified Program for Therapeutics in Children (UPTiC)
儿童治疗统一计划 (UPTiC)
- 批准号:
10676078 - 财政年份:2019
- 资助金额:
$ 45.97万 - 项目类别:
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