Quantification of combinatorial epigenetic modifications using defined nucleosome standards
使用定义的核小体标准对组合表观遗传修饰进行定量
基本信息
- 批准号:10630256
- 负责人:
- 金额:$ 102.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAntibodiesAutomationBindingBiological AssayCancerousCell physiologyCellsChIP-seqChromatinClinicalClinical ResearchCodeComplexCytolysisDNADNA MethylationDataDetectionDevelopmentDiseaseDoseDrug TargetingEpigenetic ProcessGenesGenetic TranscriptionGenomicsHistonesHumanHuman PathologyIn SituIndividualLanguageLiteratureMalignant NeoplasmsMarketingMeasuresMethodsModificationMolecularMolecular ConformationNucleosomesPerformancePharmaceutical PreparationsPharmacologic SubstancePharmacotherapyPhasePlasmaPost-Translational Protein ProcessingPreparationProtocols documentationReagentRecombinantsRecoveryRegulationResearchSamplingServicesSite-Directed MutagenesisSpecificityTailTestingTimeValidationWestern BlottingWorkassay developmentbiomarker developmentbiomarker discoverycancer cellchromatin modificationcombinatorialcommercial launchcostdetection limitdrug developmentdrug discoveryepigenetic druggenome-widegenomic signaturehistone modificationinnovationliquid biopsynovelnovel markerresponsestability testingtool
项目摘要
PROJECT SUMMARY
Post-translational modification of histone tails (histone PTMs) and DNA methylation (DNAme) on
nucleosomes form a sophisticated molecular code that regulates gene transcription. Aberrant regulation of these
chromatin modifications is associated with a vast array of human pathologies. While the majority of work in the
field has focused on signatures of individual modifications, combinations of histone PTMs and/or DNAme can
be more specific and informative than single marks alone. For instance, although healthy cells and cancerous
cells both have H3K27me3 and DNAme distributed genome-wide, the co-localization of these two modifications
occurs uniquely in cancer cells. However, existing tools to measure global levels of chromatin modifications are
low-throughput, display low sensitivity, and are unable to measure combinatorial modifications (e.g. immunoblot).
The development of assays that overcome these limitations and are compatible with multiple sample types
(including cellular samples or plasma [for detection of circulating nucleosomes, i.e. liquid biopsy]) will make the
study of chromatin modifications widely accessible for academic, clinical, and pharmaceutical research.
Here, EpiCypher will develop QuantiNucTM assays, a breakthrough epigenetics platform to quantify single
and combinatorial chromatin modifications directly on nucleosomes from cells or plasma samples. The
innovation of this proposal includes the a) application of designer nucleosomes (dNucs) to systematically identify
top-performing detection reagents and to serve as quantitative assay standards, b) development of recombinant
EpiSensors for unbiased detection of DNA and DNAme, and c) development of a proprietary targeted sample
processing method for high-throughput cell-based assays. Overall, this platform will provide a quantitative, low-
cost, and scalable approach to leverage analysis of chromatin modifications (i.e. histone PTMs and/or DNAme)
for chromatin research, drug development, and novel biomarker discovery. In Phase I, we developed a
QuantiNuc assay targeting combinatorial H3K4me3+H3K27ac, PTMs that are co-enriched at actively expressed
genes. We validated the specificity and performance of this QuantiNuc assay by establishing key analytical
parameters and applying the assay to quantify levels of H3K4me3+H3K27ac nucleosomes from human plasma
samples. In Phase II, we will develop new QuantiNuc assays to measure other high-value single and
combinatorial chromatin modifications and further validate these assays for use with human plasma samples
(i.e. liquid biopsy). In addition, we will develop a novel targeted sample processing method for cell-based
QuantiNuc assays, which will streamline the process of cell lysis and chromatin fragmentation to deliver a high-
throughput, low-cost approach for clinical research. Finally, we will prepare for commercial launch of QuantiNuc
assays by assembling beta-kits and performing internal and external validation testing of both liquid biopsy and
cell-based assays, which will be used to develop reliable assay protocols and product literature. Market
availability of these assays will transform biomarker discovery and accelerate epigenetic drug development.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrea Lynn Johnstone其他文献
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- 资助金额:
$ 102.45万 - 项目类别:
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Development of a high-throughput epigenomic mapping platform to molecularly phenotype Crohn's disease
开发克罗恩病分子表型的高通量表观基因组作图平台
- 批准号:
10384457 - 财政年份:2021
- 资助金额:
$ 102.45万 - 项目类别:
Quantification of combinatorial epigenetic modifications using defined nucleosome standards
使用定义的核小体标准对组合表观遗传修饰进行定量
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Rapid quantification of nuclear citrullination in human neutrophils
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